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Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients

Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical... Background: Ghrelin (GHRL) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether GHRL polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between GHRL polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping GHRL alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response. Methods: Four SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects. Results: There were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (P > 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (P < 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (P < 0.05). Conclusions: These four GHRL gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss. Keywords: Schizophrenia, Ghrelin (GHRL), Polymorphrism, Body mass index (BMI), Atypical antipsychotics, Thera- peutic effects * Correspondence: dryue@bjmu.edu.cn; lvx928@126.com † Contributed equally Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China Full list of author information is available at the end of the article © 2012 Yang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 [25,26]. Several SNPs in the coding region of prepro- Background ghrelin have been described, but there is no known Schizophrenia (SZ) is a severe brain disorder afflicting specific association between genetic variations in the approximately 1% of the world’s population and often human GHRL gene and SZ risk. However, region leads to a lifetime of disability and emotional distress 3p25.1-26.1 is strongly associated with schizophrenia. In [1]. Family, twin, and adoption studies strongly indicate addition to GHRL, this region contains SYN2, HRH1, that genetics contribute to the etiology of SZ, probably and GRM7, all candidate genes for schizophrenia. The by transmission of multiple susceptibility genes each positive symptoms of schizophrenia are associated with exerting weak-to-moderate effects on predisposition dysfunction in dopaminergic signaling, which is closely [2,3]. Many candidate susceptibility genes have been associated with a GHRL mutation [27-29]. Previous stu- identified, including the dopamine receptor D2, neure- dies demonstrated that SNPs in GHRL were associated gulin1, and disrupted in schizophrenia 1 (DISC-1) [4-6]. with high BMI; the Leu72Met allele was significantly Epidemiological studies have also revealed that people associated with BMI and coronary artery disease with SZ are at greater risk for obesity, type 2 diabetes, [18,19,30], but this was not confirmed in other studies dyslipidemia, and hypertension than the general popula- [26,31,32]. tion [7]. Recently, it was suggested that SZ patients are In light of the increase metabolic syndrome symptoms at increased risk of metabolic problems and that the observed in SZ patients on AAPs, as well as the impor- associated symptoms are a serious threat to patient tant role of GHRL as a metabolic regulator and the asso- health [8]. Metabolic problems are often triggered by ciation between GHRL SNPs and metabolic indices, we antipsychotic medication. Indeed, significant weight gain hypothesized that (1) GHRL might be a candidate gene is common in AAP-treated SZ patients, especially for SZ and that (2) allelic variants of GHRL might be patients administered clozapine, olanzapine, quetiapine, associated with the propensity for BMI changes induced or risperidone [9]. by AAP treatment. In addition, we tested (3) whether a The peptide ghrelin (product of the GHRL gene) is an putative relationship between GHRL SNPs and metabolic important metabolic regulator produced by the stomach effects was specific to individual AAP types. Finally, (4) and pancreas. Specific SNPs of GHRL have been associated we examined if GHRL alleles influenced the clinical effi- with variations in BMI, blood pressure, high-density lipo- cacy of AAPs. To these ends, we genotyped four SNPs proteins, low-density lipoproteins, serum cholesterol, and investigated whether they were associated with SZ blood glucose, and metabolic syndrome [10-14]. Ghrelin, and the therapeutic and metabolic effects of AAPs in the originally isolated from the rat stomach, stimulates food intake and controls energy balance [15,16]. Studies on ani- Han Chinese population. mal models revealed that GHRL increased food intake and Methods adiposity [17,18]. However, circulating GHRL levels were The study group consisted of 634 diagnosed schizophre- decreased in obese individuals, and serum GHRL levels nic patients (332 males and 302 females; mean age: 27.14 were inversely correlated with BMI, suggesting that GHRL ± 7.53 years). Patients were unrelated Han Chinese born is not directly involved in most cases of obesity [19,20]. and living in the North Henan province, and all their bio- Studies on the relationship between WG, circulating logical grandparents were of Han Chinese ancestry. Indi- GHRL, and AAP have yielded inconsistent findings. viduals with a history of severe medical complications, Patients taking clozapine or olanzapine showed greater organic brain disease, any concomitant major psychiatric WG than patients on other antipsychotics [21]. In one disorders, or substance dependence were excluded. All study, plasma total GHRL and active GHRL were increased patients were recruited from the Department of Psychia- significantly immediately after olanzapine treatment, but try of the Second Affiliated Hospital of Xinxiang Medical the changes in BMI and body weight were not significant University,P.R.China.The consensusdiagnoses were after 6 months of treatment [22]. In contrast, another conducted by at least two experienced psychiatrists study found that serum bioactive GHRL levels decreased according to the Diagnostic and Statistical Manual of significantly from baseline after 4 weeks of olanzapine Mental Disorders, fourth Edition (DSM-IV) [33]. The monotherapy [23]. In humans, GHRL plays an important patient group included paranoid (n = 309), catatonic (n = role in the long-term regulation of body weight (BW) as 50), collapse (n = 45), residual (67), and undifferentiated well as in the short-term regulation of appetite [19,21]. (n = 163) schizophrenic types. Ghrelin stimulated preadipocyte differentiation, increased The control group consisted of 606 healthy subjects the BMI, and inhibited the anorexigenic effect of leptin (293 males and 313 females; mean age: 29.08 ± 7.80 [24]. Drug altering GHRL functionmayhavedistinct short- and long-term effects on BMI. years) recruited from communities and colleges within The human GHRL gene is located on chromosome 3 the same region and matched to the patient group for (3p25-p26), and consists of 4 exons and 3 introns age, gender ratio, and Han ethnicity. Controls were Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 recruited using a simple non-structured interview per- tail of the pro-ghrelin molecule, but it is not known how formed by psychiatrists. Individuals with personal or this affects GHRL expression or activity (Table 1). The family histories of mental illness or neurological diseases four SNPs were detected by polymerase chain reaction were excluded. The objectives and procedures of the (PCR)-based restriction fragment length polymorphism study were explained to all subjects and written (PCR-RFLP) analysis. informed consent was obtained. The Ethical Committee The primers of the four SNPs investigated are shown of the Department of Psychiatry of the Second Affiliated in Table 1. The conditions used for PCR amplification Hospital of Xinxiang Medical University approved this included an initial denaturation step at 94°C for 5 min, followed by 36 cycles of 94°C for 30 s, 55-65°C for 30 s, study. Three hundred and eighty patients were evaluated and 72°C for 1 min, followed by a final