Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.
J Diabetes. 2014 May;6(3):251-9. doi: 10.1111/1753-0407.12093. Epub 2013 Oct 29.
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.
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.
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 HHEX SNP is dropped from the GRS. Associations are not modified by BMI or n-3 PUFA intake.
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.
全基因组关联研究（GWAS）已确定与 2 型糖尿病（T2D）相关的单核苷酸多态性（SNP），主要在欧洲血统个体中。在本研究中，我们检查了这些 SNP 的频率及其与具有历史上低 T2D 患病率的阿拉斯加原住民研究人群中 T2D 相关特征的关联。我们还研究了是否可以通过可能预防 T2D 的饮食特征（例如 n-3 多不饱和脂肪酸（PUFA）的摄入）来改变这些关联。
在 1144 名Yup'ik 人中，我们检查了 GWAS 中反复鉴定出的 17 个 SNP，以评估其与 T2D 相关特征的个体和累积关联。使用通过累加风险等位基因计算的遗传风险评分（GRS）评估累积关联。检验了性别、体重指数（BMI）和 n-3 PUFA 摄入与这些关联的相互作用。
CDKAL1 中的 rs7754840 SNP 与 HbA1c 显著相关（P = 0.00091）。HHEX 附近的 rs5015480 SNP 与空腹血糖（FG）和 HbA1c 综合测量值（与欧洲人相反的方向）显著相关（P = 0.00046），与稳态模型评估的β细胞功能（HOMA-B；P = 0.0014）显著相关。仅当从 GRS 中删除 HHEX SNP 时，GRS 才与 FG 和 FG 与 HbA1c 综合测量值显著相关。BMI 或 n-3 PUFA 摄入量不改变关联。
我们的结果突出了在具有低 T2D 患病率的阿拉斯加原住民人群中，CDKAL1 和 HHEX 在葡萄糖稳态中的潜在重要性，并表明在该人群中应更详细地研究这些基因座。
