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Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the Multi-Ethnic Study of Atherosclerosis (MESA).

ABSTRACT: Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding which genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity-stratified single-variant association analysis and trans-ethnic meta-analysis of 6201 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we discovered five statistically significant common and low-frequency variants: HGF missense polymorphism rs5745687 (p.E299K) as well as four variants (rs16844364, rs4690098, rs114303452, rs3748034) within or in proximity to HGFAC. We also identified two significant ethnicity-specific gene-level associations (A1BG in African Americans; FASN in Chinese Americans) based upon low-frequency/rare variants, while meta-analysis of gene-level results identified a significant association for HGFAC. However, identified single-variant associations explained modest proportions of the total trait variation and were not significantly associated with coronary artery calcium or coronary heart disease. Our findings indicate that genetic factors influencing circulating HGF levels may be complex and ethnically diverse.

SUBMITTER: Larson NB

PROVIDER: S-EPMC4474777 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the Multi-Ethnic Study of Atherosclerosis (MESA).

Larson Nicholas B NB Berardi Cecilia C Decker Paul A PA Wassel Christina L CL Kirsch Phillip S PS Pankow James S JS Sale Michele M MM de Andrade Mariza M Sicotte Hugues H Tang Weihong W Hanson Naomi Q NQ Tsai Michael Y MY Taylor Kent D KD Bielinski Suzette J SJ

Annals of human genetics 20150522 4

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that regulates cell growth, motility, mitogenesis, and morphogenesis in a variety of cells, and increased serum levels of HGF have been linked to a number of clinical and subclinical cardiovascular disease phenotypes. However, little is currently known regarding which genetic factors influence HGF levels, despite evidence of substantial genetic contributions to HGF variation. Based upon ethnicity-stratified single-variant ...[more]

PMID: 25998175

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Project description:Dairy consumption is linked to a lower risk of type 2 diabetes, but constituents responsible for this relation are not established. Emerging evidence suggests that trans-palmitoleate (trans 16:1n-7), a fatty acid in dairy and also partially hydrogenated oils, may be associated with a more favorable metabolic profile and less incident diabetes.We investigated the association of trans-palmitoleate with metabolic risk and incident diabetes in a multiethnic US cohort.Phospholipid fatty acids and metabolic risk factors were measured in 2000-2002 among 2617 adults in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of white, black, Hispanic, and Chinese Americans. In 2281 participants free of baseline diabetes, we also prospectively assessed the risk of new-onset diabetes (205 cases) from baseline to 2005-2007.trans-Palmitoleate concentrations correlated positively with self-reported consumption of whole-fat dairy, butter, margarine, and baked desserts and with other circulating biomarkers of both dairy fat and partially hydrogenated oil consumption, which suggested mixed dietary sources. After multivariable adjustment, trans-palmitoleate concentrations were associated with higher LDL cholesterol (quintile 5 compared with quintile 1: +6.4%; P-trend = 0.005), lower triglycerides (-19.1%; P-trend < 0.001), lower fasting insulin (-9.1%; P-trend = 0.002), and lower systolic blood pressure (-2.4 mm Hg; P-trend = 0.01). In prospective analyses, trans-palmitoleate was independently associated with lower incident diabetes (P-trend = 0.02), including a 48% lower risk in quintile 5 compared with quintile 1 (HR: 0.52; 95% CI: 0.32, 0.85). All findings were similar between men and women and between different race-ethnic subgroups.Circulating trans-palmitoleate is associated with higher LDL cholesterol but also with lower triglycerides, fasting insulin, blood pressure, and incident diabetes in a multiethnic US cohort. Our findings support the need for further experimental and dietary intervention studies that target circulating trans-palmitoleate. The MESA trial was registered at clinicaltrials.gov as NCT00005487.

Dataset Information

Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the Multi-Ethnic Study of Atherosclerosis (MESA).

Publications

Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the Multi-Ethnic Study of Atherosclerosis (MESA).

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