extension at 72° using the Positive and Negative Symptom Scale C for 10 min. Small volumes (10 μl) of these PCR pro- (PANSS) [34] before and after an 8-week administration ducts were completely digested with 2U of restriction of antipsychotic medications. Only those patients with enzyme (Dra I for -604 G/A, Mwo I for -501A/C, Bsr I total PANSS scores ≥ 60 before treatment were for Leu72Met, and Bcn I for -1062 G > C). The frag- included. The reduction in PANSS scores from baseline ments were separated on 2-4% agarose gels and visua- after the 8-week treatment regime was used to evaluate lized under ultraviolet light after staining with ethidium the efficacy of each AAP. Patients were divided into 2 bromide. groups basedon the reductioninPANSS score, a The statistical power of the sample size was calculated responder group exhibiting a > 50% reduction and by the genetic power calculator (GPC, http://pngu.mgh. none-responder group exhibiting a ≤ 50% reduction harvard.edu/~purcell/gpc/cc2.html) [36]. Deviations in [35]. the genotype counts from Hardy-Weinberg equilibrium We excluded patients with incomplete clinical data. A were tested using a c goodness-of-fit test. Statistical total of 569 patients were treated by monotherapy using differences in genotypic, allelic, and haplotypic distribu- an AAP not previously prescribed. Patients were treated tions between SZ and control subjects were evaluated with clozapine (n = 103, 100-700 mg/d), risperidone by the c test with a significance level of 0.05. Odds (n = 181, 2-6 mg/d), olanzapine (n = 60, 5-20 mg/d), ratios (OR) and 95% confidence intervals (95% CI) were quetiapine (n = 126, 400-750 mg/d), ziprasidone (n = calculated to evaluate the effects of different alleles on 61, 80-160 mg/d), or aripiprazole (n = 38, 10-30 mg/d). SZ risk. Pair-wise linkage disequilibrium (LD) analysis Body weight and BMI was measured before and after 4 was applied to detect the inter-marker relationship weeks of AAP treatment. Individual BMIs were calcu- using D’ and r values. Case-control association analysis lated as BMI = weight (kg)/height (m). was performed by SHEsis software http://analysis.bio-x. Peripheral blood samples were obtained from the sub- cn/myAnalysis.php[37], a powerful software platform for jects and genomic DNA was prepared using the QIAamp analyses of LD, haplotype construction, and genetic DNA blood Mini Kit (QIAGEN, Hilden, Germany). Four association at polymorphic loci. Associations between SNPs [rs696217 (Leu72Met), rs26802 (-501A/C), rs27647 response to a specific AAP and genotype were deter- (-604 G/A), and rs26311 (-1062 G > C)] were selected mined by t-tests and analysis of variance (ANOVA) tests according to the dbSNP database http://www.ncbi.nlm. using SPSS 13.0 software. Results were considered sig- nih.gov/SNP/. The SNPs rs27647 and rs26311 are located nificant at P < 0.05 (two-tailed). in the promoter region, rs26802 in intron 1, and The size of our sample was sufficient to detect a sig- rs696217 in exon 3 of GHRL. All these SNPs effect GHRL nificant difference with a power of more than 70% function and have been linked to metabolic symptoms. assuming an OR value for AA of 1.5 with a minor allele The rs696217 amino-acid change (Leu72Met) affects the frequency of 0.1 and type I error rate set at 0.05. Table 1 SNPs and primers of PCRs and corresponding restriction enzymes Marker Location Primer sequence (5’-3’) Product (bp) Annealing temperature (°C) RFLP Allele (bp) rs27647 Promoter 5’-CACAGCAACAAAGCTGCACC-3’ 929 65 Dra I A(929) 5’-AAGTCCAGCCAGAGCATGCC-3’ G(664,265) rs26802 Intron 1 5’-AGAACAAACGCCAGTCATCC-3’, 205 55 Mwo I A(205) 5’-GTCTTCCAGCCAGACAGTCC-3’ C(104,101) rs696217 Exon 3 5’-GCTGGGCTCCTACCTGAGC-3’ 618 65 Bsr I T(618) 5’-GGACCCTGTTCACTGCCAC-3’ G(517,101) rs26311 Promoter 5’-GGCAGCAGTCACGGACAATAAA-3’ 779 55 Bcn I G (572,252) 5’-CTCAGAAGAGGCATCCGCTAAA-3’ C(527,191,61) Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 constructed from two SNPs showed no significant differ- Results ences between patients and controls (Table 5). Four SNPs in the GHRL locus were analyzed: Leu72Met, Of the 634 patients with SZ, 380 completed the PANSS -501A/C, -604 G/A, and -1062 G > C. As shown in to assess psychopathological syndromes. The results Table 2, none of the genotype distributions of these four revealed that there were no significant differences in SNPs showed significant deviation from Hardy-Wein- PANSS score reduction among the different genotypes of berg equilibrium, and none of the allele frequencies or the four SNPs (-604 G/A, -501A/C, Leu72Met and -1062 the genotype distribution differed between patients and G > C) after 8 weeks treatment with AAPs (Table 6). controls (P >0.05). There wasalsonosignificant asso- ciation between any allele or genotype and SZ when However, in the responder group with the larger decreases in PANSS scores (> 50%), there was a significant associa- patients were subdivided by gender (Table 3). tion between BW and BMI increase (Table 7). The To further analyze the haplotype structure in our responder group exhibited significantly greater BW and sample, pair-wise linkage disequilibrium (LD) of the BMI increases than none responders, and patients in spe- four SNPs in the control group was computed using the cific AAP treatment groups with high weight gain showed standardized measures D’ and r values. There was strong greater improvements than those with low weight gain LD in Leu72Met and -501A/C, so haplotype analyses when subdivided according to drug (Table 8). were performed (Table 4). However, the haplotypes Table 2 Genotype and allele frequencies of four SNPs in GHRL gene between schizophrenia patients and healthy controls a b b c Marker N Genotype HWE P-value Allele P-value OR (95%CI) rs696217 GG GT TT G T Patients 634 427(0.684) 180(0.288) 17(0.027) 0.704 0.649 1034(0.829) 214(0.171) 0.773 1.03(0.83-1.27) Controls 606 400(0.670) 184(0.308) 13(0.022) 0.123 984(0.824) 210(0.176) rs26802 AA AC CC A C Patients 634 534(0.842) 95(0.150) 5(0.008) 0.732 0.944 1163(0.917) 105(0.083) 0.922 1.01(0.76-1.35) Controls 606 505(0.839) 93(0.154) 4(0.007) 0.900 1103(0.916) 101(0.084) rs27647 AA AG GG A G Patients 634 10(0.016) 133(0.210) 491(0.774) 0.773 0.410 153(0.121) 1115(0.879) 0.301 1.13(0.88-1.46) Controls 606 5(0.008) 120(0.198) 480(0.793) 0.400 130(0.107) 1080(0.893) rs26311 CC CG GG C G Patients 634 253(0.402) 298(0.474) 78(0.124) 0.498 0.826 804(0.639) 454(0.361) 0.723 1.03(0.87-1.21) Controls 606 234(0.387) 297(0.491) 74(0.122) 0.171 765(0.632) 445(0.368) Number of samples which are well genotyped Frequencies are shown in parenthesis Odds ratios of alleles were calculated for each reference vs. variant allele Table 3 Genotype frequencies of the four SNPs interaction with gender dbSNP ID Genotype Female Male Patients Controls p-value Patients Controls p-value rs696217 GG 224 191 0.689 203 209 0.896 GT 93 91 87 93 TT 11 7 6 6 rs26802 AA 279 247 0.306 255 258 0.723 AC 50 41 45 52 CC 32 22 rs27647 AA 4 2 0.151 6 3 0.368 AG 77 51 56 69 GG 251 240 240 240 rs26311 CC 142 118 0.358 111 116 0.876 CG 150 139 148 158 GG 37 36 41 38 Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 Table 4 Pairwise linkage disequilibrium among four SNPs could reflect the relatively small sample size of paranoid in the GHRL gene (D’ values is shown above and r schizophrenic patients in our cohort. Furthermore, we values below the diagonal) found no haplotypes with significantly higher frequency rs696217 rs26802 rs27647 rs26311 between cases and controls. Therefore, we suggest that rs696217 0.901 0.004 0.261 GHRL is not a predisposing gene for SZ in the Chinese rs26802 0.016 0.175 0.193 Han population. rs27647 0.000 0.000 0.116 In the present study, no association between PANSS rs26311 0.025 0.006 0.001 reduction during AAP treatment and GHRL gene poly- morphisms was