Variation in the Resistin Gene is Associated with Diabetes-Related Phenotypes in Finns
Conneely, K.N., Silander, K., Lazaridis, K.N., Mohlke, K.L., Scott, L.J., Valle, T.T., Watanabe, R.M., Buchanan, T.A., Bergman, R.N., Tuomilehto, J., Collins, F.S., Boehnke, M.
Resistin is a peptide hormone produced by adipocytes that is present at higher levels in obese mice and may be involved in glucose homeostasis, possibly through regulation of insulin sensitivity. Human studies have found associations between polymorphisms of the resistin gene and BMI, insulin-related variables, and blood pressure. Associations between resistin and type 2 diabetes (T2D) have been reported, but not in all studies. The aim of the Finland-U.S. Investigation of NIDDM Genetics (FUSION) Study is to identify genetic variants that contribute to the development of T2D. We analyzed 781 T2D cases and 409 controls for association between resistin and T2D and related traits. Three previously identified common, non-coding SNPs were typed: one from the promoter region (-420C>G) and two from intron 2 (+156C>T, +298G>A). The three SNPs were in strong linkage disequilibrium and formed two main haplotypes: CCG (76.9%) and GTA (21.6%). We found no significant association between the SNPs and T2D (p>.55), but did find associations with T2D-related phenotypes. For cases, the number of copies of the CCG haplotype was positively associated with weight-related traits. Mean BMI was 29.0, 29.6, and 30.4 kg/m2 for cases with 0, 1, or 2 copies of CCG (p=.025, all tests based on age-sex adjusted additive effects of haplotypes on transformed variables.) Mean waist circumference was 99.5, 101.0, and 103.9 cm for cases with 0, 1, or 2 copies of CCG (p=.001). Positive associations were also found for weight (p=.006), weight change since age 20 (p=.014), and waist-hip ratio (p=.022). We saw similar results for individual SNPs. For controls, the C allele of SNP -420C>G was associated with lower insulin sensitivity (p=.008) and higher acute insulin response (p=.017) assessed by intravenous glucose tolerance test. Our results provide evidence that resistin is associated with variation in weight, fat distribution, and insulin resistance.
1st category: Genetic Epidemiology and Population Genetics
2nd category: Linkage Mapping and Polymorphisms
Keywords: genotype-phenotype correlation, mapping complex traits, phenotype, identification of disease genes, polymorphism