Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the multi-ethnic study of atherosclerosis (MESA)

Nicholas B. Larson; Cecilia Berardi; Paul A. Decker; Christina L. Wassel; Phillip S. Kirsch; James S. Pankow; Michele M. Sale; Mariza de Andrade; Hugues Sicotte; Weihong Tang; Naomi Q. Hanson; Michael Y. Tsai; Kent D. Taylor; Suzette J. Bielinski

doi:10.1111/ahg.12119

Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the multi-ethnic study of atherosclerosis (MESA)

Nicholas B. Larson, Cecilia Berardi, Paul A. Decker, Christina L. Wassel, Phillip S. Kirsch, James S. Pankow, Michele M. Sale, Mariza de Andrade, Hugues Sicotte, Weihong Tang, Naomi Q. Hanson, Michael Y. Tsai, Kent D. Taylor, Suzette J. Bielinski

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	264-274
Number of pages	11
Journal	Annals of Human Genetics
Volume	79
Issue number	4
DOIs	https://doi.org/10.1111/ahg.12119
State	Published - Jul 1 2015

Keywords

Circulation
Genetic association
Genome-wide analysis
Protein

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1111/ahg.12119

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Larson, N. B., Berardi, C., Decker, P. A., Wassel, C. L., Kirsch, P. S., Pankow, J. S., Sale, M. M., de Andrade, M., Sicotte, H., Tang, W., Hanson, N. Q., Tsai, M. Y., Taylor, K. D., & Bielinski, S. J. (2015). Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the multi-ethnic study of atherosclerosis (MESA). Annals of Human Genetics, 79(4), 264-274. https://doi.org/10.1111/ahg.12119

Larson, NB, Berardi, C, Decker, PA, Wassel, CL, Kirsch, PS, Pankow, JS, Sale, MM, de Andrade, M, Sicotte, H, Tang, W, Hanson, NQ, Tsai, MY, Taylor, KD & Bielinski, SJ 2015, 'Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the multi-ethnic study of atherosclerosis (MESA)', Annals of Human Genetics, vol. 79, no. 4, pp. 264-274. https://doi.org/10.1111/ahg.12119

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title = "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.",

keywords = "Circulation, Genetic association, Genome-wide analysis, Protein",

author = "Larson, {Nicholas B.} and Cecilia Berardi and Decker, {Paul A.} and Wassel, {Christina L.} and Kirsch, {Phillip S.} and Pankow, {James S.} and Sale, {Michele M.} and {de Andrade}, Mariza and Hugues Sicotte and Weihong Tang and Hanson, {Naomi Q.} and Tsai, {Michael Y.} and Taylor, {Kent D.} and Bielinski, {Suzette J.}",

note = "Publisher Copyright: {\textcopyright} 2015 John Wiley & Sons Ltd/University College London.",

year = "2015",

month = jul,

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doi = "10.1111/ahg.12119",

language = "English (US)",

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T1 - Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the multi-ethnic study of atherosclerosis (MESA)

AU - Larson, Nicholas B.

AU - Berardi, Cecilia

AU - Decker, Paul A.

AU - Wassel, Christina L.

AU - Kirsch, Phillip S.

AU - Pankow, James S.

AU - Sale, Michele M.

AU - de Andrade, Mariza

AU - Sicotte, Hugues

AU - Tang, Weihong

AU - Hanson, Naomi Q.

AU - Tsai, Michael Y.

AU - Taylor, Kent D.

AU - Bielinski, Suzette J.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

KW - Circulation

KW - Genetic association

KW - Genome-wide analysis

KW - Protein

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SN - 0003-4800

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SP - 264

EP - 274

JO - Annals of Human Genetics

JF - Annals of Human Genetics

IS - 4

ER -

Trans-ethnic meta-analysis identifies common and rare variants associated with hepatocyte growth factor levels in the multi-ethnic study of atherosclerosis (MESA)

Abstract

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