Human Molecular Genetics Advance Access published online on July 25, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm202
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Genome Wide Mapping of Modifier Chromosomal Loci for Human Hypertrophic Cardiomyopathy
1 Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, 77030 2 Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030 3 University of Ottawa Heart Institute, Ottawa, Canada
* Corresponding author 6770 Bertner Street, DAC 900A, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX 77030, 713 500 2350 (direct) or 713 500 2345 713 500 2320 (Fax) Ali.J.Marian{at}uth.tmc.edu
Received June 19, 2007; Revised July 19, 2007; Accepted July 19, 2007
Hypertrophic cardiomyopathy (HCM) is a disease of mutant sarcomeric proteins (except for phenocopy). Cardiac hypertrophy is the clinical diagnostic hallmark of HCM and a major determinant of morbidity and mortality in various cardiovascular diseases. However, there is remarkable variability in expression of hypertrophy, even among HCM patients with identical causal mutations. We hypothesized modifier genes are partly responsible for the variation in hypertrophic expressivity.
To map the modifier loci, we typed 811 short-tandem repeat markers (
5cM dense) in 100 members of an HCM family including 36 with the InsG791 mutation in MYBPC3. We performed oligogenic simultaneous segregation and linkage analyses using Markov Chain Monte Carlo methods and detected linkage on 3q26.2 (180cM), 10p13 (41cM), 17q24 (108cM) with log of the posterior placement probability ratio (LOP) of 3.51, 4.86 and 4.17, respectively, and suggestive linkage (LOP of 2.40) on 16q12.2 (73cM). The effect sizes varied according to the modifier locus, age and sex. It ranged from 8 grams shift in left ventricular mass for 10p13 locus heterozygosity for the common allele to 90 grams for 3q26.2 locus homozygosity for the uncommon allele. Refining the 10p13 locus restricted the candidate modifier genes to ITGA8, C10orf97 (CARP) and PTER. ITGA8 and CARP are biologically plausible candidates as they are implicated in cardiac fibrosis and apoptosis, respectively. Since cardiac hypertrophy is a major determinant of total and cardiovascular mortality and morbidity, regardless of the etiology, identification of the specific modifier genes could have significant prognostic and therapeutic implications for various cardiovascular diseases.
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