found. However, the magnitude of the PANSS score reduction was significantly associated with The main clinical and biochemical characteristics of the the increase in BW and BMI during AAP treatment. schizophrenic patients were analyzed with nonparametric Meanwhile, the reduction rate of PANSS total score in tests. There was a significant association between BW and responder and none-responder groups had significant BMI measured before and after 4-week AAP treatment association with BW and BMI increase. The same finding (P = 0.005 and 0.004 respectively). Patients with the -604 was also revealed when patients were subdivided accord- G/A exhibited significantly higher BWs and BMIs after ing the specific AAP taken. Atypical antipsychotics treatment (P = 0.028 and 0.011, respectively) (Table 9). induced weight gain in a significant fraction of SZ Similarly, paranoid SZ patients (n = 309) demonstrated patients [9], but factors that are predictive of weight gain greater WG and BMI increases (P = 0.020 and 0.011, during AAP therapy are unclear. We found that patients respectively). In addition, there were significant differences exhibiting the greatest weight gains while receiving olan- in the BW and BMI increases between G allele carriers zapine, risperidone, clozapine, or quetiapine also showed and homozygous allele A carriers in patients harboring greater improvements in symptoms than those showing SNP-604 G/A (P = 0.039 and 0.013, respectively). lower weight gain. This result is in partial accord with a previous study that found olanzapine-induced weight Discussion gain correlated negatively with baseline BMI and posi- The associations between GHRL polymorphisms and tively with clinical global improvement and the length of SZ risk, changes in weight/BMI, and therapeutic olanzapine treatment [39]. responses to AAPs were evaluated in a population of The GHRL gene may be a promising candidate under- SZ patients of Han Chinese ethnicity. While we found lying AP-induced weight gain [40]. We found significant no association between GHRL gene polymorphisms differences between the three -604 G/A genotypes, with and SZ susceptibility in this case-control study, analy- patients harboring AA showing the greatest weight gain sis did reveal significant BW and BMI increases during and increase in BMI. In addition to BMI, -604 G/A has AAP treatment in patients harboring the -604 G/A been linked to variations in blood pressure [12]. Pre- polymorphism. vious studies have also reported that the Leu72Met To our knowledge, no previous study has examined the polymorphism was significantly associated with BMI association between GHRL gene polymorphisms and sus- [10,11]. However, we found no association between ceptibility to SZ. Our study revealed no significant differ- Leu72Met polymorphisms and the AAP-induced BMI ences in allele and genotype frequency of four GHRL increase, consistent with previous findings [26,31,32]. In SNPs between schizophrenic patients and controls even addition to the significant association between the AA when patients were subdivided by gender. Thus, GHRL is genotype and BMI, we also found that paranoid SZ not a likely SZ risk gene despite the fact that it is in a sus- patients demonstrated higher weight gain than patients ceptibility locus (3p25-p26). Furthermore, we also exam- with other subtypes of SZ, including catatonic, collapse, ined paranoid SZ cases in light of the study by Scassellati residual, and undifferentiated patients. Therefore, our et al. [38]. Again, we found no significant differences in results provide suggestive evidencefor alinkbetween the frequency of these four SNPs or the genotype distribu- -604 G/A and metabolic syndrome in paranoid SZ. tion between paranoid patients and controls, but this Table 5 Estimated haplotype frequencies and case-control haplotype results SNP Haplotype Frequencies c P-value OR (95%CI) Global Cases Controls c P-value rs696217–rs26802 G-A 930.15(0.745) 883.02(0.742) 0.007 0.933 1.008(0.840~1.209) 0.022 0.989 G-C 103.85(0.083) 97.98(0.082) 0.004 0.952 1.009(0.756~1.346) T-A 213.85(0.171) 205.98(0.173) 0.020 0.888 0.985(0.798~1.216) Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 Table 6 Reduction of PANSS scores in patients with different GHRL genotypes ( x ± s ) SNP Genotype N Before treatment After 8 weeks treatment Reduction rate (%)* a b c a b c Total** P N G total P N G rs27647 GG 292 88.06 ± 21.64 24.49 ± 6.63 21.46 ± 8.00 42.11 ± 12.34 45.84 ± 12.63 10.87 ± 3.69 11.65 ± 4.85 23.32 ± 6.33 0.72 ± 0.19 GA+AA 88 87.38 ± 23.51 23.05 ± 6.92 22.81 ± 8.28 41.52 ± 13.4 45.40 ± 10.86 10.68 ± 3.53 12.24 ± 5.05 22.48 ± 4.88 0.72 ± 0.19 P 0.799 0.076 0.169 0.702 0.767 0.672 0.321 0.250 0.988 rs26802 AA 322 88.61 ± 22.47 24.35 ± 6.80 21.74 ± 8.26 42.52 ± 12.76 45.91 ± 12.47 10.90 ± 3.76 11.76 ± 4.97 23.25 ± 6.17 0.72 ± 0.19 AC+CC 58 83.97 ± 19.33 23.09 ± 6.16 21.91 ± 7.00 38.97 ± 11.20 44.79 ± 10.85 10.43 ± 2.96 11.93 ± 4.49 22.43 ± 5.15 0.72 ± 0.18 P 0.140 0.187 0.882 0.048 0.524 0.371 0.805 0.341 0.929 rs696217 GG 253 87.91 ± 22.94 24.23 ± 6.53 21.66 ± 8.36 42.02 ± 13.15 45.09 ± 11.31 10.63 ± 3.60 11.61 ± 4.70 22.85 ± 5.34 0.73 ± 0.18 GT+TT 120 87.65 ± 19.38 24.11 ± 6.96 21.82 ± 7.36 41.73 ± 10.91 45.97 ± 11.41 11.01 ± 3.31 11.74 ± 4.70 23.22 ± 6.10 0.71 ± 0.20 P 0.915 0.870 0.864 0.834 0.484 0.329 0.798 0.555 0.309 rs26311 CC 153 87.25 ± 22.59 24.09 ± 6.84 21.58 ± 7.52 41.58 ± 13.06 45.30 ± 11.10 10.85 ± 3.70 11.52 ± 4.52 22.93 ± 5.35 0.72 ± 0.19 GG+GC 223 87.66 ± 21.04 24.09 ± 6.59 21.74 ± 8.36 41.83 ± 11.82 46.01 ± 13.04 10.79 ± 3.63 11.96 ± 5.15 23.25 ± 6.49 0.72 ± 0.19 P 0.857 0.998 0.845 0.848 0.582 0.884 0.385 0.619 0.883 a b c *reduction rates of PANSS total scores; ** total scores; Positive score; negative score; general pathology score Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 Table 7 The BW and BMI change in responder group and none-responder groups a b c Two group N BW change ( ) kg BMI change ( ) x ± s x ± s responder group 339 0.68 ± 4.00 0.27 ± 1.47 none-responder group 41 -1.13 ± 2.35 -0.42 ± 0.87 P-value 0.000 0.000 Patients were divided into 2 groups based on reduction rates of PANSS total scores, namely, responder group (> 50%) and none-responder group (≤ 50%) Body weight change = body weight (4-week) - body weight(0 week) BMI change = BMI (4-week) - BMI (0 week) Table 8 The BW and BMI change in responder group and none-responder groups when subdivided according to different AAPs ( x ± s ) a b Two groups AAP N BW change (kg) P-value BMI change P-value responder group clozapine 63 0.60 ± 3.94 0.012 0.21 ± 1.41 0.009 risperidone 115 1.20 ± 3.71 0.46 ± 1.41 olanzapine 25 1.94 ± 4.47 0.76 ± 1.68 quetiapine 76 1.01 ± 3.41 0.37 ± 1.26 ziprasidone 32 -1.66 ± 4.78 -0.60 ± 1.74 aripiprazole 26 -0.67 ± 4.42 -0.19 ± 1.49 none-responder group clozapine 7 -1.57 ± 2.30 0.917 -0.55 ± 0.80 0.834 risperidone 11 -1.18 ± 1.99 -0.47 ± 0.79 olanzapine 5 -0.60 ± 1.82 -0.18 ± 0.62 quetiapine 8 -0.44 ± 2.87 -0.16 ± 1.07 ziprasidone 6 -1.5 ± 2.74 -0.56 ± 0.95 aripiprazole 3 -1.8 ± 3.69 -0.73 ± 1.42 responder group and none-responder group atypical antipsychotics treatment with AAPs. Surprisingly, patients showing Conclusion While we did not find an association between GHRL the greatest weight gain also showed the greatest improvements in symptoms. In order to more precisely alleles and susceptibility to SZ in the Chinese Han define the impact of antipsychotic medications on population, the -604 G/A polymorphism, and particu- metabolic parameters, control of patient subtype, sam- larly the AA genotype, was associated with larger ple size, as well as monitoring of multiple metabolic increases in BW and BMI in SZ patients under Table 9 The association analysis of BW and BMI in four SNPs SNP Genotype BW(0 week, kg) BW(4 week, kg) BW change (kg) BMI(0 week) BMI(4 week) BMI change rs27647 GG 