Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals
| Autor: | M. Juhani Junttila, Jean-Claude Tardif, Bruno H. Stricker, Renu Virmani, André G. Uitterlinden, W. H. Linda Kao, Xiaoqing Zhao, Christopher Newton-Cheh, L. Adrienne Cupples, Bruce M. Psaty, Y. Antero Kesäniemi, Georg Ehret, Fernando Rivadeneira, Connie R. Bezzina, Greg L. Burke, Aravinda Chakravarti, Audrey Uy-Evanado, Adriana Huertas-Vazquez, Mark Eijgelsheim, John D. Rioux, Carmen Teodorescu, Jacqueline C.M. Witteman, Marja-Leena Kortelainen, Anna Köttgen, Ronald J. Prineas, Kyndaron Reinier, Hanno L. Tan, Albert Hofman, Rudolph W. Koster, Philippe Goyette, Wendy S. Post, Abdennasser Bardai, David S. Siscovick, Caroline Lagacé, Peter M. Spooner, Gabrielle Boucher, Eduardo Marbán, Anna Moes, Pallav Bhatnagar, Gordon F. Tomaselli, Abbas Dehghan, Sumeet S. Chugh, Roos F. Marsman, Gina Hilton, Nona Sotoodehnia, Arthur A.M. Wilde, Heikki V. Huikuri, Christine M. Albert, Eric Boerwinkle, Naima Carter-Monroe, Josef Coresh, Shih-Jen Hwang, Dan E. Arking, Man Li, Raha Pazoki, Christopher J. O'Donnell, Frank D. Kolodgie, Marieke T. Blom, Jonathan Jui, Karen Gunson, Kari S. Kaikkonen |
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| Přispěvatelé: | Cardiology, Ehret, Georg Benedikt, ACS - Amsterdam Cardiovascular Sciences, APH - Amsterdam Public Health, Medical Biology, Epidemiology and Data Science, Epidemiology, Internal Medicine, Medical Informatics |
| Rok vydání: | 2011 |
| Předmět: |
Male
Cancer Research Genome-wide association study Coronary Artery Disease Arrhythmias 030204 cardiovascular system & hematology Cardiovascular Sudden cardiac death Coronary artery disease 0302 clinical medicine hemic and lymphatic diseases Epidemiology Chromosomes Human Pair 2/genetics European Continental Ancestry Group/genetics Genetics (clinical) ddc:616 Genetics 0303 health sciences Genetic Predisposition to Disease/genetics Myocardial Contraction/genetics Middle Aged Polymorphism Single Nucleotide/genetics 3. Good health Chromosomes Human Pair 2 Genetic Loci/genetics Medicine Female Research Article Adult medicine.medical_specialty lcsh:QH426-470 Single-nucleotide polymorphism Locus (genetics) Biology Polymorphism Single Nucleotide White People 03 medical and health sciences Internal medicine Genome-Wide Association Studies medicine Humans Genetic Predisposition to Disease cardiovascular diseases Allele Molecular Biology Genotyping Alleles Ecology Evolution Behavior and Systematics Aged 030304 developmental biology Acute Cardiovascular Problems Human Genetics medicine.disease Myocardial Contraction lcsh:Genetics Death Sudden Cardiac Genetic Loci Genetics of Disease Genome-Wide Association Study |
| Zdroj: | Arking, D E, Junttila, M J, Goyette, P, Huertas-Vazquez, A, Eijgelsheim, M, Blom, M T, Newton-Cheh, C, Reinier, K, Teodorescu, C, Uy-Evanado, A, Carter-Monroe, N, Kaikkonen, K S, Kortelainen, M L, Boucher, G, Lagacé, C, Moes, A, Zhao, X Q, Kolodgie, F, Rivadeneira, F, Hofman, A, Witteman, J C M, Uitterlinden, A G, Marsman, R F, Pazoki, R, Bardai, A, Koster, R W, Dehghan, A, Hwang, S J, Bhatnagar, P, Post, W, Hilton, G, Prineas, R J, Li, M, Köttgen, A, Ehret, G, Boerwinkle, E, Coresh, J, Kao, W H L, Psaty, B M, Tomaselli, G F, Sotoodehnia, N, Siscovick, D S, Burke, G L, Marbán, E, Spooner, P M, Cupples, L A, Jui, J, Gunson, K, Kesäniemi, Y A, Wilde, A A M, Tardif, J C, O'Donnell, C J, Bezzina, C R, Virmani, R, Stricker, B H C H, Tan, H L, Albert, C M, Chakravarti, A, Rioux, J D, Huikuri, H V & Chugh, S S 2011, ' Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in european ancestry individuals ', PLoS Genetics, vol. 7, no. 6, e1002158 . https://doi.org/10.1371/journal.pgen.1002158 PLoS Genetics, 7(6):e1002158. Public Library of Science PLOS Genetics, Vol. 7, No 6 (2011) P. e1002158 PLoS Genetics PLoS genetics, 7(6). Public Library of Science PLoS Genetics, Vol 7, Iss 6, p e1002158 (2011) PLoS Genetics (print), 7(6). Public Library of Science |
| ISSN: | 1553-7404 1553-7390 |
| DOI: | 10.1371/journal.pgen.1002158 |
| Popis: | Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006). Author Summary Family studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), however genetic studies have been limited by available samples. Here we have assembled over 4,400 SCD cases with >30,000 controls, all of European ancestry, and utilize a two-stage study design. In the first stage, we conducted an unbiased genome-wide scan in 1,283 SCD cases and >20,000 controls, and then performed follow-up genotyping in the remainder of the samples. We demonstrate strong association to a region of the genome not previously implicated in SCD, the BAZ2B locus, which contains 3 genes not previously known to play a role in cardiac biology. In addition, we used the genome-wide scan data to test a focused hypothesis that genetic variants that modulate ECG traits associated with SCD (QT, QRS, and RR intervals) also modify risk for SCD, and we demonstrate that QT- and QRS-prolonging alleles are, as a group, associated with increased risk of SCD. Taken together, these findings begin to elucidate the genetic contribution to SCD susceptibility and provide important targets for functional studies to investigate the etiology and pathogenesis of SCD. |
| Databáze: | OpenAIRE |
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