Trans‐Ethnic Meta‐Analysis Identifies Common and Rare Variants Associated with Hepatocyte Growth Factor Levels in the Multi‐Ethnic Study of Atherosclerosis (MESA)

Abstract

Summary 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 what 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 genetic factors influencing circulating HGF levels may be complex and ethnically diverse.

Genetics of 35 blood and urine biomarkers in the UK Biobank

“…These two variants show significant associations with a number of diverse biomarker traits, including lipids, IGF-1, albumin, and calcium ( Figure 3d ). In addition, rs114303452 has been previously associated with serum HGF levels 47 , supporting the role of HGFAC in control of a number of other serum biomarkers through regulation of hepatocyte growth factor.…”

Hepatocyte Growth Factor Is Positively Associated With Risk of Stroke

“…In particular, future research should explore the HGF-stroke relation by race/ethnicity, as race/ethnicity-specific genetic regulation of HGF levels justifies exploration of heterogeneity of phenotypes. 24 Also, although we did not detect an association between HGF and hemorrhagic stroke, we were underpowered with only 39 events to date. Finally, HGF was measured in the total cohort only once at baseline, and stroke events could have occurred more than a decade after this measurement.…”

From genome-wide associations to candidate causal variants by statistical fine-mapping

“…This heterogeneity can result from differences in study designs, differences due to interactions with other SNPs, or differences due to environmental or lifestyle factors that influence the effects of genes. METASOFT 66 , which implements a modified form of the traditional random-effects approach, is popular among trans-ethnic studies 67–70 . Alternative methods that model the heterogeneity can improve fine-mapping resolution.…”