62.69 ± 11.86 63.16 ± 11.19 0.55 ± 3.85 22.65 ± 3.60 22.84 ± 3.44 0.21 ± 1.42 AG 62.85 ± 12.44 62.87 ± 11.88 -0.18 ± 3.35 22.16 ± 3.59 22.13 ± 3.48 -0.04 ± 1.18 AA 58.4 ± 7.40 61.39 ± 10.25 2.61 ± 3.46 21.4 ± 2.91 23.05 ± 3.71 1.15 ± 1.21 P-value 0.426 0.810 0.028* 0.392 0.181 0.011* rs26802 AA 62.53 ± 12.13 62.90 ± 11.33 0.40 ± 3.79 22.54 ± 3.62 22.68 ± 3.45 0.17 ± 1.39 AC 63.35 ± 10.90 64.40 ± 11.28 0.87 ± 3.36 22.51 ± 3.54 22.95 ± 3.55 0.30 ± 1.21 CC 59.70 ± 9.78 56.8 ± 6.30 -2.9 ± 6.07 21.66 ± 2.03 20.68 ± 1.28 -0.97 ± 2.17 P-value 0.572 0.163 0.247 0.839 0.275 0.269 rs696217 GG 62.16 ± 11.75 62.77 ± 11.29 0.62 ± 3.60 22.33 ± 3.45 22.58 ± 3.37 0.24 ± 1.30 GT 63.57 ± 12.05 63.67 ± 11.08 0.10 ± 3.85 22.83 ± 3.57 22.86 ± 3.34 0.05 ± 1.41 TT 63.75 ± 15.14 63.67 ± 14.83 -0.08 ± 6.49 23.60 ± 6.07 23.60 ± 6.08 0.002 ± 2.51 P-value 0.446 0.589 0.319 0.358 0.676 0.254 rs26311 GG 63.30 ± 12.10 63.09 ± 10.36 0.41 ± 3.39 23.13 ± 3.74 23.12 ± 3.43 0.15 ± 1.28 GC 62.29 ± 12.25 62.89 ± 11.32 0.49 ± 3.90 22.63 ± 3.75 22.86 ± 3.48 0.20 ± 1.43 CC 62.77 ± 11.52 63.24 ± 11.65 0.41 ± 3.71 22.21 ± 3.34 22.39 ± 3.44 0.16 ± 1.34 P-value 0.792 0.925 0.804 0.343 0.344 0.765 Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 8 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 8. Herberth M, Koethe D, Cheng TM, Krzyszton ND, Schoeffmann S, Guest PC, indices during antipsychotic therapy are of paramount et al: Impaired glycolytic response in peripheral blood mononuclear cells importance. of first-onset antipsychotic-naive schizophrenia patients. Mol Psychiatry 2011, 16(8):848-859. 9. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, Abbreviations et al: Head-to-head comparisons of metabolic side effects of second SZ: Schizophrenia; GHRL: Ghrelin; WG: Weight gain; AAPs: Atypical generation antipsychotics in the treatment of schizophrenia: a antipsychotics; BMI: Body mass index; SNPs: Single nucleotide systematic review and meta-analysis. Schizophr Res 2010, 123(2-3):225-233. polymorphisms; BW: Body weight; DSM-IV: Diagnostic and statistical manual 10. Ando T, Ichimaru Y, Konjiki F, Shoji M, Komaki G: Variations in the of mental disorders fourth edition; PCR-RFLP: Polymerase chain reaction- preproghrelin gene correlate with higher body mass index, fat mass, based-restriction fragment length polymorphism; OR: Odds ratio; 95% CI: and body dissatisfaction in young Japanese women. Am J Clin Nutr 2007, 95% confidence intervals; LD: Linkage disequilibrium; ANOVA: Analysis of 86(1):25-32. variance; PANSS: Positive and negative symptom scale. 11. Kuzuya M, Ando F, Iguchi A, Shimokata H: Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large Acknowledgements cohort. Int J Obes (Lond) 2006, 30(11):1609-1614. We thank Zhaoxi ZHONG, Zheng ZHAO, Jun CHENG, Yunhong DU, Yuchun 12. Mager U, Kolehmainen M, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, LI, Yuling LI, Dexiang DUAN and Fang GUO(Department of Psychiatry of the et al: Association between ghrelin gene variations and blood pressure in Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, PR subjects with impaired glucose tolerance. Am J Hypertens 2006, China) for their works of collect the clinical materiales, and thank Yan RUAN, 19(9):920-926. Lifang WANG, Lei WANG, Tianlan LU, Jian QIN, Zhilin LUAN, Lin TIAN and 13. Choi HJ, Cho YM, Moon MK, Choi HH, Shin HD, Jang HC, et al: Hao YAN. (Institute of Mental Health, Peking University, Beijing, 100083, PR Polymorphisms in the ghrelin gene are associated with serum high- China) for their assistance in doing experiment. density lipoprotein cholesterol level and not with type 2 diabetes The research was supported by Ministry of Health Research Fund of the mellitus in Koreans. J Clin Endocrinol Metab 2006, 91(11):4657-4663. People’s Republic of China (Grant No.200801009), and the Supported by 14. Steinle NI, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR: Variants in the Program for Innovative Research Team (in Science and Technology) in ghrelin gene are associated with metabolic syndrome in the Old Order University of Henan Province (Grant No.2008IRTSTHN008), the National Amish. J Clin Endocrinol Metab 2005, 90(12):6672-6677. Natural Science Foundation of China (30530290, 81071090, 81071091), the 15. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is National High Technology Research and Development Program of China a growth-hormone-releasing acylated peptide from stomach. Nature (2009AA022702), the National Basic Research Program of China 1999, 402(6762):656-660. (2007CB512301). 16. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Bloom SR, et al: Ghrelin enhances appetite and increases food intake in humans. J Author details Clin Endocrinol Metab 2001, 86(12):5992. Department of Psychiatry, The Second Affiliated Hospital of Xinxiang 17. Tschöp M, Smiley DL, Heiman ML: Ghrelin induces adiposity in rodents. Medical University, Xinxiang, China. Henan Mental Hospital, Henan Key Lab Nature 2000, 407(6806):908-913. of Biological Psychiatry, Xinxiang, China. First Affiliated Hospital of 18. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al: The Zhengzhou University, Zhengzhou, China. Key Laboratory for Mental Health, novel hypothalamic peptide ghrelin stimulates food intake and growth Ministry of Health, Institute of Mental Health, Peking University, Beijing, hormone secretion. Endocrinology 2000, 141(11):4325-4328. China. 19. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al: Plasma ghrelin levels in lean and obese humans and the effect of glucose on Authors’ contributions ghrelin secretion. J Clin Endocrinol Metab 2002, 87(1):240-244. LL, WY and DZ participated in the design of the study and made final 20. Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J: Alterations in the approval of the version to be published. YY were involved in drafting the dynamics of circulating ghrelin, adiponectin, and leptin in human manuscript and data analysis. WL, YY, HY, HZ, XS, BX, and GY carried out the obesity. Proc Natl Acad Sci USA 2004, 101(28):10434-10439. molecular genetic examination. YY, WY, CJ, and JZ conducted sample 21. Himmerich H, Fulda S, Künzel HE, Pfennig A, Dzaja A, Cummings DE, et al: selection and data management. All authors read and approved the final Ghrelin plasma levels during psychopharmacological treatment. manuscript. Neuropsychobiology 2005, 52:11-16. 22. Murashita M, Kusumi I, Inoue T, Takahashi Y, Hosoda H, Kangawa K, et al: Competing interests Olanzapine increases plasma ghrelin level in patients with The authors declare that they have no competing interests. schizophrenia. Psychoneuroendocrinology 2005, 30:106-110. 23. Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, et al: Early Received: 10 April 2011 Accepted: 28 February 2012 effects of olanzapine on serum levels of ghrelin, adiponectin and leptin Published: 28 February 2012 in patients with schizophrenia. J Psychopharmacol 2006, 20:75-79. 24. Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB: Ghrelin-a hormone with multiple functions. Front Neuroendocrinol 2004, 25(1):27-68. References 25. Wajanrajch MP, Ten IS, Gertner JM, Leibel RL: Genomic organization of 1. Lewis DA, Lieberman JA: Catching up on schizophrenia: natural history human ghrelin gene. J Endocr Genet 2000, 1:231-233. and neurobiology. Neuron 2000, 28(2):325-334. 26. Garcia EA, King P, Sidhu K, Ohgusu H, Walley A, Lecoeur C, et al: The role 2. Hallmayer J: The epidemiology of the genetic liability for schizophrenia. of ghrelin and ghrelin-receptor gene variants and promoter activity in Aust N Z J Psychiatr 2000, 34(Suppl):47-55. type 2 diabetes. Eur J Endocrinol 2009, 161(2):307-315. 3. McGuffin P, Owen MJ, Farmer AE: Genetic basis of schizophrenia. Lancet Correll CU, Malhotra AK: Pharmacogenetics of antipsychotic-induced 1995, 346(8976):678-682. weight gain. Psychopharmacology (Berl) 2004, 174(4):477-489. 