Predictive performance of a genetic risk score using 11 susceptibility alleles for the incidence of Type 2 diabetes in a general Japanese population: a nested case-control study

Diabet Med. 2018 May;35(5):602-611. doi: 10.1111/dme.13602. Epub 2018 Mar 12.

Abstract

Aims: To assess the predictive ability of a genetic risk score for the incidence of Type 2 diabetes in a general Japanese population.

Methods: This prospective case-control study, nested within a Japan Public Health Centre-based prospective study, included 466 participants with incident Type 2 diabetes over a 5-year period (cases) and 1361 control participants, as well as 1463 participants with existing diabetes and 1463 control participants. Eleven susceptibility single nucleotide polymorphisms, identified through genome-wide association studies and replicated in Japanese populations, were analysed.

Results: Most single nucleotide polymorphism loci showed directionally consistent associations with diabetes. From the combined samples, one single nucleotide polymorphism (rs2206734 at CDKAL1) reached a genome-wide significance level (odds ratio 1.28, 95% CI 1.18-1.40; P = 1.8 × 10-8 ). Three single nucleotide polymorphisms (rs2206734 in CDKAL1, rs2383208 in CDKN2A/B, and rs2237892 in KCNQ1) were nominally significantly associated with incident diabetes. Compared with the lowest quintile of the total number of risk alleles, the highest quintile had a higher odds of incident diabetes (odds ratio 2.34, 95% CI 1.59-3.46) after adjusting for conventional risk factors such as age, sex and BMI. The addition to the conventional risk factor-based model of a genetic risk score using the 11 single nucleotide polymorphisms significantly improved predictive performance; the c-statistic increased by 0.021, net reclassification improved by 6.2%, and integrated discrimination improved by 0.003.

Conclusions: Our prospective findings suggest that the addition of a genetic risk score may provide modest but significant incremental predictive performance beyond that of the conventional risk factor-based model without biochemical markers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Asian Continental Ancestry Group / genetics*
  • Case-Control Studies
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Homeodomain Proteins / genetics
  • Humans
  • Incidence
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin-Like Growth Factor Binding Protein 2 / genetics
  • Japan / epidemiology
  • KCNQ1 Potassium Channel / genetics
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics
  • PPAR gamma / genetics
  • Potassium Channels, Inwardly Rectifying / genetics
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcription Factors / genetics
  • Ubiquitin-Conjugating Enzymes / genetics
  • tRNA Methyltransferases / genetics

Substances

  • C2CD4A protein, human
  • CDKN2A protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • HHEX protein, human
  • Homeodomain Proteins
  • IGFBP-2 protein, human
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor Binding Protein 2
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Kir6.2 channel
  • Nuclear Proteins
  • PPAR gamma
  • Potassium Channels, Inwardly Rectifying
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • tRNA Methyltransferases
  • UBE2E2 protein, human
  • Ubiquitin-Conjugating Enzymes
  • CDKAL1 protein, human