Studies of Metabolic Phenotypic Correlates of 15 Obesity Associated Gene Variants

Abstract

AimsGenome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms.Methods15 gene variants in 14 loci including TMEM18 (rs7561317), SH2B1 (rs7498665), KCTD15 (rs29941), NEGR1 (rs2568958), ETV5 (rs7647305), BDNF (rs4923461, rs925946), SEC16B (rs10913469), FAIM2 (rs7138803), GNPDA2 (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes.ResultsFive of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15–1.20 for overweight, 1.10–1.25 for obesity, and 1.41–1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78–0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07–1.27, p = 7.8×10−4)).ConclusionsAssociations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI.

Obesity polymorphisms identified in genome-wide association studies interact with n-3 polyunsaturated fatty acid intake and modify the genetic association with adiposity phenotypes in Yup’ik people

“…The GRS is represented as a categorical variable with three groups by tertiles (T1-T3) where T1 is lowest obesity GRS and T3 is highest obesity GRS developing T2D in Yup'ik people due to our cross-sectional study design. Interestingly, we found the ETV5 (rs7647305) associations with adiposity phenotypes in Yup'ik people were ''opposite'' to those reported in participants of European ancestry (Elks et al 2010;Sandholt et al 2011). Although this lack of consistency can be attributed to type I error, theoretical modeling has argued that ''flip-flop'' association can be attributed to population differences that occur when the SNP of interest is correlated with the causal variant through linkage disequilibrium (Lin et al 2007).…”

“…In contrast to rs9939609 (FTO), candidate gene studies that have replicated the rs7647305 (ETV5) association with obesity remain limited (Elks et al 2010;Li et al 2011;Sandholt et al 2011). A prospective sample of 7,146 European children showed the ETV5 (rs7647305) SNP was associated with increased BMI and body weight (Elks et al 2010), and a cohort of 18,014 middle-aged Danish adults demonstrated the ETV5 (rs7647305) SNP was associated with increased odds of being overweight and/or obese (Sandholt et al 2011).…”

“…A prospective sample of 7,146 European children showed the ETV5 (rs7647305) SNP was associated with increased BMI and body weight (Elks et al 2010), and a cohort of 18,014 middle-aged Danish adults demonstrated the ETV5 (rs7647305) SNP was associated with increased odds of being overweight and/or obese (Sandholt et al 2011). Finally, a prospective study among 20,428 European adults with an average follow-up of 12.9 years demonstrated the ETV5 (rs7647305) SNP was associated with protection from developing T2D, and this association was stronger after correcting for BMI (Li et al 2011).…”

SH2B1 regulation of energy balance, body weight, and glucose metabolism

“…In agreement, SH2B1 rs4788102 is associated with type 2 diabetes after adjustment for BMI in Japanese [100] . SH2B1 rs7498665 is associated with increased risk for type 2 diabetes independently of BMI in middle aged Danes [122] . SH2B1 rs7359397 is associated with insulin resistance after adjustment of BMI in Sweden men at 71 years of age [123] .…”

Genetics of Obesity

“…In addition to associations between the SH2B1 and whole body fat mass in females (Jamshidi et al 2007;Hotta et al 2011), the distribution of body fat and the amount of visceral adipose tissue (Hotta et al 2011) and the amount of visceral fat area (Haupt et al 2010), SH2B1 variants have also been associated with type 2 diabetes independently of BMI (Sandholt et al 2011). Circulating GDF-15 concentrations are increased with type 2 diabetes (Dostálová et al 2009;Vila et al 2011), and GDF-15 predicts future insulin resistance glucose control (Kempf et al 2012).…”