Variants in genes encoding pyrophosphate metabolizing enzymes are associated with Pseudoxanthoma elasticum

Objectives Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder characterized by progressive calcification and fragmentation of elastic fibers. Because of the great clinical variability between PXE patients the involvement of modifier genes was recently suggested. Therefore, we investigated the association of single nucleotide variants (SNVs) in selected candidate genes known to regulate cellular pyrophosphate metabolism. Design and methods We used RLFP analyses to evaluate the distribution of SNVs in alkaline phosphatase (ALP), ectonucleotide pyrophosphatase 1 (ENPP1) and ankylosis (ANKH) in DNA samples from 190 German PXE patients and 190 age- and sex-matched healthy controls. Statistical analyses were performed using Fisher exact test and Bonferroni correction. Results The screening revealed three different SNVs in three genes, which were associated with PXE. The SNV c.1190-65C > A (rs1780329, minor allele frequency (MAF) patients: 0.17; controls: 0.11; P = 0.04) in the ALP gene was significantly more frequent in PXE patients. Furthermore, PXE was highly associated with ANKH p.A98A genotype TT (P = 0.0012), although the MAF was not different between patients and controls. After correction for multiple testing according to the Bonferroni method, one SNV in the ENPP1 gene (c.313 + 9G > T, rs7773477) remained significantly associated with PXE with significantly higher MAF values in the patient cohort (MAF: 0.04 vs. 0.00; P = 0.0024) and a high association with PXE susceptibility (OR 27.96). Conclusion Polymorphisms in ALP, ENPP1 and ANKH are important genetic risk factors contributing to PXE.