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

ABSTRACT: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes.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.The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele ?=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele ?=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).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.

SUBMITTER: Tin A

PROVIDER: S-EPMC4819009 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Tin A A Balakrishnan P P Beaty T H TH Boerwinkle E E Hoogeveen R C RC Young J H JH Kao W H L WH

Diabetic medicine : a journal of the British Diabetic Association 20151030 7

<h4>Aim</h4>To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes.<h4>Methods</h4>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 inter ...[more]

PMID: 26433129

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Project description:Cardiovascular risk factors such as aging, smoking, and insulin resistance may lead to atherosclerosis through various mechanisms of which their association with mitochondrial dysfunction may be one of them. In order to examine this hypothesis, we assessed the association between elevated blood lactate, a marker of mitochondrial dysfunction, and carotid atherosclerosis.From a total of 2066 participants from the Atherosclerosis Risk In Communities Carotid MRI study, 1496 were included for this analysis. Wall Thickness and Lipid core presence were measured using gadolinium-enhanced MRI. Blood lactate was categorized into quartiles (Q1: <5.9 mg/dl, Q2: 5.9-7.2 mg/dl, Q3: 7.3-9.2 mg/dl, and Q4: >9.2 mg/dl).Of the 1496 study participants, 763 (51%) were females, 296 (19.8%) African American, 539 (36%) obese and 308 (20.6%) had diabetes. There was a strong and graded association between lactate and wall thickness [Q1: 1.08 mm (95% CI: 1.01 mm-1.15 mm), Q2: 1.33 mm (95% CI: 1.19 mm-1.47 mm), Q3: 1.44 (95% CI: 1.34 mm-1.54 mm) and Q4: 1.62 (95% CI: 1.53 mm-1.71 mm); p for trend <0.001] after adjusting for age, gender, ethnicity, stature, body mass index (BMI), waist circumference, LDL, High sensitivity C reactive protein (HsCRP), statin use, thiazolidinedione use, hypertension, and diabetes. This association was attenuated, but still significant, after adjusting for a marker of insulin resistance, the triglyceride/HDL ratio, [Q1: 0.96 mm (95% CI: 0.82 mm-1.10 mm), Q2: 1.17 mm (95% CI: 1.08 mm-1.26 mm), Q3: 1.18 mm (95% CI: 1.07 mm-1.29 mm), Q4: 1.22 mm (95% CI: 1.13 mm-1.31 mm), p for linear trend 0.039]. There was no association of lactate with lipid core presence after adjustment for wall thickness.Blood lactate is associated with carotid atherosclerosis. Attenuation of the association with adjustment for triglyceride/HDL ratio, a marker of insulin resistance, suggests that lactate's association with carotid atherosclerosis may be related to insulin resistance.

Project description:<p>The Atherosclerosis Risk in Communities (ARIC) Study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. The four communities are Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date.</p> <p>ARIC includes two parts: the Cohort Component and the Community Surveillance Component. The Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam was in 1996-98. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort.</p> <p>In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. Starting in 2006, the study conducts community surveillance of inpatient (ages 55 years and older) and outpatient heart failure (ages 65 years and older) for heart failure events beginning in 2005.</p> <p>ARIC is currently funded through January 31, 2012.</p> <p>This study is part of the Gene Environment Association Studies initiative (GENEVA, <a href="http://www.genevastudy.org" target="_blank">http://www.genevastudy.org</a>) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to atherosclerosis and cardiovascular disease through large-scale genome-wide association studies of well-characterized cohorts of adults in four defined populations. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.</p>

Dataset Information

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

Publications

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

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