Association of genetic variants in the FTO, INSIG2 and GCK genes with BMI or obesity in family-based population

Background Obesity has become the most common human disorder and poses a serious threat to public health through its association with diabetes, hypertension, cardiovascular disease, and cancer. Family and twin studies have shown that genetic factors contribute 40--70% to the variation in common obesity. Recently, genome-wide association studies revealed the associations of several SNPs in FTO, INSIG2 or GCK with BMI or obesity. However, the results haven't been consistently replicated in later studies. In this study, we aimed to investigate the associations between three genetic variants and BMI or obesity in a family-based population.Methods The investigators genotyped 3 SNPs (FTO rs9939609, INSIG2 rs7566605, GCK rs1799884) in a randomly selected family-based population. We first analyzed their associations with BMI or obesity using FBAT. Then we analyzed their associations with the binary obesity status (BMI>=30 kg/m2) using a GEE model and quantitative BMI using a linear mixed model.Results (1) The minor allele frequencies of FTO rs9939609, INSIG2 rs7566605 and GCK rs1799884 genes in this population were 0.46, 0.28 and 0.17, respectively. (2) Under FBAT, the C allele of rs7566605 was strongly associated with obesity (p=0.008) and BMI (p=0.012). (3) Under the GEE model, rs7566605 SNP was significantly associated with obesity (OR=2.08, P<0.001), and the genotypic odds ratio for obesity was 2.31 (P=0.007) of CC genotype and 2.03 (P<0.001) of CG genotype. INSIG2 conferred more obesity risk in male than in female (OR=1.96, P=0.003). (4) In European Americans, rs7566605 was significantly associated with obesity (OR=1.35, p=0.039). In African Americans, rs7566605 was significantly associated with obesity (OR=1.46, p=0.023), and the genotypic odds ratio for obesity was 1.26 (p=0.019) of CG genotype. (5) Under the linear mixed model, there was a borderline significant association between rs7566605 and increased BMI (p=0.076) and the genotypic association of CG was also marginally significant (p=0.056). (6) In African Americans, there was a significant association between rs1799884 and increased BMI (p=0.026), while in European Americans, the association between rs1799884 and decreased BMI was significant (p=0.038). The association between rs7566605 and increased BMI was also significant (p=0.036), and the genotypic association of CC was significant (p=0.045) in both African and European Americans.Conclusions The C allele of INSIG2 rs7566605 is strongly associated with obesity and BMI, and it confers more obesity risk in males than in females. Moreover, INSIG2 rs7566605 confers obesity risk in tobacco-dependence population but not in tobacco independence population. GCK rs1799884 is significantly associated with increased BMI in African Americans but with decreased BMI in European Americans. There is no significant association between FTO rs9939609 and obesity or BMI.