Abstract P262: Evidence for association between SH2B1 gene variants and glycated hemoglobin in non-diabetic European American young adults: The Add Health study

Abstract

Introduction: Glycated hemoglobin (HbA1c) is a marker of long-term glycemic control, and elevated HbA1c is a risk factor for type 2 diabetes and cardiovascular disease. Few genome-wide association studies(GWAS) have been performed for HbA1c, although very large scale GWAS for obesity, a related trait, have identified multiple loci that have been widely replicated. We tested 43 single nucleotide polymorphisms (SNPs) from 41 well-established obesity susceptibility gene regions for association with HbA1c in a nationally representative sample of European American (EA), African American (AA) and Hispanic American (HA) young adults. Methods: We performed association analysis in race-stratified models using data from participants (age 24-34 years, median age=28 years) from the National Longitudinal Study of Adolescent Health (Add Health) Study (n = 5641 EA; n = 1740 AA; n = 1444 HA) without type 2 diabetes. We tested for additive genotype effects at each locus using linear mixed models, including a random intercept for school and family clusters, and two levels of covariate adjustment (model 1: age, sex, smoking, and geographic region; model 2: model 1 covariates plus BMI). We used Bonferroni adjustment for 43 SNPs and considered P < 0.0011 to be statistically significant. Results: Means (SD) for HbA1c % across the sample were 5.4(0.3) in EA, 5.7(0.4) in AA, and 5.5(0.3) in HA. We observed significant evidence for association with HbA1c for two SNPs near SH2B1 in EAs (rs4788102, P = 2.2x10-4; rs7359397, P = 9.8x10-4) for the model 1 adjustment, although both results were slightly attenuated after additional adjustment for BMI (rs4788102, P = 1.7x10-3; rs7359397, P = 4.6x10-3). No SNPs reached statistical significance after multiple test correction in either AAs or HAs. SH2B1 rs4788102 was nominally significant in AAs for the BMI-adjusted model (P = 0.02), although the estimated direction of effect was in the opposite direction as that observed in EAs. Conclusions: These results suggest that polymorphisms in the obesity gene SH2B1 , for which rare deletions and mutations have been observed in obese individuals with extremely high insulin resistance, are associated with HbA1c in EA young adults. Our findings further suggest these associations are largely independent of BMI.