NEW YORK (GenomeWeb) – Many of the same loci implicated in type 2 diabetes risk and glycemic trait profiles in European populations are also at play in China, new research suggests, though their allele frequencies appear to vary somewhat from one Chinese province to the next.
Through a genome-wide association study involving almost 7,200 individuals from nine provinces in China, the researchers searched for variants associated with T2D and/or related glycemic traits such as fasting glucose, insulin, and glycated hemoglobin (HbA1c). The findings, appearing online today in PLOS Genetics, highlighted new and known variants at 32 loci linked to T2D or fasting glucose in past studies.
At loci linked to fasting glucose, the team not only tracked down a new variant, but also uncovered a regulatory region affecting the expression of the SIX3 and SIX2 genes in pancreatic islet cells using data from both Asian and European populations — regulatory patterns they verified using reporter assays in mouse insulinoma cells.
"This cross-ancestry comparison helped define a molecular mechanism that supports, in humans, a role for the SIX3 and/or SIX2 transcription factors affecting insulin secretion," co-senior author Karen Mohlke, a genetics researcher at the University of North Carolina, Chapel Hill, said in a statement.
Mohlke and colleagues started with data for more than 8,400 genotyped participants from the China Health and Nutrition Survey.
Based on patterns for more than 8 million SNPs that were directly assessed or imputed using data from the 1000 Genomes Project, the researchers looked for variants coinciding with fasting glucose, fasting insulin, or HbA1c profiles for up to 7,178 of the individuals. They also did a T2D GWAS focused on 748 individuals with the chronic condition and 4,983 without.
For fasting glucose profiles, for example, the team identified apparent associations at eight loci already implicated in the metabolic trait in individuals from East Asia or Europe. Variants at two of those loci reached genome-wide significant associations: a SNP neighboring G6PC2 on chromosome 2 and another chromosome 2 SNP near the SIX3 and SIX2 genes.
When they dug into these associations, the researchers uncovered another fasting glucose level-linked missense variant near G6PC2. At the other locus, meanwhile, they saw overlap with a documented expression quantitative trait locus affecting the expression of the SIX3 and SIX2 genes, along with a handful of non-coding transcripts, in pancreatic islet cells.
The team saw signs of genetic drift and population structuring between Chinese provinces when it looked at fasting glucose-associated allele frequencies, though the differences did not reach statistical significance.
With their association analyses, the researchers validated dozens more loci previously implicated in fasting insulin, HbA1c levels, and/or T2D itself. While a handful more suspicious sites turned up in the analyses, they did not see new variants or loci with genome-wide significant ties to those traits.
"Further functional analyses of the variants identified in this study is the next step to confirm which variants and genes are affected," the authors concluded, noting that "[r]eplication of the moderately significant associations would be useful to better understand the genetic architecture of glycemic traits."