4. Talkowski ME, Bamne M, Mansour H, Nimgaonkar VL: Dopamin genes and 28. Horvath TL, Castañeda T, Tang-Christensen M, et al: Ghrelin as a potential schizophrenia: case closed or evidence pending? Schizophr Bull 2007, anti-obesity target. Curr Pharm Des 2003, 9(17):1383-1395. 33(5):1071-1081. 29. Online datebase center, sponsored by NARSAD and the Mental Health 5. Tomppo L, Hennah W, Miettunen J, Järvelin MR, Veijola J, Ripatti S, et al: Research Association [DB/OL]. 2005 [http://www.schizophreniaforum.org/ Association of variants in DISC1 with psychosis-related traits in a large res/sczgene/default.asp]. population cohort. Arch Gen Psychiatry 2009, 66(2):134-141. 30. Zhang Q, Huang WD, Lv XY, Yang YM: The association of ghrelin 6. Zhang HX, Zhao JP, Lv LX, Li WQ, Xu L, Ouyang X, et al: Explorative study polymorphisms with coronary artery disease and ischemic chronic heart on the expression of neuregulin-1 gene in peripheral blood of failure in an elderly Chinese population. Clin Biochem 2011, 44(5- schizophrenia. Neurosci Lett 2008, 438(1):1-5. 6):386-390. 7. Citrome L, Vreeland B: Schizophrenia, obesity, and antipsychotic medications: what can we do? Postgrad Med 2008, 120(2):18-33. Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 9 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 31. Hubácek JA, Bohuslavová R, Skodová Z, Adámková V: Variants within the ghrelin gene-association with HDL-cholesterol, but not with body mass index. Folia Biol (Praha) 2007, 53(6):202-206. 32. Mager U, Lindi V, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, et al: Association of the Leu72Met polymorphism of the ghrelin gene with the risk of type 2 diabetes in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study. Diabet Med 2006, 23(6):685-689. 33. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Press;, fourth 1994. 34. Kay SR, Opler LA, Lindenmayer JP: Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res 1988, 23(1):99-110. 35. Zhang ML: Relationship in dosage, serum concentration and clinical response of olanzap ine in schizophrenic patients. Chin J Psychiatry 2003, 36(3):139. 36. Purcell S, Cherny SS, Sham PC: Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003, 19(1):149-150. 37. Shi YY, He L: SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005, 15(2):97-98. 38. Scassellati C, Bonvicini C, Perez J, Bocchio-Chiavetto L, Tura GB, Rossi G, et al: Association study of -1727 A/T, -50 C/T and (CAA)n repeat GSK- 3beta gene polymorphisms with schizophrenia. Neuropsychobiology 2004, 50(1):16-20. 39. Ujike H, Nomura A, Morita Y, Morio A, Okahisa Y, Kotaka T, et al: Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. J Clin Psychiatry 2008, 69:1416-1422. 40. Correll CU, Malhotra AK: Pharmacogenetics of antipsychotic-induced weight gain. Psychopharmacology 2004, 174(4):477-489. doi:10.1186/1744-9081-8-11 Cite this article as: Yang et al.: Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients. 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Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients

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Copyright © 2012 by Yang et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: Ghrelin (GHRL) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether GHRL polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between GHRL polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping GHRL alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response. Methods: Four SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects. Results: There were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (P > 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (P < 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (P < 0.05). Conclusions: These four GHRL gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss. Keywords: Schizophrenia, Ghrelin (GHRL), Polymorphrism, Body mass index (BMI), Atypical antipsychotics, Thera- peutic effects * Correspondence: dryue@bjmu.edu.cn; lvx928@126.com † Contributed equally Department of Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, Beijing, China Full list of author information is available at the end of the article © 2012 Yang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 [25,26]. Several SNPs in the coding region of prepro- Background ghrelin have been described, but there is no known Schizophrenia (SZ) is a severe brain disorder afflicting specific association between genetic variations in the approximately 1% of the world’s population and often human GHRL gene and SZ risk. However, region leads to a lifetime of disability and emotional distress 3p25.1-26.1 is strongly associated with schizophrenia. In [1]. Family, twin, and adoption studies strongly indicate addition to GHRL, this region contains SYN2, HRH1, that genetics contribute to the etiology of SZ, probably and GRM7, all candidate genes for schizophrenia. The by transmission of multiple susceptibility genes each positive symptoms of schizophrenia are associated with exerting weak-to-moderate effects on predisposition dysfunction in dopaminergic signaling, which is closely [2,3]. Many candidate susceptibility genes have been associated with a GHRL mutation [27-29]. Previous stu- identified, including the dopamine receptor D2, neure- dies demonstrated that SNPs in GHRL were associated gulin1, and disrupted in schizophrenia 1 (DISC-1) [4-6]. with high BMI; the Leu72Met allele was significantly Epidemiological studies have also revealed that people associated with BMI and coronary artery disease with SZ are at greater risk for obesity, type 2 diabetes, [18,19,30], but this was not confirmed in other studies dyslipidemia, and hypertension than the general popula- [26,31,32]. tion [7]. Recently, it was suggested that SZ patients are In light of the increase metabolic syndrome symptoms at increased risk of metabolic problems and that the observed in SZ patients on AAPs, as well as the impor- associated symptoms are a serious threat to patient tant role of GHRL as a metabolic regulator and the asso- health [8]. Metabolic problems are often triggered by ciation between GHRL SNPs and metabolic indices, we antipsychotic medication. Indeed, significant weight gain hypothesized that (1) GHRL might be a candidate gene is common in AAP-treated SZ patients, especially for SZ and that (2) allelic variants of GHRL might be patients administered clozapine, olanzapine, quetiapine, associated with the propensity for BMI changes induced or risperidone [9]. by AAP treatment. In addition, we tested (3) whether a The peptide ghrelin (product of the GHRL gene) is an putative relationship between GHRL SNPs and metabolic important metabolic regulator produced by the stomach effects was specific to individual AAP types. Finally, (4) and pancreas. Specific SNPs of GHRL have been associated we examined if GHRL alleles influenced the clinical effi- with variations in BMI, blood pressure, high-density lipo- cacy of AAPs. To these ends, we genotyped four SNPs proteins, low-density lipoproteins, serum cholesterol, and investigated whether they were associated with SZ blood glucose, and metabolic syndrome [10-14]. Ghrelin, and the therapeutic and metabolic effects of AAPs in the originally isolated from the rat stomach, stimulates food intake and controls energy balance [15,16]. Studies on ani- Han Chinese population. mal models revealed that GHRL increased food intake and Methods adiposity [17,18]. However, circulating GHRL levels were The study group consisted of 634 diagnosed schizophre- decreased in obese individuals, and serum GHRL levels nic patients (332 males and 302 females; mean age: 27.14 were inversely correlated with BMI, suggesting that GHRL ± 7.53 years). Patients were unrelated Han Chinese born is not directly involved in most cases of obesity [19,20]. and living