A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels

Several studies have shown that healthy individuals with fasting plasma glucose ( FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single- nucleotide polymorphisms ( SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP ( rs560887, P = 4 x 10(-7)) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose- 6- phosphatase catalytic subunit- related protein ( also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG ( linear regression coefficient beta = -0.06 millimoles per liter per A allele, combined P = 4 x 10(-23)) and with pancreatic beta cell function ( Homa-B model, combined P = 3 x 10(-13)) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose- stimulated insulin secretion in pancreatic beta cells.