J Thorac Cardiovasc Surg 2006;132:988-989
© 2006 The American Association for Thoracic Surgery
Reply to the Editor
Li Chen, PhD,
Xing Li Wang, MD, PhD,
Joseph S. Coselli, MD,
Scott A. LeMaire, MD
Texas Heart Institute at St Luke's Episcopal Hospital, Baylor College of Medicine, Houston, Tex
We appreciate the comments by Ahmad and colleagues regarding our initial investigation of single nucleotide polymorphisms (SNPs) involving the matrix metalloproteinase 9 gene (MMP9) in patients with thoracic aortic pathology.1
Selection of a control group that is perfectly matched for ethnic ancestry with a group of affected individuals is indeed a major challenge in studying the associations between candidate genes and diseases. Not surprisingly, most published studies have imperfectly matched case-control populations. Nevertheless, the substantial geographic difference between our control and study populations clearly warrants discussion.
Although geographically diverse, white populations from Australia and the United States are genetically similar. The majority of the white Australian population has ancestors who, within only a few generations, originated from the European continent. Previous studies of other genetic polymorphisms have demonstrated great similarities between the white Australian population and white subjects residing on other continents.2,3 Our American patients with thoracic aortic disease were classified as white with European origin and therefore share a similar genetic origin with white Australians. Although the Australian and American populations have resided on two different continents for a number of generations, the migration and constitutive establishment for both countries date back only approximately 200 years. The founder effect is generally small within such a short period. Still, even within a given white population, genetic admixture can be large for certain genes. Because of this and other inherent limitations, studies in separate populations are required to confirm any significant genetic associations observed from one particular population.
Given the genetic similarities between white Australians and white Americans (despite the geographic difference), we chose our control population for the absence of angiographic evidence of proximal thoracic aortic aneurysms or dissection. This reduced the likelihood that control subjects had thoracic aortic disease, which would have confounded the comparisons with our patient groups. To address at least somewhat the issue of geographic diversity in our study, we demonstrated that the frequencies of the three MMP9 SNPs in our control group were not significantly different from those previously described by Applied Biosystems (Foster City, Calif) in a white population from the United States.1 The presence of Hardy-Weinberg equilibrium in the control group is also reassuring; there was no significant deviation from Hardy-Weinberg equilibrium for the three MMP9 polymorphisms in the control group (P = .81 for -8202A/G; P = .98 for IVS4 + 3G/T; P = .93 for 2003A/G). No significant deviation from Hardy-Weinberg equilibrium was observed for IVS4+3G/T and 2003A/G in patients with thoracic aortic aneurysms or dissection; a significant deviation from Hardy-Weinberg equilibrium was observed for -8202A/G in our case patients.
Recent publications have suggested the existence of haplotype blocks. Haplotypes at these blocks could serve as multiallelic markers in disease-association studies.4 Examining all observed haplotypes for associations, rather than just those that are proxies for known SNPs, increases power to detect rare causal alleles, but at the cost of reduced power to detect common causal alleles. Furthermore, the haplotype-SNP–based approach does not always have higher power than the single-SNP–based study, as is supported by theoretic considerations. With the data collected in our population, some linkage analysis can be conducted for haplotype construction. Estimated haplotype frequencies cannot be treated as observed data, however, and therefore there is no valid statistical test for evaluating the possible contribution of individual haplotypes. Although testing haplotype blocks of the MMP9 locus and surrounding regions by including more SNPs might provide additional information, the most effective way to validate the findings reported in our study is to confirm the association in other case-control populations.
As with all genetic association studies, our study has limitations and the findings should be interpreted cautiously. Studies in separate populations will be required to confirm the association that we observed between the MMP9 -8202A/G polymorphism and thoracic aortic aneurysms and dissection. We hope that our data will stimulate expanded research regarding the genetic aspects of thoracic aortic disease, particularly in patients who do not have archetypal heritable disorders such as Marfan syndrome. Our participation in the newly established Specialized Center of Clinically Oriented Research in Thoracic Aortic Aneurysms and Dissection will provide exciting opportunities to perform such studies and expand our understanding of the genetic determinants that underlie thoracic aortic disease.
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References
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- Chen L, Wang X, Carter SA, Shen YH, Bartsch HR, Thompson RW, et al. A single nucleotide polymorphism in the matrix metalloproteinase 9 gene (-8202A/G) is associated with thoracic aortic aneurysms and thoracic aortic dissection. J Thorac Cardiovasc Surg 2006;131:1045-1052.[Abstract/Free Full Text]
- Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab 2000;70:241-251.[Medline]
- Wang XL, Raveendran M, Wang J. Genetic influence on cigarette-induced cardiovascular risk. Prog Cardiovasc Dis 2003;45:361-382.[Medline]
- de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D. Efficiency and power in genetic association studies. Nat Genet. 2005;37:1217-1223.[Medline]
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