in the North Henan province, and all their bio- Studies on the relationship between WG, circulating logical grandparents were of Han Chinese ancestry. Indi- GHRL, and AAP have yielded inconsistent findings. viduals with a history of severe medical complications, Patients taking clozapine or olanzapine showed greater organic brain disease, any concomitant major psychiatric WG than patients on other antipsychotics [21]. In one disorders, or substance dependence were excluded. All study, plasma total GHRL and active GHRL were increased patients were recruited from the Department of Psychia- significantly immediately after olanzapine treatment, but try of the Second Affiliated Hospital of Xinxiang Medical the changes in BMI and body weight were not significant University,P.R.China.The consensusdiagnoses were after 6 months of treatment [22]. In contrast, another conducted by at least two experienced psychiatrists study found that serum bioactive GHRL levels decreased according to the Diagnostic and Statistical Manual of significantly from baseline after 4 weeks of olanzapine Mental Disorders, fourth Edition (DSM-IV) [33]. The monotherapy [23]. In humans, GHRL plays an important patient group included paranoid (n = 309), catatonic (n = role in the long-term regulation of body weight (BW) as 50), collapse (n = 45), residual (67), and undifferentiated well as in the short-term regulation of appetite [19,21]. (n = 163) schizophrenic types. Ghrelin stimulated preadipocyte differentiation, increased The control group consisted of 606 healthy subjects the BMI, and inhibited the anorexigenic effect of leptin (293 males and 313 females; mean age: 29.08 ± 7.80 [24]. Drug altering GHRL functionmayhavedistinct short- and long-term effects on BMI. years) recruited from communities and colleges within The human GHRL gene is located on chromosome 3 the same region and matched to the patient group for (3p25-p26), and consists of 4 exons and 3 introns age, gender ratio, and Han ethnicity. Controls were Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 recruited using a simple non-structured interview per- tail of the pro-ghrelin molecule, but it is not known how formed by psychiatrists. Individuals with personal or this affects GHRL expression or activity (Table 1). The family histories of mental illness or neurological diseases four SNPs were detected by polymerase chain reaction were excluded. The objectives and procedures of the (PCR)-based restriction fragment length polymorphism study were explained to all subjects and written (PCR-RFLP) analysis. informed consent was obtained. The Ethical Committee The primers of the four SNPs investigated are shown of the Department of Psychiatry of the Second Affiliated in Table 1. The conditions used for PCR amplification Hospital of Xinxiang Medical University approved this included an initial denaturation step at 94°C for 5 min, followed by 36 cycles of 94°C for 30 s, 55-65°C for 30 s, study. Three hundred and eighty patients were evaluated and 72°C for 1 min, followed by a final extension at 72° using the Positive and Negative Symptom Scale C for 10 min. Small volumes (10 μl) of these PCR pro- (PANSS) [34] before and after an 8-week administration ducts were completely digested with 2U of restriction of antipsychotic medications. Only those patients with enzyme (Dra I for -604 G/A, Mwo I for -501A/C, Bsr I total PANSS scores ≥ 60 before treatment were for Leu72Met, and Bcn I for -1062 G > C). The frag- included. The reduction in PANSS scores from baseline ments were separated on 2-4% agarose gels and visua- after the 8-week treatment regime was used to evaluate lized under ultraviolet light after staining with ethidium the efficacy of each AAP. Patients were divided into 2 bromide. groups basedon the reductioninPANSS score, a The statistical power of the sample size was calculated responder group exhibiting a > 50% reduction and by the genetic power calculator (GPC, http://pngu.mgh. none-responder group exhibiting a ≤ 50% reduction harvard.edu/~purcell/gpc/cc2.html) [36]. Deviations in [35]. the genotype counts from Hardy-Weinberg equilibrium We excluded patients with incomplete clinical data. A were tested using a c goodness-of-fit test. Statistical total of 569 patients were treated by monotherapy using differences in genotypic, allelic, and haplotypic distribu- an AAP not previously prescribed. Patients were treated tions between SZ and control subjects were evaluated with clozapine (n = 103, 100-700 mg/d), risperidone by the c test with a significance level of 0.05. Odds (n = 181, 2-6 mg/d), olanzapine (n = 60, 5-20 mg/d), ratios (OR) and 95% confidence intervals (95% CI) were quetiapine (n = 126, 400-750 mg/d), ziprasidone (n = calculated to evaluate the effects of different alleles on 61, 80-160 mg/d), or aripiprazole (n = 38, 10-30 mg/d). SZ risk. Pair-wise linkage disequilibrium (LD) analysis Body weight and BMI was measured before and after 4 was applied to detect the inter-marker relationship weeks of AAP treatment. Individual BMIs were calcu- using D’ and r values. Case-control association analysis lated as BMI = weight (kg)/height (m). was performed by SHEsis software http://analysis.bio-x. Peripheral blood samples were obtained from the sub- cn/myAnalysis.php[37], a powerful software platform for jects and genomic DNA was prepared using the QIAamp analyses of LD, haplotype construction, and genetic DNA blood Mini Kit (QIAGEN, Hilden, Germany). Four association at polymorphic loci. Associations between SNPs [rs696217 (Leu72Met), rs26802 (-501A/C), rs27647 response to a specific AAP and genotype were deter- (-604 G/A), and rs26311 (-1062 G > C)] were selected mined by t-tests and analysis of variance (ANOVA) tests according to the dbSNP database http://www.ncbi.nlm. using SPSS 13.0 software. Results were considered sig- nih.gov/SNP/. The SNPs rs27647 and rs26311 are located nificant at P < 0.05 (two-tailed). in the promoter region, rs26802 in intron 1, and The size of our sample was sufficient to detect a sig- rs696217 in exon 3 of GHRL. All these SNPs effect GHRL nificant difference with a power of more than 70% function and have been linked to metabolic symptoms. assuming an OR value for AA of 1.5 with a minor allele The rs696217 amino-acid change (Leu72Met) affects the frequency of 0.1 and type I error rate set at 0.05. Table 1 SNPs and primers of PCRs and corresponding restriction enzymes Marker Location Primer sequence (5’-3’) Product (bp) Annealing temperature (°C) RFLP Allele (bp) rs27647 Promoter 5’-CACAGCAACAAAGCTGCACC-3’ 929 65 Dra I A(929) 5’-AAGTCCAGCCAGAGCATGCC-3’ G(664,265) rs26802 Intron 1 5’-AGAACAAACGCCAGTCATCC-3’, 205 55 Mwo I A(205) 5’-GTCTTCCAGCCAGACAGTCC-3’ C(104,101) rs696217 Exon 3 5’-GCTGGGCTCCTACCTGAGC-3’ 618 65 Bsr I T(618) 5’-GGACCCTGTTCACTGCCAC-3’ G(517,101) rs26311 Promoter 5’-GGCAGCAGTCACGGACAATAAA-3’ 779 55 Bcn I G (572,252) 5’-CTCAGAAGAGGCATCCGCTAAA-3’ C(527,191,61) Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 constructed from two SNPs showed no significant differ- Results ences between patients and controls (Table 5). Four SNPs in the GHRL locus were analyzed: Leu72Met, Of the 634 patients with SZ, 380 completed the PANSS -501A/C, -604 G/A, and -1062 G > C. As shown in to assess psychopathological syndromes. The results Table 2, none of the genotype distributions of these four revealed that there were no significant differences in SNPs showed significant deviation from Hardy-Wein- PANSS score reduction among the different genotypes of berg equilibrium, and none of the allele frequencies or the four SNPs (-604 G/A, -501A/C, Leu72Met and -1062 the genotype distribution differed between patients and G > C) after 8 weeks treatment with AAPs (Table 6). controls (P >0.05). There wasalsonosignificant asso- ciation between any allele or genotype and SZ when