9th February 2009

The genetics of heart disease

Two studies uncover novel genome regions associated with heart attack

snps

SNPs associated with myocardial infarction. The GWAS P-value for the lead SNPs (rs9818870 (3q22.3), rs2259816 (12q24.31)) is denoted by a red diamond. Blue diamonds indicate P-values for the lead SNPs in the replication sample. Proxies are indicated with diamonds of smaller size, with colours determined from their pairwise r2 from HapMap CEU (red: high LD with lead SNP (r2 > 0.8); orange: moderate LD with lead SNP (0.5 < r2 < 0.8); yellow: weak LD with lead SNP (0.2 < r2 < 0.5); white: no LD with the lead SNP (r2 < 0.2) or no information available). The locations of the genes in the region are shown.

Two new studies pick out four genome regions that influence the risk of heart disease. The studies, published in Nature Genetics, included more than 20,000 heart disease patients and involved a total of more than 33,000 samples.

The first study, conducted by the Myocardial Infarction Genetics Consortium, examined early-onset heart disease, and found three new genetic loci associated with increased risk. The second, undertaken by the Cardiogenics consortium and involving researchers from more than 30 labs, found a new locus on chromosome 3 strongly associated with heart disease. Previously, only seven regions had been identified.

Although the researchers caution that further work is required, their results suggest that, together, nine of the variants are as good a predictor of Myocardial Infarction (MI) as other established factors such as plasma LDL cholesterol.

Myocardial infarction - commonly known as heart attack - is a leading cause of death worldwide: early-onset MI appears to show some family history and so study of MI in younger people should be valuable in the search for genetic variants involved in increased risk of MI. Both studies started with patients who displayed early-onset MI.

" We need to do much more: in larger screens, in looking at more variation and in investigating the roles of the genes we have found, but it is exciting to be bringing these discoveries into the light of further investigation. "

Prof Leena Peltonen

"Our large studies show that much can still be revealed about the genetic causes behind our common disease," says Professor Leena Peltonen, Head of Human Genetics at the Wellcome Trust Sanger Institute. "Although many decades have been spent searching for genes that influence heart disease, new genetic analyses have the power to pick out three novel SNPs."

"We need to do much more: in larger screens, in looking at more variation and in investigating the roles of the genes we have found, but it is exciting to be bringing these discoveries into the light of further investigation."

Both studies used large initial groups of patients to identify candidate genetic variants - single-letter differences called SNPs - that might be related to MI: they then subjected those candidates to more stringent testing in many more samples. This phased approach is thought to be the most discerning mechanism for finding strong candidates.

The MIGEN study identified, in an independent sample, four regions that had been previously reported by other researchers. Such reconfirmation supports the validity of other findings of the work. The roles of the genes within the three novel regions identified in this work still remain to be determined. There is a suggestion that one gene, PHARCTR1, might lead directly to MI by promoting hardening of arteries.

The Cardiogenics consortium, in partnership with the Wellcome Trust Case Control Consortium, extended the initial study which reported six loci associated with Coronary Artery Disease back in 2007, identifying two novel loci strongly associated with risk to this condition. One region on chromosome 3 was refined through more than 25,000 samples to point towards a gene called MRAS that has been shown to be active in the heart.

"We had already found several regions that were implicated with CAD risk, but enlarging the discovery sample was key to identifying new loci. The chromosome 3 region harbouring the MRAS gene stood out as the strongest finding; this is a new confirmed CAD locus," says Dr Panos Deloukas, Senior Investigator at the Wellcome Trust Sanger Institute. "Our work as that of the MIGEN consortium shows that by joining forces we can increase our power to dissect the genetic component of an important common disease such as myocardial infarction."

Although the effects of the individual variants are modest - at this time the true causative variants remain unknown - the effects of the variants combined were more significant. The risk to individuals in the top 20% for 'bad' variants was twice that of those in the bottom 20%.

The results obtained in these studies could be combined with others to examine the usefulness of a test across the best-validated SNPs for increased risk of MI. However, the aggregate genetic studies can explain only a small part of the overall variation in the chance of MI: much remains unclear.The MIGEN study included an examination of the role of structural variants as well as single-base differences in MI, but found no association. Clearly, further studies are required to scan the genome comprehensively for structural variants and epigenetic factors that may contribute to disease risk.

Notes to Editors

Publication details

  • Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

    Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Kathiresan S, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Kathiresan S, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Voight BF, Purcell S, Nemesh J, Korn JM, McCarroll SA, Schwartz SM, Yee J, Kathiresan S, Lucas G, Subirana I, Elosua R, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, Samani NJ, Thompson JR, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall A, Wellcome Trust Case Control Consortium, Schunkert H, Erdmann J, Linsel-Nitschke P, Lieb W, Ziegler A, König I, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Schunkert H, Samani NJ, Erdmann J, Ouwehand W, Hengstenberg C, Deloukas P, Scholz M, Cambien F, Reilly MP, Li M, Chen Z, Wilensky R, Matthai W, Qasim A, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Scheffold T, Berger K, Stoll M, Huge A, Girelli D, Martinelli N, Olivieri O, Corrocher R, Morgan T, Spertus JA, McKeown P, Patterson CC, Schunkert H, Erdmann E, Linsel-Nitschke P, Lieb W, Ziegler A, König IR, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Hólm H, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Engert JC, Do R, Xie C, Anand S, Kathiresan S, Ardissino D, Mannucci PM, Siscovick D, O'Donnell CJ, Samani NJ, Melander O, Elosua R, Peltonen L, Salomaa V, Schwartz SM and Altshuler D

    Nature genetics 2009;41;3;334-41

  • New susceptibility locus for coronary artery disease on chromosome 3q22.3.

    Erdmann J, Grosshennig A, Braund PS, König IR, Hengstenberg C, Hall AS, Linsel-Nitschke P, Kathiresan S, Wright B, Trégouët DA, Cambien F, Bruse P, Aherrahrou Z, Wagner AK, Stark K, Schwartz SM, Salomaa V, Elosua R, Melander O, Voight BF, O'Donnell CJ, Peltonen L, Siscovick DS, Altshuler D, Merlini PA, Peyvandi F, Bernardinelli L, Ardissino D, Schillert A, Blankenberg S, Zeller T, Wild P, Schwarz DF, Tiret L, Perret C, Schreiber S, El Mokhtari NE, Schäfer A, März W, Renner W, Bugert P, Klüter H, Schrezenmeir J, Rubin D, Ball SG, Balmforth AJ, Wichmann HE, Meitinger T, Fischer M, Meisinger C, Baumert J, Peters A, Ouwehand WH, Italian Atherosclerosis, Thrombosis, and Vascular Biology Working Group, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Cardiogenics Consortium, Deloukas P, Thompson JR, Ziegler A, Samani NJ and Schunkert H

    Nature genetics 2009;41;3;280-2

Funding

A full list of participating centres and funding agencies is available at the Nature website.




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