Plakophilin-2 c.419C>T and risk of heart failure and arrhythmias in the general population.
A rare genetic variant in the desmosomal gene plakophilin-2 (PKP2) c.419C>T(p.(S140F)) has repeatedly been identified in patients with dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Whether this is a disease-causing variant remains highly controversial. We tested this hypothesis using three approaches. Initially, in a prospective study of 10 407 individuals from the general population, including 2688 who developed heart failure or arrhythmias during >14 years of follow-up, PKP2 c.419C>T was identified in 98 individuals (0.94%). PKP2 genotype was not associated with electrocardiographic or echocardiographic changes, or with plasma levels of probrain natriuretic peptide (all P≥0.05). In c.419C>T carriers versus non-carriers, multifactorially adjusted hazard ratios were 1.26 (95% confidence interval: 0.77-2.07) for heart failure, 1.40 (0.90-2.17) for arrhythmias, 1.15 (0.78-1.71) for end points combined, and 1.33 (0.98-1.80) for all-cause mortality. The cumulative survival as a function of age and PKP2 genotype was similar among carriers and non-carriers (P=0.14). Second, comparing 517 patients referred for genetic testing with 1918 matched controls, odds ratios as a function of c.419C>T genotype were 2.11 (0.50-8.99) for ARVC, 0.72 (0.16-3.28) for hypertrophic cardiomyopathy (HCM)/DCM, and 1.28 (0.46-3.54) for end points combined. Third, in in vitro studies cellular localization of plakophilin-2, plakoglobin, connexin-43, or N-cadherin were similar in cells transfected with wild-type or mutant plakophilin-2. In conclusion, combining epidemiological data, with data on patients referred for genetic testing for ARVC or HCM/DCM, and data from in vitro studies, PKP2 c.419C>T did not associate with heart failure, arrhythmias, or premature death, with ARVC or HCM/DCM, or with effects in vitro, suggesting that this is not a disease-causing variant.
Department of Cardiology, Bispebjerg Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Alex Hørby
AH
Christensen
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Pia Rørbœk
PR
Kamstrup
Inserm/UMR_S1166, ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
Estelle
E
Gandjbakhch
Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Marianne
M
Benn
Department of Cardiology, Gentofte Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jan Skov
JS
Jensen
Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
Henning
H
Bundgaard
Inserm/UMR_S1166, ICAN, Hôpital Pitié-Salpêtrière, Paris, France.
Eric
E
Villard
Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.|The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Copenhagen, Denmark.
Anne
A
Tybjærg-Hansen
D000368:Aged; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000453:epidemiology / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D051191:Plakophilins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D018497:Ventricular Dysfunction, Right / Q000453:epidemiology / Q000235:genetics*
C495337:PKP2 protein, human; D051191:Plakophilins