However, in the responder group with the larger decreases in PANSS scores (> 50%), there was a significant associa- patients were subdivided by gender (Table 3). tion between BW and BMI increase (Table 7). The To further analyze the haplotype structure in our responder group exhibited significantly greater BW and sample, pair-wise linkage disequilibrium (LD) of the BMI increases than none responders, and patients in spe- four SNPs in the control group was computed using the cific AAP treatment groups with high weight gain showed standardized measures D’ and r values. There was strong greater improvements than those with low weight gain LD in Leu72Met and -501A/C, so haplotype analyses when subdivided according to drug (Table 8). were performed (Table 4). However, the haplotypes Table 2 Genotype and allele frequencies of four SNPs in GHRL gene between schizophrenia patients and healthy controls a b b c Marker N Genotype HWE P-value Allele P-value OR (95%CI) rs696217 GG GT TT G T Patients 634 427(0.684) 180(0.288) 17(0.027) 0.704 0.649 1034(0.829) 214(0.171) 0.773 1.03(0.83-1.27) Controls 606 400(0.670) 184(0.308) 13(0.022) 0.123 984(0.824) 210(0.176) rs26802 AA AC CC A C Patients 634 534(0.842) 95(0.150) 5(0.008) 0.732 0.944 1163(0.917) 105(0.083) 0.922 1.01(0.76-1.35) Controls 606 505(0.839) 93(0.154) 4(0.007) 0.900 1103(0.916) 101(0.084) rs27647 AA AG GG A G Patients 634 10(0.016) 133(0.210) 491(0.774) 0.773 0.410 153(0.121) 1115(0.879) 0.301 1.13(0.88-1.46) Controls 606 5(0.008) 120(0.198) 480(0.793) 0.400 130(0.107) 1080(0.893) rs26311 CC CG GG C G Patients 634 253(0.402) 298(0.474) 78(0.124) 0.498 0.826 804(0.639) 454(0.361) 0.723 1.03(0.87-1.21) Controls 606 234(0.387) 297(0.491) 74(0.122) 0.171 765(0.632) 445(0.368) Number of samples which are well genotyped Frequencies are shown in parenthesis Odds ratios of alleles were calculated for each reference vs. variant allele Table 3 Genotype frequencies of the four SNPs interaction with gender dbSNP ID Genotype Female Male Patients Controls p-value Patients Controls p-value rs696217 GG 224 191 0.689 203 209 0.896 GT 93 91 87 93 TT 11 7 6 6 rs26802 AA 279 247 0.306 255 258 0.723 AC 50 41 45 52 CC 32 22 rs27647 AA 4 2 0.151 6 3 0.368 AG 77 51 56 69 GG 251 240 240 240 rs26311 CC 142 118 0.358 111 116 0.876 CG 150 139 148 158 GG 37 36 41 38 Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 Table 4 Pairwise linkage disequilibrium among four SNPs could reflect the relatively small sample size of paranoid in the GHRL gene (D’ values is shown above and r schizophrenic patients in our cohort. Furthermore, we values below the diagonal) found no haplotypes with significantly higher frequency rs696217 rs26802 rs27647 rs26311 between cases and controls. Therefore, we suggest that rs696217 0.901 0.004 0.261 GHRL is not a predisposing gene for SZ in the Chinese rs26802 0.016 0.175 0.193 Han population. rs27647 0.000 0.000 0.116 In the present study, no association between PANSS rs26311 0.025 0.006 0.001 reduction during AAP treatment and GHRL gene poly- morphisms was found. However, the magnitude of the PANSS score reduction was significantly associated with The main clinical and biochemical characteristics of the the increase in BW and BMI during AAP treatment. schizophrenic patients were analyzed with nonparametric Meanwhile, the reduction rate of PANSS total score in tests. There was a significant association between BW and responder and none-responder groups had significant BMI measured before and after 4-week AAP treatment association with BW and BMI increase. The same finding (P = 0.005 and 0.004 respectively). Patients with the -604 was also revealed when patients were subdivided accord- G/A exhibited significantly higher BWs and BMIs after ing the specific AAP taken. Atypical antipsychotics treatment (P = 0.028 and 0.011, respectively) (Table 9). induced weight gain in a significant fraction of SZ Similarly, paranoid SZ patients (n = 309) demonstrated patients [9], but factors that are predictive of weight gain greater WG and BMI increases (P = 0.020 and 0.011, during AAP therapy are unclear. We found that patients respectively). In addition, there were significant differences exhibiting the greatest weight gains while receiving olan- in the BW and BMI increases between G allele carriers zapine, risperidone, clozapine, or quetiapine also showed and homozygous allele A carriers in patients harboring greater improvements in symptoms than those showing SNP-604 G/A (P = 0.039 and 0.013, respectively). lower weight gain. This result is in partial accord with a previous study that found olanzapine-induced weight Discussion gain correlated negatively with baseline BMI and posi- The associations between GHRL polymorphisms and tively with clinical global improvement and the length of SZ risk, changes in weight/BMI, and therapeutic olanzapine treatment [39]. responses to AAPs were evaluated in a population of The GHRL gene may be a promising candidate under- SZ patients of Han Chinese ethnicity. While we found lying AP-induced weight gain [40]. We found significant no association between GHRL gene polymorphisms differences between the three -604 G/A genotypes, with and SZ susceptibility in this case-control study, analy- patients harboring AA showing the greatest weight gain sis did reveal significant BW and BMI increases during and increase in BMI. In addition to BMI, -604 G/A has AAP treatment in patients harboring the -604 G/A been linked to variations in blood pressure [12]. Pre- polymorphism. vious studies have also reported that the Leu72Met To our knowledge, no previous study has examined the polymorphism was significantly associated with BMI association between GHRL gene polymorphisms and sus- [10,11]. However, we found no association between ceptibility to SZ. Our study revealed no significant differ- Leu72Met polymorphisms and the AAP-induced BMI ences in allele and genotype frequency of four GHRL increase, consistent with previous findings [26,31,32]. In SNPs between schizophrenic patients and controls even addition to the significant association between the AA when patients were subdivided by gender. Thus, GHRL is genotype and BMI, we also found that paranoid SZ not a likely SZ risk gene despite the fact that it is in a sus- patients demonstrated higher weight gain than patients ceptibility locus (3p25-p26). Furthermore, we also exam- with other subtypes of SZ, including catatonic, collapse, ined paranoid SZ cases in light of the study by Scassellati residual, and undifferentiated patients. Therefore, our et al. [38]. Again, we found no significant differences in results provide suggestive evidencefor alinkbetween the frequency of these four SNPs or the genotype distribu- -604 G/A and metabolic syndrome in paranoid SZ. tion between paranoid patients and controls, but this Table 5 Estimated haplotype frequencies and case-control haplotype results SNP Haplotype Frequencies c P-value OR (95%CI) Global Cases Controls c P-value rs696217–rs26802 G-A 930.15(0.745) 883.02(0.742) 0.007 0.933 1.008(0.840~1.209) 0.022 0.989 G-C 103.85(0.083) 97.98(0.082) 0.004 0.952 1.009(0.756~1.346) T-A 213.85(0.171) 205.98(0.173) 0.020 0.888 0.985(0.798~1.216) Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 Table 6 Reduction of PANSS scores in patients with different GHRL genotypes ( x ± s ) SNP Genotype N Before treatment After 8 weeks treatment Reduction rate (%)* a b c a b c Total** P N G total P N G rs27647 GG 292 88.06 ± 21.64 24.49 ± 6.63 21.46 ± 8.00 42.11 ± 12.34 45.84 ± 12.63 10.87 ± 3.69 11.65 ± 4.85 23.32 ± 6.33 0.72 ± 0.19 GA+AA 88 87.38 ± 23.51 23.05 ± 6.92 22.81 ± 8.28 41.52 ± 13.4 45.40 ± 10.86 10.68 ± 3.53 12.24 ± 5.05 22.48 ± 4.88 0.72 ± 0.19 P 0.799 0.076 0.169 0.702 0.767 0.672 0.321 0.250 0.988 rs26802 AA 322 88.61 ± 22.47 24.35 ± 6.80 21.74 ± 8.26 42.52 ± 12.76 45.91 ± 12.47 10.90 ± 3.76 