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Background: The leptin receptor gene (LEPR) polymorphism Q223R is one of the most common in the general population, and is thought to be associated with an impaired signaling capacity of the leptin receptor and with higher mean circulating levels of leptin. Leptin is a hormone primarily produced in adipose tissue. Increased levels of leptin have been positively correlated with obesity. We have determined the frequency of the leptin receptor polymorphism (LEPR Q223R) in healthy populations from various ethnic groups, and compared plasma leptin levels across the LEPR Q223R polymorphism in healthy African-Caribbean and Caucasian women. Results: The study population consists of 1,418 healthy subjects from various ethnic groups. The LEPR Q223R homozygous variant was observed overall in 19% of subjects (n = 1,418), with significant differences based on self reported ethnicity: the proportion of subjects with the homozygous variant was lower in Caucasians (14%, n = 883) than in African-Caribbean (n = 194), African-American (n = 36) and Asian/other ethnic groups (n = 26), (35%, 33% and 34.6% respectively); the frequency in Africans (20%), was similar to the overall study population. The mean ± standard deviation (SD), circulating leptin levels for African-Caribbean women was 44.7 ± 31.4 ng/ml, while for Caucasian women the mean was 42.4 ± 34.8 ng/ml. Adjusted circulating leptin levels in post-menopausal Caucasian women who were LEPR Q223R homozygous variant were marginally statistically significantly higher than in women with the wild-type genotype (p = 0.098). No significant differences in leptin levels by genotype were observed for African-Caribbean women, (heterozygous: p = 0.765, homozygous variant: p = 0.485). Conclusion: These findings suggest an association between mean circulating leptin levels and the LEPR Q223R genotype among post-menopausal Caucasian women. Page 1 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S13 http://www.infectagentscancer.com/content/4/S1/S13 of susceptibility ; African-American and African sub- Introduction Leptin, a product of the ob gene, is a biologically active jects were part of a study on ethnic differences in polymor- polypeptide (16 kDa) primarily produced in adipose tis- phisms of genes involved in tobacco metabolism ; sue . Increased levels of leptin have been shown to cor- African-Caribbean subjects were recruited as part of a relate with obesity , a known risk factor for study on cervical and oral HPV infection . Ethnicity postmenopausal breast cancer [3-7]. Some studies have for all subjects was self-reported. Nineteen of the 26 Asian reported that leptin stimulates the proliferation of normal subjects were recruited from the Caribbean but self- and malignant breast epithelial cells  and others have reported their ethnicity as East Indian. suggested that leptin levels may be associated with breast cancer [9,10] as well as cancer at other sites . Leptin Women had no history of hormone replacement therapy binds to the human leptin receptor, a cytokine receptor (HRT) as determined from questionnaire data. There were that promotes gene transcription via activating signal 6 African-Caribbean women and one Asian who reported transduction pathways . The function of leptin is ever HRT users and for 36 African-Caribbean and two mediated through the leptin receptor, and both leptin and Asian women HRT use was not reported. Menopausal sta- its receptor are involved in the homeostatic control of tus was determined by using a self reported questionnaire appetite, weight, metabolism and reproductive functions on whether their menses has stopped and/or date at the in women . A number of polymorphisms have been last menstrual cycle. If the date of last menstruation was reported in the human LEPR gene . The LEPR poly- prior to six months from recruitment, women were con- morphism Q223R is one of the most common and is sidered post-menopausal. One subject who reported that thought to be associated with an impaired signaling her menses stopped 3 months before recruitment was capacity of the leptin receptor; this polymorphism has included in the post-menopausal group. Twenty-nine 29 been associated with higher mean circulating levels of lep- African-Caribbean women responses were missing there- tin [15,16]. fore were unable to define their menopausal status. We have previously conducted a meta-analysis (n = 18 Leptin levels studies) to examine the frequencies of LEPR polymor- Nonfasting plasma leptin levels were determined for a subpopulation of women (N = 574) using a commercially phisms in the general population . From this analysis of the literature, it became apparent that only one study available leptin ELISA kit (Biosource International, included subjects of African