The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease.

Loss-of-function mutations of ABCC6 cause pseudoxanthoma elasticum (PXE). This Mendelian disorder is characterized by elastic calcification leading to dermal, ocular, and cardiovascular symptoms like coronary artery disease (CAD) and stroke. Although PXE is a recessive disease, microscopic dermal lesions, serum alterations, and higher anecdotal incidence of stroke or CAD among carriers were reported. Here we investigated the association of the c.3421C>T loss-of-function mutation of ABCC6 and CAD and stroke. A previous study demonstrated the association of the c.3421C>T mutation with CAD; however, the frequency found in the control population was unexpectedly high, contradicting, thus, the prevalence of PXE. In the present study, genomic DNA from 749 healthy blood donors was used as control, while 363 and 361 patients suffering from stroke and CAD were investigated, respectively. One carrier was found in our control group, which is in accordance with the reported prevalence of this mutation. No significant association was found between carrier status and stroke in our cohort. In contrast, a significant association of carrier status and CAD was observed (5/361 carriers: p = 0.016, odds ratio [OR] = 10.5). We propose that carriers of ABCC6 loss-of-function mutations benefit from CAD prevention therapy.