11.76 ± 4.97 23.25 ± 6.17 0.72 ± 0.19 AC+CC 58 83.97 ± 19.33 23.09 ± 6.16 21.91 ± 7.00 38.97 ± 11.20 44.79 ± 10.85 10.43 ± 2.96 11.93 ± 4.49 22.43 ± 5.15 0.72 ± 0.18 P 0.140 0.187 0.882 0.048 0.524 0.371 0.805 0.341 0.929 rs696217 GG 253 87.91 ± 22.94 24.23 ± 6.53 21.66 ± 8.36 42.02 ± 13.15 45.09 ± 11.31 10.63 ± 3.60 11.61 ± 4.70 22.85 ± 5.34 0.73 ± 0.18 GT+TT 120 87.65 ± 19.38 24.11 ± 6.96 21.82 ± 7.36 41.73 ± 10.91 45.97 ± 11.41 11.01 ± 3.31 11.74 ± 4.70 23.22 ± 6.10 0.71 ± 0.20 P 0.915 0.870 0.864 0.834 0.484 0.329 0.798 0.555 0.309 rs26311 CC 153 87.25 ± 22.59 24.09 ± 6.84 21.58 ± 7.52 41.58 ± 13.06 45.30 ± 11.10 10.85 ± 3.70 11.52 ± 4.52 22.93 ± 5.35 0.72 ± 0.19 GG+GC 223 87.66 ± 21.04 24.09 ± 6.59 21.74 ± 8.36 41.83 ± 11.82 46.01 ± 13.04 10.79 ± 3.63 11.96 ± 5.15 23.25 ± 6.49 0.72 ± 0.19 P 0.857 0.998 0.845 0.848 0.582 0.884 0.385 0.619 0.883 a b c *reduction rates of PANSS total scores; ** total scores; Positive score; negative score; general pathology score Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 Table 7 The BW and BMI change in responder group and none-responder groups a b c Two group N BW change ( ) kg BMI change ( ) x ± s x ± s responder group 339 0.68 ± 4.00 0.27 ± 1.47 none-responder group 41 -1.13 ± 2.35 -0.42 ± 0.87 P-value 0.000 0.000 Patients were divided into 2 groups based on reduction rates of PANSS total scores, namely, responder group (> 50%) and none-responder group (≤ 50%) Body weight change = body weight (4-week) - body weight(0 week) BMI change = BMI (4-week) - BMI (0 week) Table 8 The BW and BMI change in responder group and none-responder groups when subdivided according to different AAPs ( x ± s ) a b Two groups AAP N BW change (kg) P-value BMI change P-value responder group clozapine 63 0.60 ± 3.94 0.012 0.21 ± 1.41 0.009 risperidone 115 1.20 ± 3.71 0.46 ± 1.41 olanzapine 25 1.94 ± 4.47 0.76 ± 1.68 quetiapine 76 1.01 ± 3.41 0.37 ± 1.26 ziprasidone 32 -1.66 ± 4.78 -0.60 ± 1.74 aripiprazole 26 -0.67 ± 4.42 -0.19 ± 1.49 none-responder group clozapine 7 -1.57 ± 2.30 0.917 -0.55 ± 0.80 0.834 risperidone 11 -1.18 ± 1.99 -0.47 ± 0.79 olanzapine 5 -0.60 ± 1.82 -0.18 ± 0.62 quetiapine 8 -0.44 ± 2.87 -0.16 ± 1.07 ziprasidone 6 -1.5 ± 2.74 -0.56 ± 0.95 aripiprazole 3 -1.8 ± 3.69 -0.73 ± 1.42 responder group and none-responder group atypical antipsychotics treatment with AAPs. Surprisingly, patients showing Conclusion While we did not find an association between GHRL the greatest weight gain also showed the greatest improvements in symptoms. In order to more precisely alleles and susceptibility to SZ in the Chinese Han define the impact of antipsychotic medications on population, the -604 G/A polymorphism, and particu- metabolic parameters, control of patient subtype, sam- larly the AA genotype, was associated with larger ple size, as well as monitoring of multiple metabolic increases in BW and BMI in SZ patients under Table 9 The association analysis of BW and BMI in four SNPs SNP Genotype BW(0 week, kg) BW(4 week, kg) BW change (kg) BMI(0 week) BMI(4 week) BMI change rs27647 GG 62.69 ± 11.86 63.16 ± 11.19 0.55 ± 3.85 22.65 ± 3.60 22.84 ± 3.44 0.21 ± 1.42 AG 62.85 ± 12.44 62.87 ± 11.88 -0.18 ± 3.35 22.16 ± 3.59 22.13 ± 3.48 -0.04 ± 1.18 AA 58.4 ± 7.40 61.39 ± 10.25 2.61 ± 3.46 21.4 ± 2.91 23.05 ± 3.71 1.15 ± 1.21 P-value 0.426 0.810 0.028* 0.392 0.181 0.011* rs26802 AA 62.53 ± 12.13 62.90 ± 11.33 0.40 ± 3.79 22.54 ± 3.62 22.68 ± 3.45 0.17 ± 1.39 AC 63.35 ± 10.90 64.40 ± 11.28 0.87 ± 3.36 22.51 ± 3.54 22.95 ± 3.55 0.30 ± 1.21 CC 59.70 ± 9.78 56.8 ± 6.30 -2.9 ± 6.07 21.66 ± 2.03 20.68 ± 1.28 -0.97 ± 2.17 P-value 0.572 0.163 0.247 0.839 0.275 0.269 rs696217 GG 62.16 ± 11.75 62.77 ± 11.29 0.62 ± 3.60 22.33 ± 3.45 22.58 ± 3.37 0.24 ± 1.30 GT 63.57 ± 12.05 63.67 ± 11.08 0.10 ± 3.85 22.83 ± 3.57 22.86 ± 3.34 0.05 ± 1.41 TT 63.75 ± 15.14 63.67 ± 14.83 -0.08 ± 6.49 23.60 ± 6.07 23.60 ± 6.08 0.002 ± 2.51 P-value 0.446 0.589 0.319 0.358 0.676 0.254 rs26311 GG 63.30 ± 12.10 63.09 ± 10.36 0.41 ± 3.39 23.13 ± 3.74 23.12 ± 3.43 0.15 ± 1.28 GC 62.29 ± 12.25 62.89 ± 11.32 0.49 ± 3.90 22.63 ± 3.75 22.86 ± 3.48 0.20 ± 1.43 CC 62.77 ± 11.52 63.24 ± 11.65 0.41 ± 3.71 22.21 ± 3.34 22.39 ± 3.44 0.16 ± 1.34 P-value 0.792 0.925 0.804 0.343 0.344 0.765 Yang et al. Behavioral and Brain Functions 2012, 8:11 Page 8 of 9 http://www.behavioralandbrainfunctions.com/content/8/1/11 8. Herberth M, Koethe D, Cheng TM, Krzyszton ND, Schoeffmann S, Guest PC, indices during antipsychotic therapy are of paramount et al: Impaired glycolytic response in peripheral blood mononuclear cells importance. of first-onset antipsychotic-naive schizophrenia patients. Mol Psychiatry 2011, 16(8):848-859. 9. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, Abbreviations et al: Head-to-head comparisons of metabolic side effects of second SZ: Schizophrenia; GHRL: Ghrelin; WG: Weight gain; AAPs: Atypical generation antipsychotics in the treatment of schizophrenia: a antipsychotics; BMI: Body mass index; SNPs: Single nucleotide systematic review and meta-analysis. Schizophr Res 2010, 123(2-3):225-233. polymorphisms; BW: Body weight; DSM-IV: Diagnostic and statistical manual 10. Ando T, Ichimaru Y, Konjiki F, Shoji M, Komaki G: Variations in the of mental disorders fourth edition; PCR-RFLP: Polymerase chain reaction- preproghrelin gene correlate with higher body mass index, fat mass, based-restriction fragment length polymorphism; OR: Odds ratio; 95% CI: and body dissatisfaction in young Japanese women. Am J Clin Nutr 2007, 95% confidence intervals; LD: Linkage disequilibrium; ANOVA: Analysis of 86(1):25-32. variance; PANSS: Positive and negative symptom scale. 11. Kuzuya M, Ando F, Iguchi A, Shimokata H: Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large Acknowledgements cohort. Int J Obes (Lond) 2006, 30(11):1609-1614. We thank Zhaoxi ZHONG, Zheng ZHAO, Jun CHENG, Yunhong DU, Yuchun 12. Mager U, Kolehmainen M, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, LI, Yuling LI, Dexiang DUAN and Fang GUO(Department of Psychiatry of the et al: Association between ghrelin gene variations and blood pressure in Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, PR subjects with impaired glucose tolerance. Am J Hypertens 2006, China) for their works of collect the clinical materiales, and thank Yan RUAN, 19(9):920-926. Lifang WANG, Lei WANG, Tianlan LU, Jian QIN, Zhilin LUAN, Lin TIAN and 13. Choi HJ, Cho YM, Moon MK, Choi HH, Shin HD, Jang HC, et al: Hao YAN. (Institute of Mental Health, Peking University, Beijing, 100083, PR Polymorphisms in the ghrelin gene are associated with serum high- China) for their assistance in doing experiment. density lipoprotein cholesterol level and not with type 2 diabetes The research was supported by Ministry of Health Research Fund of the mellitus in Koreans. J Clin Endocrinol Metab 2006, 91(11):4657-4663. People’s Republic of China (Grant No.200801009), and the Supported by 14. Steinle NI, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR: Variants in the Program for Innovative Research Team (in Science and Technology) in ghrelin gene are associated with metabolic syndrome in the Old Order University of Henan Province (Grant No.2008IRTSTHN008), the National Amish. J Clin Endocrinol Metab 2005, 90(12):6672-6677. Natural Science Foundation of China (30530290, 81071090, 81071091), the 15. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is National High Technology Research and Development Program of China a growth-hormone-releasing acylated peptide from stomach. Nature (2009AA022702), the National Basic Research Program of China 1999, 402(6762):656-660. (2007CB512301). 16. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Bloom SR, et al: Ghrelin enhances appetite and increases food intake in humans. J Author details Clin Endocrinol Metab 2001, 86(12):5992. 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