CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Yohan Bossé, PhD*,
Patrick Mathieu, MD and
Philippe Pibarot, DVM, PhD, FACC, FAHA
* Laval University, Department of Anatomy and Physiology, Laval Hospital Research Center, 2725, chemin Sainte-Foy, Quebec City, Quebec G1V 4G5, Canada (Email: yohan.bosse{at}crhl.ulaval.ca).
We appreciate the precision comments by Dr. Bella concerning our recent review on the genetics/genomics of calcific aortic valve stenosis (1). The Hypertension Genetic Epidemiology Network (HyperGEN) Study Group conducted a genome-wide linkage scan on aortic valve sclerosis (2) that deserves to be discussed. This HyperGEN cohort was a substudy of a larger National Heart, Lung, and Blood Institute program, the Family Blood Pressure Program, designed to search for hypertension/blood pressure genes. The authors reported familial aggregation of aortic valve sclerosis with a sibling recurrence risk ratio of 2.3 and identified many linkage signals throughout the genome, suggesting the multilocus nature of aortic valve sclerosis. However, their results also highlighted the challenge of collecting samples of a sufficient size to study this disease. Major research resources were invested in the HyperGEN cohort to phenotype and genotype 1,871 patients. However, in the end, only 41 patients with isolated aortic valve sclerosis from families with at least 2 affected siblings were informative for the genetic linkage analyses. The authors also recognized the limitation of their ascertainment scheme that was based on hypertension to identify genetic loci influencing aortic valve sclerosis. Accordingly, recycling data from larger studies conducted on related traits provided a cost-effective way to identify new leads. However, studies specifically designed to study calcific aortic valve disease are likely to be more powerful and are clearly warranted.
By addressing study design and focusing on genomic approaches that are likely to be more successful, we should re-emphasize the need for genome-wide association scans on case-control studies. The identification of genes of complex diseases by this approach was considered one of the scientific breakthroughs of the year in 2007 (3). In contrast, genome-wide linkage studies have been used extensively in the past and have proven to be very productive to identify genes for monogenic traits. However, limited success has been reported for complex diseases (4), and a good example is the results from the Family Blood Pressure Program (5). Even in studies in which strong linkage peaks were originally identified, positional cloning attempts to find the causal genes responsible for the linkage signals have often been disappointing (4). Hence, the article by Bella et al. (2) is certainly worth mentioning, but the results of this study also provide an impetus for the design and realization of future genomic studies with a population and methodology that are more suitable for a complex disease such as calcific aortic valve stenosis.
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References
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- Bosse Y, Mathieu P, Pibarot P. Genomics: the next step to elucidate the etiology of calcific aortic valve stenosis J Am Coll Cardiol 2008;51:1327-1336.[Abstract/Free Full Text]
- Bella JN, Tang W, Kraja A, et al. Genome-wide linkage mapping for valve calcification susceptibility loci in hypertensive sibships: the Hypertension Genetic Epidemiology Network Study Hypertension 2007;49:453-460.[Abstract/Free Full Text]
- Pennisi E. Breakthrough of the year. Human genetic variation. Science 2007;318:1842-1843.[Abstract/Free Full Text]
- Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M. Genomewide scans of complex human diseases: true linkage is hard to find Am J Hum Genet 2001;69:936-950.[CrossRef][ISI][Medline]
- Province MA, Kardia SL, Ranade K, et al. A meta-analysis of genome-wide linkage scans for hypertension: the National Heart, Lung and Blood Institute Family Blood Pressure Program Am J Hypertens 2003;16:144-147.[CrossRef][ISI][Medline]
Related Article
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Genomics of Aortic Valve Disease
- Jonathan N. Bella
J. Am. Coll. Cardiol. 2008 52: 498.
[Full Text]
[PDF]
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