GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study

Abstract

Aim: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes.

Methods: We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects.

Results: The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele β=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele β=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01).

Conclusions: We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.

FIGURE 1

Plot of –log10(P-Value) by genomic position from the genome-wide association study of plasma lactate levels

FIGURE 2

Regional association plots of the GCKR and PPP1R3B loci.