ancestry; however, this study Camarilli, CA, USA). Batches were performed using 96 sample was predominantly Caucasian . Although well plates which included ~38 samples, 8 leptin stand- research has been conducted on circulating leptin levels ards and quality controls. Forty blinded duplicates were among healthy populations of women including women included as a means of assessing the reliability of the of African descent [18-24], few studies have evaluated assay. Each sample was run in duplicate within the same mean circulating leptin levels according to the LEPR plate and a coefficient of variation (CV) was calculated. Q223R genotype [15,16,25] among healthy populations All CV's greater than 15% were repeated. The average of of women. Furthermore, no previous study has evaluated the two leptin measurements was used for this analysis. leptin levels by the LEPR Q223R polymorphism among African-Caribbean women. LEPR Q223R genotyping DNA was extracted from blood samples and the allelic fre- In this study, we have determined the frequency of leptin quency of LEPR Q223R was evaluated for all subjects by receptor polymorphism (LEPR Q223R) in healthy popu- polymerase chain reaction (PCR) of the extracted DNA, lations from various ethnic groups (African, African- followed by MspI restriction enzyme digestion. The PCR American, African-Caribbean, Caucasian, Asian/and other primers and cycling conditions used have been previously ethnic groups). We have also compared the LEPR Q223R published . Briefly, amplification of the 80bp LEPR polymorphism with plasma leptin levels in healthy Afri- PCR product was visualized following PCR amplification can-Caribbean and Caucasian women. and agarose gel electrophoreses. The amplified product was then subjected to MspI restriction enzyme digestion at 37°C overnight. Samples from subjects with the wild-type Materials and methods Study population gene yielded an 80bp DNA band after MspI digestion. A The study population consists of 1,418 healthy subjects heterozygous subject sample was indicated by 80 bp, 58 (883 Caucasians, 279 Africans, 36 African-Americans, 194 bp and 22 bp PCR products while a homozygous variant African-Caribbean, 26 Asian/other ethnic groups). Cauca- was indicated by 8 bp and 22 bp PCR products only. sian subjects were recruited as part of a study on hormo- Twenty samples were randomly chosen and repeated in nal determinants of mammographic density  as well blind fashion to assess the reproducibility of the method. as a study of hormones, bone density and genetic markers Page 2 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S13 http://www.infectagentscancer.com/content/4/S1/S13 Statistical analysis leptin level of 43.5 ± 33.3 ng/ml. A summary of the mean Statistical analyses were performed using STATA (version plasma leptin levels stratified by menopausal status is SE 10.0) software (StataCorp. LP, College Station, TX). shown in Table 2. Caucasian and African-American popu- Pearson's and the likelihood-ratio chi-squared test were lations consisted of post-menopausal women only, with used to assess Hardy-Weinberg equilibrium. Leptin levels an overall mean circulating leptin level of 42.4 ± 34.8 ng/ were square root transformed in order to obtain a normal ml and 61.1 ± 26.7, respectively ng/ml. Mean age was distribution for parametric tests. The independent effect available for all ethnic groups (African: 44.7 years, Afri- of body mass index, age, menopausal status and LEPR can-American: 46.5 years, Caribbean: 41.1 years, Cauca- genotype on leptin levels by ethnic group was assessed sian: 50.1 years and Asian/other ethnic groups: 43.7 using a two-way analysis of variance (ANOVA). years), but body mass index (BMI) was not available for the Caribbean population (African: 24.7 kg/m , African- 2 2 American: 28.9 kg/m , Caucasian: 26.2 kg/m and Asian/ Results LEPR Q223R polymorphism distribution other ethnic groups: 24.7 kg/m ). After adjusting the The LEPR Q223R genotype frequency based on ethnicity transformed mean leptin levels for age and BMI, the mean is summarized in Table 1. For the overall study popula- circulating plasma leptin level for African-Americans was tion, the frequency of the heterozygous (GA) and marginally statistically significantly higher than Cauca- homozygous (AA) variants was 50% and 18.97% respec- sians women (p = 0.07). All other ethnic groups consisted tively and significant differences were observed based on of both pre- and post-menopausal women. African-Carib- ethnicity (p < 0.0001). bean women had a mean overall plasma leptin level of 44.7 ± 31.4 ng/ml (pre-menopausal = 41.8 ± 27.8 ng/ml Higher frequencies of the AA variant was observed among vs. post-menopausal subjects = 51.7 ± 38.2 ng/ml, African-Caribbean 35.1%), African-Americans (33.3%) adjusted transformed mean comparisons: p > 