Abstract 14908: Genetic Variants Involved in Telomere Maintenance and Type 2 Diabetes in American Indians: A Pathway Association Analysis
Background: Type 2 diabetes (T2D) is highly prevalent among American Indians. Telomeres shorten significantly with age, providing a marker for cellular aging and age-related disorders including T2D. Existing studies primarily focused on single gene analysis, but the joint contribution of multiple genes may explain more trait heritability than that of a single gene.
Objective: To examine the joint association of 46 tagging SNPs in 8 genes involved in telomere regulation with T2D in American Indians participating in the Strong Heart Study (SHS).
Methods: Forty-six tagging SNPs in eight genes involved in telomere metabolism, including TERT, TERC, TNKS, TNKS2, POT1, OBFC1, TEP1 and KLHL33, were genotyped in 1,221 American Indians (35-74 years, all from the SHS Dakota Center) participating in the first clinical examination in 1989-1991. Single SNP analysis was done using logistic regression, adjusting for age, sex, BMI, socioeconomic status, estimated glomerular filtration rate (eGFR) and lifestyle (physical activity, alcohol intake and smoking status). Gene-based association was assessed by combining p-values of all SNPs within a gene based on single SNP analysis using a weighted truncated product method. The gene-family association was performed by combining p-values of all 8 genes using the same method. Sensitivity analysis was conducted to evaluate whether the observed associations were primarily driven by the most significant SNPs. Multiple testing was controlled using Bonferroni correction.
Results: Three SNPs (rs12696304 in TERC, rs6601327 and rs6601328 in TNKS) were significantly associated with insulin resistance (p<0.0003) after correction for multiple testing. The TERC gene was significant associated with both T2D and insulin resistance (both P<0.0006), and TNKS2 was associated with T2D (p=0.01) and TNKS with insulin resistance (p=0.0001). The gene family as a whole was significantly associated with both T2D and insulin resistance (both P<0.0001). Removing the most significant SNPs did not change our results.
Conclusion: Variants involved in telomere maintenance jointly contribute to T2D in American Indians. Our findings provide valuable information for risk stratification and individualized strategy for prevention of diabetes.
- © 2013 by American Heart Association, Inc.