Association of an intronic, but not any exonic, FRMD4B sequence variant and heart failure.

Scot J Matkovich
Scot J Matkovich
Center for Pharmacogenomics
Thomas P Cappola
Thomas P Cappola
Penn Cardiovascular Institute
United States
Gerald W Dorn
Gerald W Dorn
Center for Pharmacogenomics
Palo Alto | United States

Clin Transl Sci 2010 Aug;3(4):134-9

The Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Common forms of heart failure (HF) exhibit familial clustering, but specific genetic risk factors have been challenging to identify. A recent single-nucleotide polymorphism (SNP) microarray study implicated a locus within an intron of FRMD4B in Caucasian HF. Here, we used next-generation resequencing of pooled DNA and individual Sequenom genotyping to test for associations between FRMD4B SNPs and ischemic and/or nonischemic cardiomyopathy in two independent populations. Exonic resequencing of Caucasians and African-Americans identified 32 FRMD4B SNPs, 13 of which had allele frequencies greater than 1%. None of these common FRMD4B SNPs were significantly associated with ischemic, nonischemic, or all-cause HF in either of the study populations. We individually genotyped the seminal intronic rs6787362 FRMD4B SNP in the primary study population and compared genotypes between HF cases and controls. The rs6787362 variant allele was more frequent in Caucasians with ischemic cardiomyopathy, and carriers (heterozygous or homozygous) of the variant allele had increased risk of HF (OR 1.437, CI 1.085-1.904; p= 0.0118). No such association was seen for African-American HF. These results confirm an association between the intronic rs6787362 FRMD4B SNP and ischemic cardiomyopathy in a European-derived population, but do not support the proposition that coding FRMD4B variants are susceptibility factors in common HF.

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August 2010
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