0.1). The and Asian/Other subjects (34.6%) as compared to the overall mean levels observed in African-Caribbean overall study population. In contrast, Caucasian subjects women were statistically significantly higher than Cauca- had the lowest frequency of the AA variant (14.2%); the sian women after adjusting for age (p = 0.04); body mass frequency of the AA variant in Africans was similar to the index data was not available for the African-Caribbean overall study population. women. For Asian and other ethnic groups, the mean overall plasma leptin level was 35.3 ± 26.3 ng/ml (pre- We observed no violation of Hardy Hardy-Weinberg equi- menopausal = 37.9 ± 30.4 ng/ml; post-menopausal = 31.6 librium for either the overall study population or after ± 20.0 ng/ml). After adjusting for age and BMI, the mean stratification by ethnic groups (p > 0.1). The highest pro- transformed levels observed for post-menopausal Asian/ portion of subjects with the heterozygous (GA) variant other women was not statistical significantly different was observed in African subjects (55.7%), while Cauca- from that of Caucasians (p > 0.1). For pre-menopausal sian subjects had the lowest frequency of the GA variant women we did not observe a statistically significant differ- (47.9%). ence between African-Caribbean and Asian/other ethnic groups, after adjusting for age (p = 0.15). Circulating plasma leptin levels in females Plasma leptin levels were available for 574 female subject Circulating leptin levels and LEPR Q223R genotype (149 pre-menopausal and 425 post-menopausal). These Figure 1 shows the mean circulating leptin levels in Afri- included 340 Caucasians and 19 African-Americans post- can-Caribbean women stratified by LEPR Q223R geno- menopausal women, 191 African-Caribbean women type. Comparisons of the transformed mean circulating (135: pre-menopausal and 56: post-menopausal), and 24 leptin levels stratified by LEPR Q223R genotype was women of Asian and other ethnic derivations (14: pre- accomplished after adjusting for age and menopausal sta- menopausal and 10: post-menopausal). For the entire tus (BMI data was not available for these subjects). For study population, we observed a mean circulating plasma subjects with the wild-type (GG) genotype the mean cir- Table 1: Distribution of the LEPR Q223R genotype across ethnic groups. LEPR Q223R African African-American N African-Caribbean N Caucasian N (%) Asian/Other N (%) TOTAL N (%) (%) (%) N (%) GG 69 (24.73) 6 (16.67) 26 (13.40) 335 (37.94) 4 (15.38) 440 (31.03) GA 155 (55.56) 18 (50.00) 100 (51.55) 423 (47.90) 13 (50.00) 709 (50.00) AA 55 (19.71) 12 (33.33) 68 (35.05) 125 (14.16) 9 (34.62) 269 (18.97) Total 279 (100) 36 (100) 194 (100) 883 (100) 26 (100) 1,418 (100) Page 3 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S13 http://www.infectagentscancer.com/content/4/S1/S13 Table 2: Mean circulating leptin levels according to ethnicity and menopausal status. Mean plasma Leptin levels ± SD Race/Ethnicity Pre-menopausal N Post-menopausal N p-value African-American (N = 19) - - 61.1 ng/ml ± 26.7 19 0.074* African-Caribbean (N = 191) 41.8 ng/ml ± 27.8 135 51.7 ng/ml ± 38.2 56 0.039** Caucasian (N = 340) - - 42.4 ng/ml ± 34.8 340 Asian/Other (N = 24) 37.9 ng/ml ± 30.4 14 31.6 ng/ml ± 20.0 10 0.427* The p-values presented are for post-menopausal women, calculated with Caucasians as the reference group and *adjusted for body mass index and age; **adjusted for age only (BMI was not available fore these subjects). SD = standard deviation, N = number. culating leptin levels were 43.1 ± 35.6 ng/ml, while the jects with the heterozygous and wild-type variants heterozygous (GA) and homozygous (AA) variants had (adjusted p > 0.1). Although higher leptin levels were mean leptin levels of 44.9 ± 32.2 ng/ml and 44.4 ± 28.7 observed among African Americans there was no statisti- ng/ml, respectively. These mean plasma leptin levels were cally significant difference observed when stratified by not statistically significantly different from each other genotype; however, there were only 19 African-American (adjusted p > 0.1). There were no statistically significant subjects (adjusted p > 0.1). differences in mean leptin levels across the LEPRQ223R genotype variants among pre-menopausal African-Carib- Discussion bean women (GG: 41.5 ± 31 ng/ml, GA: 42.9 ± 26.9 ng/ To our knowledge, we have for the first time described the ml, AA: 39.1 ± 28.0 ng/ml, adjusted p > 0.1). In post-men- frequency of the LEPR Q223R variant in healthy popula- opausal women mean leptin levels were higher for the tions of various ethnic groups. We have also compared the variant genotypes, but they were not statistically signifi- genotype frequency in a subset of female subjects with cantly different (GG: 47.5 ± 49.4 ng/ml, GA: 50.9 ± 44.3 their mean circulating leptin