Journal
CIRCULATION-GENOMIC AND PRECISION MEDICINE
Volume 13, Issue 6, Pages 599-608Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGEN.120.002911
Keywords
Brugada syndrome; genetics; human; penetrance; phenotype; risk score
Funding
- James Lancaster Memorial Fund - McColl's RG Ltd.
- National Institute of Health Research
- Higher Education Funding Council for England
- British Heart Foundation (BHF)
- BHF Project Grant [PG/15/107/31908]
- BHF Clinical Research Training Fellowship [FS/11/71/28918]
- Medical Research Council
- Dutch Heart Foundation
- Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]
- Philippa and Marvin Carsley Cardiology Chair
- Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program
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Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS >= 4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS >= 4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS >= 4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting >= 4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
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