Pathogenic variants in theABCC6gene are associated with an increased risk for ischemic stroke

Abstract

AbstractIschemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated theABCC6gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenicABCC6variants, the higher cardiovascular risk in heterozygous carriers and the established role ofABCC6dysfunction in myocardial ischemia. We established segregation of a known pathogenicABCC6variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case‐control study in 424 ischemic stroke patients and 250 healthy controls, pathogenicABCC6variants were 4.9 times more frequent (P= 0.036; 95% CI 1.11–21.33) in the ischemic stroke patient cohort. To study cellular consequences ofABCC6deficiency in the brain, immunostaining of brain sections inAbcc6‐deficient mice and wild‐type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified inAbcc6−/− mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro‐ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenicABCC6variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygousABCC6variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfβ (Eng) signaling in the brain ofAbcc6−/− mice could lead to a pro‐ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of theABCC6gene in patients diagnosed with cryptogenic ischemic stroke.