Plakophilin-2 c.419C>T and risk of heart failure and arrhythmias in the general population

Abstract

A rare genetic variant in the desmosomal gene plakophilin-2 (PKP2) c.419C4T(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 414 years of follow-up, PKP2 c.419C4T 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.419C4T 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 allcause 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.419C4T 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.419C4T 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.

Genetics and genomics of dilated cardiomyopathy and systolic heart failure

“…However, some of the more recent associations of desmosomal protein gene variants have limited variant curation and segregation data, such as PKP2 [ 62 ] (which encodes plakophilin 2), and these associations are less clear. One such PKP2 variant (c.419C > T(p.(S140F)), previously linked to DCM has been shown not to be associated with heart failure phenotypes [ 63 ]. Therefore, of the desmosomal proteins, DSP variants have the most robust association with DCM.…”