Abstract
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).
Highlights
Despite recent progress in treatment and prevention of coronary heart disease, sudden cardiac death (SCD) remains a major public health problem, with an annual incidence of SCD that ranges from 50 to 100 per 100,000 in the general population [1,2]
Studies have clearly demonstrated a role for genes in modifying risk for sudden cardiac death (SCD), genetic studies have been limited by available samples
We have assembled over 4,400 SCD cases with .30,000 controls, all of European ancestry, and utilize a two-stage study design
Summary
Despite recent progress in treatment and prevention of coronary heart disease, sudden cardiac death (SCD) remains a major public health problem, with an annual incidence of SCD that ranges from 50 to 100 per 100,000 in the general population [1,2]. While there has been a great deal of focus on SCD in the setting of Mendelian forms of arrhythmia (e.g. long and short QT syndromes), the vast majority of SCD events occur in the general population, with up to 50% of individuals manifesting SCD as a first sign of disease [3]. An estimated ,80% of all SCDs are associated with coronary disease, ,10–15% in the setting of cardiomyopathy and ,5% occur in persons with myocarditis, coronary anomalies or ion channelopathies (e.g. long QT/ Brugada/short QT syndromes) [4]. Despite this clinical heterogeneity, a familial component to SCD risk has been demonstrated even after adjusting for traditional cardiovascular disease risk
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