Heterozygous ABCC6 variant carriers are not at a higher risk for cardiovascular disease events than noncarriers
M Haverkamp, K Van Der Sijs, N C Onland-Moret, P A De Jong, F L J Visseren, J Van Setten, W SpieringAbstract
Background
Cardiovascular disease is a major health burden resulting from both environmental and genetic factors. Pseudoxanthoma elasticum is a rare, genetic disease caused by homozygous pathogenic ABCC6 variants, resulting in arterial calcification and increased cardiovascular risk. However, whether heterozygous carriers also have increased cardiovascular risk is uncertain.
Objectives
To evaluate the relationship between pathogenic and likely pathogenic ABCC6 variants in heterozygous carriers and the risk for cardiovascular events in two large prospective cohorts.
Methods
For this study, we included unrelated participants of White British European ancestry who participated in the UK Biobank (UKB), had whole-genome sequencing data available, and had no history of cardiovascular disease. Moreover, we included unrelated participants of European ancestry with a cardiovascular history from the high vascular risk UCC-SMART cohort. Likely pathogenic and pathogenic variants in the ABCC6 gene were identified through searching databases and international PXE cohorts. Participants with these variants were labelled as carriers. Cardiovascular endpoints included myocardial infarction (MI), stroke, and cardiovascular death (CVD), and were identified through linkage to health records using ICD-9 and ICD-10 codes (UKB) and biannual questionnaires (UCC-SMART). The relationship between ABCC6 carrier status and cardiovascular events was analyzed using Cox proportional hazards models and adjusted for potential confounders, including age, sex, and principal components.
Results
A total of 315,858 UKB participants were included, with a mean age of 57±8 years (45% males). Among these, 4,963 (1.56%) were heterozygous carriers of 154 different ABCC6 variants. Over a median follow-up period of 13.7 years [IQR 12.9-14.4], 17,627 primary cardiovascular events occurred, including 7,368 strokes, 5,982 MIs, and 4,277 CVDs. Heterozygous carriers of ABCC6 did not have a higher risk of primary cardiovascular events than noncarriers (HR in UKB 0.95; 95%CI 0.84-1.07). In the UCC-SMART cohort, 4,402 participants were included, of whom 57 were carriers of ABCC6 variants. These carriers did not have a higher risk of secondary cardiovascular events than noncarriers (HR in UCC-SMART 0.94; 95%CI 0.59-1.50).
Conclusion
Carrying a single pathogenic ABCC6 variant is not associated with higher cardiovascular risk. We found no evidence to support the current guidelines' advice to screen for cardiovascular risk factors in heterozygous carriers.Forest plot