TY - JOUR T1 - Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. JF - PLoS One Y1 - 2010 A1 - Arking, Dan E A1 - Reinier, Kyndaron A1 - Post, Wendy A1 - Jui, Jonathan A1 - Hilton, Gina A1 - O'Connor, Ashley A1 - Prineas, Ronald J A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Rea, Thomas A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Gregory L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Chakravarti, Aravinda A1 - Chugh, Sumeet S KW - Aged KW - Alleles KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Ethnic Groups KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glypicans KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Oligonucleotide Array Sequence Analysis KW - Oregon KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

VL - 5 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20360844?dopt=Abstract ER - TY - JOUR T1 - Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. JF - PLoS Genet Y1 - 2011 A1 - Arking, Dan E A1 - Junttila, M Juhani A1 - Goyette, Philippe A1 - Huertas-Vazquez, Adriana A1 - Eijgelsheim, Mark A1 - Blom, Marieke T A1 - Newton-Cheh, Christopher A1 - Reinier, Kyndaron A1 - Teodorescu, Carmen A1 - Uy-Evanado, Audrey A1 - Carter-Monroe, Naima A1 - Kaikkonen, Kari S A1 - Kortelainen, Marja-Leena A1 - Boucher, Gabrielle A1 - Lagacé, Caroline A1 - Moes, Anna A1 - Zhao, XiaoQing A1 - Kolodgie, Frank A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - Uitterlinden, André G A1 - Marsman, Roos F A1 - Pazoki, Raha A1 - Bardai, Abdennasser A1 - Koster, Rudolph W A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Bhatnagar, Pallav A1 - Post, Wendy A1 - Hilton, Gina A1 - Prineas, Ronald J A1 - Li, Man A1 - Köttgen, Anna A1 - Ehret, Georg A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Kao, W H Linda A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Greg L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Cupples, L Adrienne A1 - Jui, Jonathan A1 - Gunson, Karen A1 - Kesaniemi, Y Antero A1 - Wilde, Arthur A M A1 - Tardif, Jean-Claude A1 - O'Donnell, Christopher J A1 - Bezzina, Connie R A1 - Virmani, Renu A1 - Stricker, Bruno H C H A1 - Tan, Hanno L A1 - Albert, Christine M A1 - Chakravarti, Aravinda A1 - Rioux, John D A1 - Huikuri, Heikki V A1 - Chugh, Sumeet S KW - Adult KW - Aged KW - Alleles KW - Chromosomes, Human, Pair 2 KW - Death, Sudden, Cardiac KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Contraction KW - Polymorphism, Single Nucleotide AB -

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).

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738491?dopt=Abstract ER - TY - JOUR T1 - Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest. JF - Heart Rhythm Y1 - 2014 A1 - Lemaitre, Rozenn N A1 - Johnson, Catherine O A1 - Hesselson, Stephanie A1 - Sotoodehnia, Nona A1 - Sotoodhenia, Nona A1 - McKnight, Barbara A1 - Sitlani, Colleen M A1 - Rea, Thomas D A1 - King, Irena B A1 - Kwok, Pui-Yan A1 - Mak, Angel A1 - Li, Guo A1 - Brody, Jennifer A1 - Larson, Eric A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Huertas-Vazquez, Adriana A1 - Tardif, Jean-Claude A1 - Albert, Christine M A1 - Lyytikäinen, Leo-Pekka A1 - Arking, Dan E A1 - Kääb, Stefan A1 - Huikuri, Heikki V A1 - Krijthe, Bouwe P A1 - Eijgelsheim, Mark A1 - Wang, Ying A A1 - Reinier, Kyndaron A1 - Lehtimäki, Terho A1 - Pulit, Sara L A1 - Brugada, Ramon A1 - Müller-Nurasyid, Martina A1 - Newton-Cheh, Chris H A1 - Karhunen, Pekka J A1 - Stricker, Bruno H A1 - Goyette, Philippe A1 - Rotter, Jerome I A1 - Chugh, Sumeet S A1 - Chakravarti, Aravinda A1 - Jouven, Xavier A1 - Siscovick, David S KW - 1-Acylglycerophosphocholine O-Acyltransferase KW - Aged KW - Algorithms KW - Alleles KW - Case-Control Studies KW - Death, Sudden, Cardiac KW - Fatty Acids KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: There is limited information on genetic factors associated with sudden cardiac arrest (SCA).

OBJECTIVE: To assess the association of common variation in genes in fatty acid pathways with SCA risk.

METHODS: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases.

RESULTS: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase.

CONCLUSIONS: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24418166?dopt=Abstract ER -