Cardiovascular genetics: are we there yet?

Cardiovascular genetics Since 1900, cardiovascular disease has been the number one killer in the United States every year except 1918, the year of the great influenza pandemic. Cardiovascular disease claims more lives each year than the next five leading causes of death combined, which are cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza and pneumonia.1 Cardiovascular disease is also the leading cause of death in Europe, accounting for over 4 million deaths each year and, according to World Health Organization estimates, 16.6 million people around the globe die of cardiovascular disease each year.2 Based on the United States National Heart, Lung, and Blood Institute Family Heart Study, in its 44 year follow up of participants and a 20 year follow up of their offspring, coronary artery disease accounts for more than half of all cardiovascular events in men and women under the age of 75. Further, coronary artery disease is the single largest killer of men and women in America.1 Coronary artery disease has a complex aetiology, involving multiple genetic and environmental influences and interactions. In a recent review, Lusis estimates the total number of genes involved in cardiovascular disease by considering the risk factors for cardiovascular disease that are under genetic control.3 Some of these risk factors with a significant heritability include cholesterol levels, triglyceride levels, hypertension, obesity, diabetes, and the metabolic syndrome, all of which themselves have many genes involved in their susceptibility.3,4 Therefore, at least hundreds of genes are involved in the susceptibility to cardiovascular disease.3 The identification and characterisation of these genes has been a major undertaking and challenge for researchers. A recent call to arms from Sing et al5 makes recommendations for what needs to be done to cope with these complexities, including developing new statistical …

[1]  E. Rimm,et al.  A prospective study of parental history of myocardial infarction and coronary artery disease in men. , 1991, The American journal of cardiology.

[2]  A. Tonkin,et al.  Genome-Wide Linkage Analysis of the Acute Coronary Syndrome Suggests a Locus on Chromosome 2 , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[3]  A. Zwinderman,et al.  Thrombospondin-2 Polymorphism Is Associated With a Reduced Risk of Premature Myocardial Infarction , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[4]  J. Stengård,et al.  Genes, Environment, and Cardiovascular Disease , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[5]  G. Lyons,et al.  Mef 2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis , 1994 .

[6]  C Eng,et al.  Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. , 1998, Human molecular genetics.

[7]  D. Marsh,et al.  Germline mutation of the tumour suppressor PTEN in Proteus syndrome , 2002, Journal of medical genetics.

[8]  C. Woods,et al.  Novel PTEN mutations in patients with Cowden disease: absence of clear genotype–phenotype correlations , 1999, European Journal of Human Genetics.

[9]  L. Hoefsloot,et al.  PTEN mutation in a family with Cowden syndrome and autism. , 2001, American journal of medical genetics.

[10]  S. Hunt,et al.  Family history as an independent risk factor for incident coronary artery disease in a high-risk cohort in Utah. , 1988, The American journal of cardiology.

[11]  G. Reifenberger,et al.  Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. , 2003, American journal of human genetics.

[12]  E. Topol,et al.  Replication of the association between the thrombospondin-4 A387P polymorphism and myocardial infarction. , 2004, American heart journal.

[13]  M. Wolf,et al.  Gowden's disease. A cutaneous marker of breast cancer , 1978 .

[14]  P. McKeigue,et al.  Problems of reporting genetic associations with complex outcomes , 2003, The Lancet.

[15]  E. Topol,et al.  Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes , 2004, Journal of Medical Genetics.

[16]  C. Dina,et al.  A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27. , 2001, Human molecular genetics.

[17]  Sue-Jane Wang,et al.  Family history: a comprehensive genetic risk assessment method for the chronic conditions of adulthood. , 1997, American journal of medical genetics.

[18]  C. Eng Will the real Cowden syndrome please stand up: revised diagnostic criteria , 2000, Journal of medical genetics.

[19]  R. Hennekam,et al.  PTEN hamartoma tumour syndrome: variability of an entity , 2003, Journal of medical genetics.

[20]  J. Ivanovich,et al.  Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. , 2003, American journal of human genetics.

