Year: 2012
Type: dissertation
Study design: Observational Study
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) and long QT syndrome (LQTS) are inherited cardiac arrhythmia disorders that predispose to sudden cardiac death (SCD). In ARVC, structural and electrical abnormalities of the heart occur together with progressive replacement of the right ventricular myocardium by adipose and fibrous tissue. Mutations in desmosomal cell adhesion genes may cause ARVC. LQTS manifests with a prolonged electrocardiographic QT interval in a structurally normal heart. LQTS is caused by mutations in cardiac ion channel genes, delaying the repolarization of the ventricular myocardium. The aims of this study were to identify genetic variants predisposing to ARVC, LQTS, and SCD and to assess their prevalence and clinical significance in the Finnish population. Six (18%) of 33 ARVC probands were identified to carry mutations in desmosomal genes. Desmosomal mutations occurred together with disorganization of the intercalated disk structure and demonstrated reduced disease penetrance. The carrier frequency of the desmosomal mutations identified in this study was 1:250 as estimated in a sample of 27 670 Finns. Therefore, an unexpectedly large number of individuals could be at risk of developing ARVC in Finland. However, another trigger is likely to be needed for disease expression. In a clinical sample of 712 LQTS founder mutation carriers, KCNE1 D85N was associated with a 26-ms prolongation of QT interval in males with KCNQ1 G589D, representing thus a potential sex-specific disease-modifying factor. In a population sample of 6808 Finns, KCNE1 D85N together with 13 other genetic variants explained 8.6% of the variation in QT interval, and a 10-ms prolongation of QT interval was associated with a 19% increased risk of SCD. This information could ultimately contribute to assessment of individual susceptibility to LQTS. When studied in a total of 28 323 individuals, two novel common variants, rs41312391 in SCN5A and rs2200733 in 4q25 near PITX2, were associated with risk of SCD. In addition, the associations for rs2383207 in 9p21 and for clinical risk factors for coronary heart disease were replicated. Rare mutations in desmosomal and ion channel genes had a combined carrier frequency of 1:130 in the Finnish population and were detected in individual SCD victims. These results provide novel information for SCD risk prediction and prevention.
Source: Työväentutkimus Vuosikirja
Author: Annukka M. Lahtinen
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Massachusetts General Hospital, Foundation for Cardiovascular Research, Helsingin Yliopisto, Helsingin ja Uudenmaan Sairaanhoitopiiri, Broad Institute, Academy of Finland, Suomen Kulttuurirahasto, Tampereen Yliopisto, Sydäntutkimussäätiö, Sigrid Juséliuksen Säätiö, Terveyden ja hyvinvoinnin laitos
OpenAlex ID: W1183687374