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

J Diabetes. 2014 May;6(3):251-9. doi: 10.1111/1753-0407.12093. Epub 2013 Oct 29.


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 HHEX SNP 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.

Keywords: Alaska Native; glycemic traits; n-3 polyunsaturated fatty acids; type 2 diabetes single nucleotide polymorphisms; 阿拉斯加原住民,血糖特征,n-3多不饱和脂肪酸,2型糖尿病单核苷酸多态性.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alaska / epidemiology
  • Blood Glucose / metabolism
  • Body Mass Index
  • Cyclin-Dependent Kinase 5 / genetics*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / ethnology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diet
  • Fasting / blood
  • Fatty Acids, Omega-3 / administration & dosage
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Glycated Hemoglobin A / metabolism
  • Homeodomain Proteins / genetics*
  • Humans
  • Insulin / blood
  • Inuits / genetics*
  • Linear Models
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Risk Factors
  • Transcription Factors / genetics*
  • Young Adult
  • tRNA Methyltransferases


  • Blood Glucose
  • Fatty Acids, Omega-3
  • Glycated Hemoglobin A
  • HHEX protein, human
  • Homeodomain Proteins
  • Insulin
  • Transcription Factors
  • tRNA Methyltransferases
  • Cyclin-Dependent Kinase 5
  • CDKAL1 protein, human