A common polymorphism is associated with body mass index in Uyghur population

diabetes research and clinical practice 81 (2008) e11–e13

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A common polymorphism is associated with body mass index in Uyghur population Jun Zhang a,1, Rong Lin a,1, Fen Wang b, Ming Lu b, Ren-yong Lin c, Shi-zhen Wang c, Hao Wen c, Li Jin a, Xiao-feng Wang a,* a

MOE Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China b Clinical Epidemiology Units, Qilu Hospital of Shandong University, Jinan, China c Medical Research Center, First Affiliated Hospital, Xinjiang Medical University, Urumqi, China

article info

abstract

Article history:

We aimed at observing the association of a common genetic variant near the INSIG2 gene

Received 5 November 2007

(rs7655505) with body mass index (BMI) related obesity in a population-based association

Accepted 26 March 2008

study in Uyghur population. We observed a significant association of rs7566605 polymorph-

Published on line 2 June 2008

ism with BMI related obesity in Uyghurs with an odds ratio of 1.47 (95% CI 1.11–1.95, P = 0.006) under a dominant model (CC + GC versus GG). The mean BMI of rs7566605 CC + GC

Keywords:

was 0.59 kg/m2 higher than for GG genotype (P = 0.024), regardless of sex and age. # 2008 Elsevier Ireland Ltd. All rights reserved.

Uyghur Polymorphism Body mass index Obesity Association study

Up to now, a large number of candidate genes have been suggested to be involved in the development of human obesity, but none is associated with obesity strongly and consistently. Recently, Herbert et al. used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant (rs7655505), located 10 kb upstream of INSIG2, associated with BMI. They further observed the association in four of five separate samples composed of individuals of Western European ancestry and African Americans [1]. Since the obesity-predisposing genotype is present in 10% of individuals, they suggested that this common genetic polymorphism is important determinants of obesity. However, this positive finding was not replicated by three other extensive

association studies in Caucasians [2–4]. In this study, we aimed at replicating the association of rs7655505 with BMI in a Chinese minority group—Uyghurs with an admixed genetic background of Caucasian (42.6%) and Asian (57.4%) [5]. This study is designed to address cardiovascular risk factors in six village of Tulupan District which is located in the Xinjiang Uyghur Autonomous Region at northwest China. A total of 1271 Uyghur farmers aged 30–87 (51.8 in average) year were randomly recruited in March to May of 2005 and April of 2006. Eight subjects whose data were incomplete were excluded from further analysis. Overweight was defined as a body mass index (BMI) greater than or equal to 25 kg/m2, and obesity was defined as a BMI greater than or equal to 30 kg/m. In this study, 39% of all

* Corresponding author at: School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China. Tel.: +86 21 65643714; fax: +86 21 65642426. E-mail address: [email protected] (X.-f. Wang). 1 These authors contributed equally. 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.03.022

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diabetes research and clinical practice 81 (2008) e11–e13

Table 1 – Association between rs7566605 and BMI in Uyghurs Phenotype

Non-obese Obese

Genotype frequency (%)

Allele frequency (%)

GG

GC

CC

P-value

G

C

P-value

470 (0.48) 99 (0.39)

421 (0.43) 135 (0.52)

91 (0.09) 24 (0.09)

0.018

1361 (0.69) 333 (0.65)

603 (0.31) 183 (0.35)

0.039

Table 2 – Odds ratios for BMI related obesity for dominant model in Uyghurs Phenotype

Non-obese Obese

Genotype frequency (%) GG

GC + CC

470 (0.48) 99 (0.38)

512 (0.52) 159 (0.62)

Crude OR (95% CI)

P-value

Adjusted OR (95% CI)

1.47 (1.11–1.95)

0.006

1.20 (1.04–1.38)

P-value

0.012

Adjusted OR: adjusted for age and sex.

