CDKAL1 and HHEX are associated with type 2 diabetes-related traits among Yup'ik people

Background: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D), mainly among individuals of European ancestry. In the present study, we examined the frequency of these SNPs and their association with T2D-related traits in an Alaska Native study population with a historically low prevalence of T2D. We also investigated whether dietary characteristics that may protect against T2D, such as n-3 polyunsaturated fatty acid (PUFA) intake, modify these associations. Methods: In 1144 Yup'ik people, we examined 17 SNPs repeatedly identified in GWAS for individual and cumulative associations with T2D-related traits. Cumulative associations were evaluated using a genetic risk score (GRS) calculated by summing risk alleles. Associations were tested for interactions with sex, body mass index (BMI), and n-3 PUFA intake. Results: The rs7754840 SNP in CDKAL1 is significantly associated with HbA1c (P=0.00091). The rs5015480 SNP near HHEX is significantly associated (in opposite direction to that in Europeans) with a combined fasting glucose (FG) and HbA1c measure (P=0.00046) and with homeostatic model assessment of β-cell function (HOMA-B; P=0.0014). The GRS is significantly associated with FG and combined FG and HbA1c only when the HHEXSNP is dropped from the GRS. Associations are not modified by BMI or n-3 PUFA intake. Conclusion: Our results highlight the potential importance of CDKAL1 and HHEX in glucose homeostasis in this Alaska Native population with a low prevalence of T2D, and suggest that these loci should be examined in greater detail in this population.