Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6

• Published in: Gene 2024-11, Vol.927, p.148731, Article 148731
• Main Authors: Schott, Clara, Dilliott, Allison A., Wang, Jian, McIntyre, Adam D., Son, Surim, Colaiacovo, Samantha, Baker, Cadence, Gunaratnam, Lakshman, House, Andrew A., Susan Huang, Shih-Han, Iyer, Hariharan, Johnson, John, Lotfy, Khaled, Masellis, Mario, Munoz, Douglas P., Rehman, Faisal, Roshanov, Pavel S., Swartz, Richard H., Weir, Matthew A., Hegele, Robert A., Connaughton, Dervla M.
• Format: Article
• Language: English
• Subjects: ABCC6; Adult; Aged; calcification; Chronic kidney disease; ENPP1; Exome sequencing; Female; genes; Genetic kidney disease; Genetic Predisposition to Disease; heterozygosity; Humans; kidney diseases; Male; Middle Aged; mortality; Multidrug Resistance-Associated Proteins - genetics; neurodegenerative diseases; Ontario; pathogenesis; phenotype; Renal Insufficiency, Chronic - genetics; risk; therapeutics; