Vitamin D deficiency has been consistently associated with obesity. However, it is unclear whether vitamin D deficiency is the cause or consequence of obesity. We investigated this question by evaluating the association between genetic variants in vitamin D metabolism pathway genes and obesity-related traits. Using directly genotyped and imputed data from a genome-wide association study of 6922 women aged 25–70 years, we examined the association of 198 single-nucleotide polymorphisms (SNPs) in vitamin D pathway genes (CYP27A1, CYP27B1, CYP24A1, CYP2R1, group-specific component (GC) and vitamin D nuclear receptor (VDR)) with body mass index (BMI) and body weight. Per allele beta (β) estimates were calculated for this association using linear regression models, controlling for age, square of age, menopausal status and sample sets. Overall, only two SNPs (rs2248359 in CYP24A1 and rs10832313 in CYP2R1) had a nominally significant association with BMI and weight (P<0.05 for all), with no variation observed by menopausal status, physical activity or dietary energy intake. None of the SNPs examined in the VDR gene were associated with BMI or weight. Our findings suggest that common genetic variants in vitamin D pathway genes do not have a major role in obesity among Chinese women. This comprehensive evaluation of genetic polymorphisms in vitamin D metabolism-related genes and obesity-related traits did not provide strong evidence to support low vitamin D levels as a cause of obesity.
Obesity is an epidemic worldwide and a potential risk factor for many chronic health conditions and diseases including cancer.1, 2 Obesity and high body mass index (BMI) have been shown to be correlated to vitamin D deficiency (low level of circulating 25-hydroxyvitamin D: 25(OH)D),2, 3 which may partially explain the role of obesity in the risk of cancer.4 However, the direction of the associations between circulating 25(OH)D and obesity is unknown. Lower levels of 25(OH)D may cause obesity.5 On the other hand, obesity may cause low levels of 25(OH)D, because of its volume of distribution according to body size and amount of adipose tissue.5, 6 Studies have found associations between vitamin D pathway gene polymorphisms and circulating 25(OH)D level.7, 8, 9 Genetic variants in vitamin D pathway genes, namely in the vitamin D nuclear receptor (VDR) gene, have been associated with obesity in some,10, 11, 12, 13 but not all studies.14, 15 Studies of other genes in the vitamin D pathway, including vitamin D binding protein (DBP) or group-specific component (GC), or CYP27B1 and BMI, have also produced inconsistent results.16, 17, 18 No epidemiological study to date has comprehensively investigated associations of the multiple genes directly involved in the vitamin D metabolism and signaling pathways with obesity-related traits. The present study aimed to evaluate the role of genetic variants in these genes with BMI and body weight using genome-wide association (GWA) scan data for approximately 7000 Chinese women.
Materials and methods
This study includes a total of 6922 women (aged 25–70 years) with both anthropometrics and genomic DNA samples who participated in three ongoing, GWA studies: (1) the Shanghai Breast Cancer Genetics Study (SBCGS),19 (2) the Shanghai Endometrial Cancer Genetics Study (SECGS),20 and (3) the Shanghai Diabetes Genetics Study (SDGS).21 Detailed methods for the GWA study19, 22 and its contributing studies have been described previously.19, 23, 24 Briefly, the SBCGS included 2903 breast cancer cases; the SECGS included 829 women with endometrial cancer; and the SDGS included 885 women with type 2 diabetes. Both the SECGS and SDGS used shared controls (n=2305) from the SBCGS, who were randomly selected from the general population and were free of cancer or diabetes (for the SDGS). All these studies used population-based designs and applied similar study protocols to collect blood cell or buccal samples and relevant exposure information. Interviews were conducted in-person by trained, retired medical personnel, and anthropometric parameters including height, weight and waist-to-hip ratio were measured according to a standard protocol. All studies were approved by all participating institutions, and participants provided written, informed consent.
SNP genotyping, selection and imputation
Genotyping was performed by using the Genome-Wide Human SNP Array 6.0 (Affymetrix Inc., Santa Clara, CA, USA), which includes 906 602 single-nucleotide polymorphisms (SNPs), as described in detail previously.19, 20 The six genes (CYP27A1, CYP27B1, CYP24A1, CYP2R1, GC and VDR) evaluated in this study were selected on the basis of their potential role in the vitamin D metabolism and signaling pathways, using literature review and the informatics tool, STRING 8.3 (http://string-db.org). A total of 198 SNPs (74 directly observed; 124 imputed) in these genes with a minor allele frequency⩾0.05 were included. Of the 198 SNPs, 13 SNPs in the CYP24A1, GC and CYP2R1 genes were associated with 25(OH)D level in the Insulin Resistance Atherosclerosis Family Study8 and in a recent GWA study7, 9 (Supplementary Table S1).
Descriptive statistics and genome-wide analyses were conducted within each sample set and in aggregate using SAS Version 9.1 (SAS Institute, Cary, NC, USA) and PLINK, respectively, as described previously.22 Linear regression was used to estimate the effect of genotypes on BMI (weight, kg/height, m2) or weight under an addictive genetic model controlling for age, square of age, menopausal status and sample set and disease status. For body weight associations, we also adjusted for height. P-values were not corrected for multiple comparison tests. Linkage disequilibrium was assessed by Haploview.
In general, subjects were comparable with a few exceptions (Table 1). The mean age of participants across the four sample sets ranged from 49.6 to 54.8 years. The mean BMI was 24.9 (range: 23.4–26.7 kg m−2 across sample sets). Cases with endometrial cancer were older and postmenopausal as a result of the late age of the disease onset. As compared with healthy controls and cases with breast cancer, cases with endometrial cancer were more likely to have lower educational attainment, followed by cases with type 2 diabetes. Cases with type 2 diabetes and endometrial cancer were more likely to be heavier or overweight/obese at study enrollment than healthy controls and breast cancer cases (P<0.05 for all). There were no differences in weight at age 20, caloric intake or regular exercise among the sample groups. Of the 198 SNPs examined, only two (rs2248359 CYP24A1 and rs10832313 CYP2R1) had a nominal association with BMI or weight in the combined sample set (P<0.05 for all, Table 2), but did not remain significant after accounting for multiple testing. A similar association was observed across each of the four sample sets. Further, in analyses stratified by menopausal status, physical activity or dietary energy intake, none of the polymorphisms were associated with BMI or weight (P interaction >0.05 for all, data not shown). Neither single markers nor haplotypes in the CYP27B1, CYP27A1, GC or VDR genes were associated with obesity. Previously identified genetic variants associated with circulating 25(OH)D level had no effect on BMI or weight in our population (Supplementary Table S1).
Association studies of genetic variants in vitamin D pathway genes and BMI or obesity-related traits are limited and inconsistent.15 Xu et al.25 observed a significant association between the VDR Apal (rs7975232) polymorphism and BMI among 260 healthy postmenopausal Chinese women. Jiang et al. found a significant association of the DBP rs17467825 polymorphism and its corresponding haplotype GAA with fat mass and percentage of fat mass among 1873 European-ancestry individuals aged 19–88 years, mainly among females.18 In another study, VDR (BsmI, rs1544410) was not associated with BMI in healthy postmenopausal Polish women (n=351) aged 50–60 years.14 In a recent study of 1773 healthy women aged 35–80 years from western New York state, USA, the VDR rs3782905 polymorphism was positively associated with adiposity markers.12 However, in our study, this association was not significant. All of the above studies had a relatively small sample size and investigated only a single gene or a few SNPs. In our large scale study, we comprehensively examined associations of multiple genes involved in the vitamin D metabolism pathway in relation to BMI or weight. In general, we found no strong evidence among Chinese women of altered risk of obesity for the 198 SNPs in the six genes we studied. The association of two SNPs (rs2248359 CYP24A1 and rs10832313 CYP2R1) with BMI or weight did not stand up after an adjustment for multiple comparisons, and thus, could be due to chance. There is a need to replicate this finding in other populations.
The strengths of this study include a large sample size, population-based design, high participation rates in the parent studies, racial homogeneity, standardized measurement of anthropometrics, comprehensive analysis of common genetic variants in the vitamin D metabolism, and signaling pathway and relevance to current topics of interest in obesity and nutrition-related research.
Obesity and adiposity have been linked to vitamin D deficiency,5, 6 but the direction of the association is unknown. The advantage of studying the genetic determinants of vitamin D level and obesity is that genetic factors precede obesity and do not change with obesity status. To our knowledge, this approach has not been previously applied in research on associations of obesity and vitamin D. Having no direct measurement for 25(OH)D level is a limitation of our study. This prevented us from evaluating whether the SNPs under study are indeed associated with circulating vitamin D level in our study population. Another limitation of the study is that we did not measure circulating calcium or parathyroid hormone levels or other factors, such as kidney function, that influence vitamin D metabolism. Parathyroid hormone upregulates enzyme CYP27B1, which converts 25(OH)D to its active form 1,25-dihydroxy vitamin D (1,25(OH)2D) in the kidney, and 1,25(OH)2D regulates calcium homeostasis.1 The general health of our study participants should also be considered in interpreting our results. About 66.7% of our study participants were diagnosed with cancer or diabetes, diseases that are related to obesity. We carried out additional analyses among healthy controls and each of the three subgroups (breast cancer, endometrial cancer and type 2 diabetes) and found similar null results (data not shown). Finally, our analysis was conducted in a Chinese population, and the results may not be directly generalizable to other ethnic populations. In conclusion, this large GWA study found no strong evidence for the effect of genetic variants in vitamin D metabolism and pathway genes on BMI or the risk of obesity in Chinese women.
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We thank all study participants and the research staff for their contributions and commitment to this study; R Courtney for DNA preparation; and B Rammer for editing of the manuscript. This study was supported in part by the US National Institutes of Health (Grants R01CA124558, R01CA064277, R37CA070867, R01CA090899 and R01CA092585). Sample preparation and genotyping were conducted at the Vanderbilt Microarray Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (Grant P30 CA68485).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on International Journal of Obesity website
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Dorjgochoo, T., Shi, J., Gao, Y. et al. Genetic variants in vitamin D metabolism-related genes and body mass index: analysis of genome-wide scan data of approximately 7000 Chinese women. Int J Obes 36, 1252–1255 (2012) doi:10.1038/ijo.2011.246
- genetic variants
- body mass index
- body weight
- vitamin D pathway
- genome-wide association study
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