Journal Article

Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy

E. Warwick Daw, Suet Nee Chen, Grazyna Czernuszewicz, Raffaella Lombardi, Yue Lu, Jianzhong Ma, Robert Roberts, Sanjay Shete and Ali J. Marian

in Human Molecular Genetics

Volume 16, issue 20, pages 2463-2471
Published in print October 2007 | ISSN: 0964-6906
Published online July 2007 | e-ISSN: 1460-2083 | DOI:
Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy

Show Summary Details


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 (∼5 cMdense) 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 (180 cM), 10p13 (41 cM), 17q24 (108 cM) 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 (73 cM). The effect sizes varied according to the modifier locus, age and sex. It ranged from ∼8 g shift in left ventricular mass for 10p13 locus heterozygosity for the common allele to ∼90 g shift 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.

Journal Article.  5712 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.