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Genetic and functional association of FAM5C with myocardial infarction

Jessica J Connelly1, Svati H Shah12, Jennifer F Doss1, Shera Gadson1, Sarah Nelson1, David R Crosslin1, A Brent Hale1, Xuemei Lou1, Ty Wang1, Carol Haynes1, David Seo3, David C Crossman4, Vincent Mooser5, Christopher B Granger2, Christopher JH Jones6, William E Kraus12, Elizabeth R Hauser1 and Simon G Gregory1*

Author Affiliations

1 Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC, USA

2 Department of Medicine and Division of Cardiology, Duke University Medical Center, Durham, NC, USA

3 Miller School of Medicine, University of Miami, Miami, FL, USA

4 University of Sheffield, Sheffield, UK

5 GlaxoSmithKline, Philadelphia, PA, USA

6 University of Wales College of Medicine, Cardiff, UK

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BMC Medical Genetics 2008, 9:33  doi:10.1186/1471-2350-9-33

Published: 22 April 2008



We previously identified a 40 Mb region of linkage on chromosome 1q in our early onset coronary artery disease (CAD) genome-wide linkage scan (GENECARD) with modest evidence for linkage (n = 420, LOD 0.95). When the data are stratified by acute coronary syndrome (ACS), this modest maximum in the overall group became a well-defined LOD peak (maximum LOD of 2.17, D1S1589/D1S518). This peak overlaps a recently identified inflammatory biomarker (MCP-1) linkage region from the Framingham Heart Study (maximum LOD of 4.27, D1S1589) and a region of linkage to metabolic syndrome from the IRAS study (maximum LOD of 2.59, D1S1589/D1S518). The overlap of genetic screens in independent data sets provides evidence for the existence of a gene or genes for CAD in this region.


A peak-wide association screen (457 SNPs) was conducted of a region 1 LOD score down from the peak marker (168–198 Mb) in a linkage peak for acute coronary syndrome (ACS) on chromosome 1, within a family-based early onset coronary artery disease (CAD) sample (GENECARD).


Polymorphisms were identified within the 'family with sequence similarity 5, member C' gene (FAM5C) that show genetic linkage to and are associated with myocardial infarction (MI) in GENECARD. The association was confirmed in an independent CAD case-control sample (CATHGEN) and strong association with MI was identified with single nucleotide polymorphisms (SNPs) in the 3' end of FAM5C. FAM5C genotypes were also correlated with expression of the gene in human aorta. Expression levels of FAM5C decreased with increasing passage of proliferating aortic smooth muscle cells (SMC) suggesting a role for this molecule in smooth muscle cell proliferation and senescence.


These data implicate FAM5C alleles in the risk of myocardial infarction and suggest further functional studies of FAM5C are required to identify the gene's contribution to atherosclerosis.