Meta-analysis of genome-wide association studies identifies SNPs for proinsulin
November - 21 - 2011
Research evidence suggests a large number of genetic variants associated with type 2 diabetes (T2DM) risk but only a few have been identified to date. A meta-analysis of genome-wide association (GWA) studies was conducted to identify novel loci associated with proinsulin, the molecular precursor for insulin. Four cohorts for the discovery analysis studied consisted of 10,701 individuals and 11 cohorts of up to 16,378 individuals were included in a follow-up of 23 loci. All subjects were nondiabetic adults of European ancestry. The analysis covered approximately 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and circulating fasting proinsulin levels in these cohorts. Nine genetic variants at eight loci reached genome-wide significance. The loci LARP6 and SGSM2 were novel, whereas MADD has been associated with fasting glucose, PCSK1 with obesity and TCF7L2, SLC30A8, VPS13C/C2CD4A/B and ARAP1 with increased T2DM risk. However, the proinsulin-raising allele of ARAP1 was associated with positive traits of lower fasting glucose, improved beta-cell function and lower T2DM risk. The meta-analysis of GWAs identified nine SNPs in eight genomic regions associated with fasting proinsulin and may thus influence insulin secretion. Some of these variants (although not all) may be linked to increased susceptibility to T2DM (Strawbridge, R.J. et al. Diabetes 2011, 60(10): 2624).