participants were overweight and 21% were obese. To mimic the original findings, the samples were dichotomized into obese (BMI 30 kg/m2) and non-obese (BMI <30 kg/m2) individuals. Waist hip ratio (WHR) was calculated by dividing waist circumference by hip circumference. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by two cardiologist and fasting glucose, triglyceride, and total cholesterol levels were analyzed for every subject. Informed consents were obtained from all subjects in this study. The Human Ethnics Committee of Xinjiang Medical University approved the research. Genotyping for rs7566606 variants were accomplished by using a TaqMan assays (Applied Biosystems, Foster City). Sample DNA (10 ng) was amplified by PCR following the recommendations of the manufacturer. Fluorescence was detected using an ABI 7900HT and the alleles were scored using Sequence Detection Software (ABI). The assay ID of the Taqman probes of rs7566605 is C- 29404113-20. A logistic regression analyses and linear models were performed with an adjustment for age and sex. In post-hoc analyses, we applied the recessive model, and the dominant model. Genotyping of the rs7566605 polymorphism was successful in 1240 of 1263 individuals (98.2%). Genotype frequencies were compatible with Hardy–Weinberg expectation. The frequency of C allele is significantly higher in obese subjects (35%) than in non-obese subjects (31%) (Table 1). We did not observe significant association between rs7566605 and obesity under a recessive model (CC versus GC + GG) in Uyghurs. However, we observed a significant association under a dominant model (CC + GC versus GG) with an odds ratio of 1.47 (95% CI 1.11 to 1.95, P = 0.006). (Table 2). The mean BMI of CC + GC was 0.59 kg/

m2 higher than that for GG genotype (P = 0.024). After adjustment for age and sex, the significance remained (P = 0.049) (Table 3). Furthermore, we did not observe significant differences between subjects of GG and CC + GC genotypes and WHR, SBP, DBP, glucose, triglyceride, and cholesterol levels at rs7566605 (Table 3). In the present study, we found rs7566605 is associated with BMI related obesity in a Chinese minority group—Uyghurs. To our knowledge, this is the first association study reported in Asian on the association of rs7566605 with obesity. Our results did not fully replicate the findings made by Herbert et al. [1]. Herbert et al. found that under a recessive model, CC had an increased risk of obesity. Mean BMI of CC homozygote were 1 kg/m2 higher than for GC and GG genotypes combined. In the Uyghur population, however, under a dominant model, but not a recessive model, CC + GC had an increased risk of obesity than GG. Mean BMI of CC + GC carriers were 0.59 kg/m2 higher than for GG carriers. The obesity predisposing genotypes (CC + GC) were present in about a half of Uyghur individuals in contrast to 10% of the original finding made by Herbert et al. [1]. The other three large-scale association studies in Caucasians made even conflicting results versus the original one. Dina et al. [2] attempted to replicate this result combining family-based, case-control, and general population studies, but found no support for a major role of this variant in obesity. Loos et al. [3] found no evidence of association between rs7566605 and BMI in two large ethnically homogeneous population-based cohorts. On the contrary, they observed an opposite tendency. In 10,265 individuals, Rosskopf et al. [4] did not observe a significantly increased risk for obesity in a large

Table 3 – Clinical parameters according to rs7566605 genotypes in Uyghurs Phenotype

GC + CC

GG

P-value

BMI WHR SBP DBP Glucose Triglyceride Cholesterol

26.82  4.51 0.89  0.08 138.84  27.80 84.58  15.10 5.73  1.91 1.62  1.15 4.54  1.07

26.23  4.52 0.89  0.09 138.91  28.77 83.96  15.28 5.73  1.89 1.53  1.11 4.50  1.06

0.024 0.40 0.97 0.48 0.98 0.17 0.57

Adjusted P: adjusted for age and sex.

Adjusted P-value 0.049 0.65 0.89 0.58 0.96 0.24 0.89

diabetes research and clinical practice 81 (2008) e11–e13

cross-sectional study. But interestingly, in a subgroup analysis, they revealed that this allele significantly increased the risk for obesity in already overweight individuals. What could be the possible reasons that the association between rs7566605 and BMI is inconsistent in different cohorts? The differences in genetic background might be a factor [6]. Uyghur population is a genetic admixture of Caucasian and East Asian [5] which is different from that of Western Europeans. At the rs7566605, different frequency of C allele could be observed among different ethnic groups. As could be seen from the data of the International Hapmap Projects [7] and Herbert et al. [1], the frequencies of C allele of rs7566605 polymorphism were 28%, 36%, and 41% in American White, Chinese Han’s, Japanese, and African, respectively, Which were 37% and 31% in Western European ancestry [1]. In Uyghur population, it is 23%. Taken together, our data support a statistically significant association of the rs7566605 polymorphism with obesity for the Uyghur sample. Therefore, rs7566605 could be considered as a predictor of BMI in Uyghurs. However, based on several conflicting observations, the role of this polymorphism on obesity requires further verification in independent samples and extensive functional studies.

Acknowledgements This work was supported by a grant from 05pj14023, a grant from NSFC (30500291), and a grant from SDSTC (2006BS03022).

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Conflict of interest There are no conflicts of interest.

references

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