[21]  L. Jorde,et al.  Family history as an independent risk factor for coronary arterty disease , 1990 .

[22]  F. Arwert,et al.  The Cowden syndrome: a clinical and genetic study in 21 patients , 1986, Clinical genetics.

[23]  M. Wolf,et al.  Cowden's disease: a cutaneous marker of breast cancer. , 1978, Cancer.

[24]  S. Seal,et al.  Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? , 1994, Journal of medical genetics.

[25]  E. Topol,et al.  Mutation of MEF2A in an Inherited Disorder with Features of Coronary Artery Disease , 2003, Science.

[26]  M. Scheuner Genetic evaluation for coronary artery disease , 2003, Genetics in Medicine.

[27]  Arya M. Sharma Association studies of genetic polymorphisms and complex disease , 2000, The Lancet.

[28]  R. Weksberg,et al.  Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. , 1999, American journal of medical genetics.

[29]  S. Brandner,et al.  Lhermitte-Duclos disease in 3 children: a clinical long-term observation. , 2003, Neuropediatrics.

[30]  M Freedman,et al.  Single Nucleotide Polymorphisms in Multiple Novel Thrombospondin Genes May Be Associated With Familial Premature Myocardial Infarction , 2001, Circulation.

[31]  Aldons J. Lusis,et al.  Atherosclerosis : Vascular biology , 2000 .

[32]  E. Lander,et al.  Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease , 2003, Nature Genetics.

[33]  M. Daly,et al.  Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland. , 2000, American journal of human genetics.

[34]  M. Nelen,et al.  Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. , 1997, Human molecular genetics.

[35]  R. Sciot,et al.  Lhermitte-Duclos disease is a clinical manifestation of Cowden's syndrome. , 2001, Surgical neurology.

[36]  R. Hennekam,et al.  Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes , 2001, The Lancet.

[37]  Hiroshi Sato,et al.  Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction , 2002, Nature Genetics.

[38]  H. Izawa,et al.  Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. , 2002, The New England journal of medicine.

[39]  A. Lusis Genetic factors in cardiovascular disease. 10 questions. , 2003, Trends in cardiovascular medicine.

[40]  E. Barrett-Connor,et al.  Family history of heart attack as an independent predictor of death due to cardiovascular disease. , 1984, Circulation.

[41]  C. Kumana,et al.  Association studies of genetic polymorphisms and complex disease , 2000, The Lancet.

[42]  J. Hirschhorn,et al.  A comprehensive review of genetic association studies , 2002, Genetics in Medicine.

[43]  C. Dina,et al.  A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16 p 13 and replicates linkage with the metabolic syndrome on 3 q 27 , 2001 .

[44]  G. Lyons,et al.  Mef2 gene expression marks the cardiac and skeletal muscle lineages during mouse embryogenesis. , 1994, Development.

[45]  C. Eng,et al.  De novo germline PTEN mutation in a man with Lhermitte-Duclos disease which arose on the paternal chromosome and was transmitted to his child with polydactyly and Wormian bones , 2003, Journal of medical genetics.

[46]  Y. Ohnishi,et al.  Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction , 2003, Nature Genetics.

[47]  Lisa J. Martin,et al.  A comprehensive linkage analysis for myocardial infarction and its related risk factors , 2002, Nature Genetics.

[48]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[49]  S Shea,et al.  Family history as an independent risk factor for coronary artery disease. , 1984, Journal of the American College of Cardiology.

[50]  M. Lebwohl,et al.  Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN , 1999, Journal of medical genetics.

[51]  W. Reardon,et al.  A novel germline mutation of the PTENgene in a patient with macrocephaly, ventricular dilatation, and features of VATER association , 2001, Journal of medical genetics.

[52]  C Eng,et al.  PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. , 1999, Human molecular genetics.

[53]  E. Topol,et al.  Thrombospondin-4 and Its Variants: Expression and Differential Effects on Endothelial Cells , 2003, Circulation.

[54]  B. Cohen,et al.  The familial occurrence of hypertension and coronary artery disease, with observations concerning obesity and diabetes. , 1955, Annals of internal medicine.