Genetic markers of type 2 diabetes risk in East Asian people uncovered
medwireNews: A major genetic analysis sheds light on the similarities and differences in type 2 diabetes pathogenesis between people of East Asian and European origin.
The team found that East Asian people have “substantial” shared genetic susceptibility to type 2 diabetes with Europeans, but they also identified associations that were novel to their East Asian cohort.
The multinational collaborative study is published in Nature. It combines 23 genome-wide association studies involving 77,418 East Asian individuals with type 2 diabetes and 356,122 without.
The analysis revealed 301 distinct associations with type 2 diabetes, corresponding to 183 chromosomal loci, these being determined by the variant with the strongest association. Fifty-one of these loci have not been previously reported, and all except two of the lead genetic variants associated with the loci were common, with the minor allele being present in at least 5% of the population.
The researchers highlight a 1.4 Mb locus spanning the genes GRM8, PAX4, and LEP, which they say has not previously been linked to type 2 diabetes. This contained seven separate association signals, including for variants near LEP, which encodes the appetite regulator leptin.
Notable variants at other loci included those in genes that encode proteins involved in pancreatic islet development and glucose uptake by skeletal muscle.
Adjusting the analysis for BMI revealed an additional six loci, including four novel ones, which have been linked to lipodystrophy and body fat distribution, and may therefore “reflect the role of body fat distribution in insulin resistance and [type 2 diabetes] among East Asian individuals,” say the study authors.
Stratification for sex uncovered six more loci, two of which only appeared after further adjustment for BMI.
When comparing their East Asian findings with those from European populations, the team found the effect size of the identified alleles to be similar in both groups, especially when considering only common alleles. However, 22 alleles were associated with diabetes only in one population, and six had significantly stronger effects in one. The greatest variation was seen for variants that were extremely rare in European population but were common or present at low frequency among Asians.
Lastly, the researchers looked at 92 loci that were common to both populations but where the strongest variant within the loci differed. This uncovered 18 variants in East Asians that had effects not seen in European populations; they were primarily associated with BMI or fat mass. The team also identified genes of interest with effects on targets including subcutaneous adipose tissue, skeletal muscle, the pancreas, and islets; and genetic variants that altered the sequence of proteins with roles including adipogenesis, glucose metabolism, and insulin secretion. In addition, several loci were associated with noncoding RNAs with a role in beta-cell function.
“The identified loci point to multiple plausible molecular mechanisms and many new candidate genes that link [type 2 diabetes] susceptibility to diverse biological processes,” conclude the researchers.
They believe their findings suggest “that insulin resistance has a substantial role in [type 2 diabetes] pathogenesis among East Asian individuals, through skeletal muscle, adipose, and liver development and function.”
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