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

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).

%B PLoS Genet %V 7 %P e1002158 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21738491?dopt=Abstract %R 10.1371/journal.pgen.1002158 %0 Journal Article %J J Mol Med (Berl) %D 2015 %T Association of mitochondrial DNA levels with frailty and all-cause mortality. %A Ashar, Foram N %A Moes, Anna %A Moore, Ann Z %A Grove, Megan L %A Chaves, Paulo H M %A Coresh, Josef %A Newman, Anne B %A Matteini, Amy M %A Bandeen-Roche, Karen %A Boerwinkle, Eric %A Walston, Jeremy D %A Arking, Dan E %K African Americans %K Aged %K Aged, 80 and over %K Aging %K DNA, Mitochondrial %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Dosage %K Geriatric Assessment %K Humans %K Kaplan-Meier Estimate %K Male %K Mortality %K Odds Ratio %K Population Surveillance %K Prospective Studies %K Surveys and Questionnaires %K United States %X

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3% men) from CHS and 11,509 participants (44.9% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

%B J Mol Med (Berl) %V 93 %P 177-186 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25471480?dopt=Abstract %R 10.1007/s00109-014-1233-3 %0 Journal Article %J JAMA Cardiol %D 2017 %T Association of Mitochondrial DNA Copy Number With Cardiovascular Disease. %A Ashar, Foram N %A Zhang, Yiyi %A Longchamps, Ryan J %A Lane, John %A Moes, Anna %A Grove, Megan L %A Mychaleckyj, Josyf C %A Taylor, Kent D %A Coresh, Josef %A Rotter, Jerome I %A Boerwinkle, Eric %A Pankratz, Nathan %A Guallar, Eliseo %A Arking, Dan E %X

Importance: Mitochondrial dysfunction is a core component of the aging process and may play a key role in atherosclerotic cardiovascular disease. Mitochondrial DNA copy number (mtDNA-CN), which represents the number of mitochondria per cell and number of mitochondrial genomes per mitochondrion, is an indirect biomarker of mitochondrial function.

Objective: To determine whether mtDNA-CN, measured in an easily accessible tissue (buffy coat/circulating leukocytes), can improve risk classification for cardiovascular disease (CVD) and help guide initiation of statin therapy for primary prevention of CVD.

Design, Setting, and Participants: Prospective, population-based cohort analysis including 21 870 participants (20 163 free from CVD at baseline) from 3 studies: Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities Study (ARIC), and Multiethnic Study of Atherosclerosis (MESA). The mean follow-up was 13.5 years. The study included 11 153 participants from ARIC, 4830 from CHS, and 5887 from MESA. Analysis of the data was conducted from March 10, 2014, to January 29, 2017.

Exposures: Mitochondrial DNA-CN measured from buffy coat/circulating leukocytes.

Main Outcomes and Measures: Incident CVD, which combines coronary heart disease, defined as the first incident myocardial infarction or death owing to coronary heart disease, and stroke, defined as the first nonfatal stroke or death owing to stroke.

Results: Of the 21 870 participants, the mean age was 62.4 years (ARIC, 57.9 years; MESA, 62.4 years; and CHS, 72.5 years), and 54.7% of participants were women. The hazard ratios for incident coronary heart disease, stroke, and CVD associated with a 1-SD decrease in mtDNA-CN were 1.29 (95% CI, 1.24-1.33), 1.11 (95% CI, 1.06-1.16), and 1.23 (95% CI, 1.19-1.26). The associations persisted after adjustment for traditional CVD risk factors. Addition of mtDNA-CN to the 2013 American College of Cardiology/American Heart Association Pooled Cohorts Equations for estimating 10-year hard atherosclerosis CVD risk was associated with improved risk classification (continuous net reclassification index, 0.194; 95% CI, 0.130-0.258; P < .001). Mitochondrial DNA-CN further improved sensitivity and specificity for the 2013 American College of Cardiology/American Heart Association recommendations on initiating statin therapy for primary prevention of ASCVD (net 221 individuals appropriately downclassified and net 15 individuals appropriately upclassified).

Conclusions and Relevance: Mitochondrial DNA-CN was independently associated with incident CVD in 3 large prospective studies and may have potential clinical utility in improving CVD risk classification.

%B JAMA Cardiol %V 2 %P 1247-1255 %8 2017 Nov 01 %G eng %N 11 %R 10.1001/jamacardio.2017.3683 %0 Journal Article %J Eur Heart J %D 2018 %T A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. %A Ashar, Foram N %A Mitchell, Rebecca N %A Albert, Christine M %A Newton-Cheh, Christopher %A Brody, Jennifer A %A Müller-Nurasyid, Martina %A Moes, Anna %A Meitinger, Thomas %A Mak, Angel %A Huikuri, Heikki %A Junttila, M Juhani %A Goyette, Philippe %A Pulit, Sara L %A Pazoki, Raha %A Tanck, Michael W %A Blom, Marieke T %A Zhao, XiaoQing %A Havulinna, Aki S %A Jabbari, Reza %A Glinge, Charlotte %A Tragante, Vinicius %A Escher, Stefan A %A Chakravarti, Aravinda %A Ehret, Georg %A Coresh, Josef %A Li, Man %A Prineas, Ronald J %A Franco, Oscar H %A Kwok, Pui-Yan %A Lumley, Thomas %A Dumas, Florence %A McKnight, Barbara %A Rotter, Jerome I %A Lemaitre, Rozenn N %A Heckbert, Susan R %A O'Donnell, Christopher J %A Hwang, Shih-Jen %A Tardif, Jean-Claude %A VanDenburgh, Martin %A Uitterlinden, André G %A Hofman, Albert %A Stricker, Bruno H C %A de Bakker, Paul I W %A Franks, Paul W %A Jansson, Jan-Håkan %A Asselbergs, Folkert W %A Halushka, Marc K %A Maleszewski, Joseph J %A Tfelt-Hansen, Jacob %A Engstrøm, Thomas %A Salomaa, Veikko %A Virmani, Renu %A Kolodgie, Frank %A Wilde, Arthur A M %A Tan, Hanno L %A Bezzina, Connie R %A Eijgelsheim, Mark %A Rioux, John D %A Jouven, Xavier %A Kääb, Stefan %A Psaty, Bruce M %A Siscovick, David S %A Arking, Dan E %A Sotoodehnia, Nona %X

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

%B Eur Heart J %8 2018 Aug 28 %G eng %R 10.1093/eurheartj/ehy474