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GCKR and PPP 1R3B identified as genome‐wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities ( ARIC ) study
Author(s) -
Tin A.,
Balakrishnan P.,
Beaty T. H.,
Boerwinkle E.,
Hoogeveen R. C.,
Young J. H.,
Kao W. H. L.
Publication year - 2016
Publication title -
diabetic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.474
H-Index - 145
eISSN - 1464-5491
pISSN - 0742-3071
DOI - 10.1111/dme.12971
Subject(s) - single nucleotide polymorphism , metformin , genome wide association study , genetics , medicine , diabetes mellitus , biology , endocrinology , genotype , gene
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 PPP 1R3B/ LOC 157273 (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 PPP 1R3B/ LOC 157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP 1R3B/ LOC 157273 and plasma lactate in European‐American subjects ( P for interaction=0.01). Conclusions We identified GCKR and PPP 1R3B/ LOC 157273 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.