Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA1c

Sci Rep. 2017 Nov 23;7(1):16147. doi: 10.1038/s41598-017-16493-0.

Abstract

Glycated haemoglobin (HbA1c) is widely used as a biomarker for the diagnosis of diabetes, for population-level screening, and for monitoring the glycaemic status during medical treatment. Although the heritability of HbA1c has been estimated at ~55-75%, a much smaller proportion of phenotypic variance is explained by the HbA1c-associated variants identified so far. To search for novel loci influencing the HbA1c levels, we conducted a genome-wide meta-analysis of 2 non-diabetic Japanese populations (n = 7,704 subjects in total). We identified 2 novel loci that achieved genome-wide significance: TMC6-TMC8 (P = 5.3 × 10-20) and SIX3-SIX2 (P = 8.6 × 10-9). Data from the largest-scale European GWAS conducted for HbA1c supported an association between the novel TMC6-TMC8 locus and HbA1c (P = 2.7 × 10-3). The association analysis with glycated albumin and glycation gap conducted using our Japanese population indicated that the TMC6-TMC8 and SIX3-SIX2 loci may influence the HbA1c level through non-glycaemic and glycaemic pathways, respectively. In addition, the pathway-based analysis suggested that the linoleic acid metabolic and 14-3-3-mediated signalling pathways were associated with HbA1c. These findings provide novel insights into the molecular mechanisms that modulate the HbA1c level in non-diabetic subjects.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Asian People / genetics
  • Blood Glucose / metabolism*
  • Eye Proteins / genetics*
  • Female
  • Genome-Wide Association Study
  • Glycated Hemoglobin / metabolism*
  • Homeobox Protein SIX3
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics

Substances

  • Blood Glucose
  • Eye Proteins
  • Glycated Hemoglobin A
  • Homeodomain Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • SIX2 protein, human
  • TMC6 protein, human
  • TMC8 protein, human