levels. We observe statisti- ng/ml, AA: 53.7 ± 28.0 ng/ml, adjusted p > 0.1) (Figure 2). cally significant differences in genotype frequency and mean circulating leptin levels based on ethnicity. African- Leptin levels were compared in post-menopausal African- Caribbean and African-American subjects had higher fre- Caribbean women and post-menopausal Caucasian and quencies of the AA homozygous variant compared to Cau- African-American women (Figure 2); in general, African- casian and African subjects. Since ethnicity was self- Americans had higher leptin levels, while Caucasian reported, it is difficult to evaluate the degree and type of women had lower leptin levels. After adjusting for age and admixture present in the populations of African descent BMI, post-menopausal Caucasian women carrying the (African-American and African-Caribbean). The analysis homozygous (AA) variant genotype had marginally statis- of the available African populations present in our study tically significantly higher leptin levels than women with indicates that there is a great variability in the LEPR the wild-type genotype (52.1 ± 45.4 ng/ml vs. 40.2 ± 32.9 homozygous variant frequency in Africa, with Nigerian ng/ml, adjusted p = 0.056). There was no statistically sig- subjects having a higher frequency (21%) than subjects nificant difference in leptin levels between Caucasian sub- from Mali (12%). It is possible that the geographic areas from which the African populations were taken during the slave trades could influence the variations in the LEPR gene frequency in populations of African descent. For example, historical data seem to indicate that a higher proportion of slaves were taken to the US and Caribbean from Nigeria rather than Mali . 20 Among post-menopausal women, we observed significant differences in the mean plasma leptin levels between Cau- casians (42.4 ng/ml) and subjects of African Ancestry (African-Americans: 61.1 ng/ml, African-Caribbeans: 51.7 GG GA AA ng/ml). These observed differences may be partly due to LEPR Q223R differences in overall body mass index in these popula- tions . In our study, average BMI in African-American Mean circulating le ty Figure 1 pe in African-Caribbean wom ptin levels acco enrding to LEPR Q223R geno- post-menopausal women was statistically significantly Mean circulating leptin levels according to LEPR Q223R geno- type in African-Caribbean women. higher than BMI in Caucasians (data not shown). The role of BMI in determining the differences in leptin levels Page 4 of 6 (page number not for citation purposes) Mean Plasma Leptin levels (ng/ml) Infectious Agents and Cancer 2009, 4(Suppl 1):S13 http://www.infectagentscancer.com/content/4/S1/S13 Authors' contributions CD, CR, ET, FM, MO and SG contributed the samples and corresponding data sets that were included in this analy- sis. CR performed the data analysis and JC performed the laboratory testing. Caucasian African-Caribbean Acknowledgements African-American This work is supported in part by NIH/R13 CA130596A and also in part by the UPCI Cancer Education and Career Development NIH/NCI R25CA089507 awards to C.R, the 1 P20 CA132385-01 to ET, and R25 CA57703 to CD. This work was also supported in part by the Department of Defense grant number DAMD17-02-1-0553, the Pennsylvania Depart- ment of Health grant number P2777693, and NIH/NCRR General Clinical GG GA AA Research Center grant MO1-RR000056 to FMM. 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Obes Res 2004, 12:1680-1689. scientist can read your work free of charge 33. Lovejoy JC, Windhauser MM, Rood JC, de la Bretonne JA: Effect of a controlled high-fat versus low-fat diet on insulin sensitivity "BioMed Central will be the most significant development for and leptin levels in African-American and Caucasian women. disseminating the results of biomedical researc h in our lifetime." Metabolism 1998, 47:1520-1524. Sir Paul Nurse, Cancer Research UK 34. Havel PJ, Townsend R, Chaump L, Teff K: High-fat meals reduce 24-h circulating leptin concentrations in women. Diabetes Your research papers will be: 1999, 48:334-341. available free of charge to the entire biomedical community 35. Koutsari C, Karpe F, Humphreys SM, Frayn KN, Hardman AE: Plasma leptin is influenced by diet composition and exercise. peer reviewed and published immediately upon acceptance Int J Obes Relat Metab Disord 2003, 27:901-906. cited in PubMed and archived on PubMed Central 36. Mammes O, Betoulle D, Aubert R, Giraud V, Tuzet S, Petiet A, et al.: Novel polymorphisms in the 5' region of the LEP gene: asso- yours — you keep the copyright ciation with leptin levels and response to low-calorie diet in BioMedcentral human obesity. Diabetes 1998, 47:487-489. Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes)
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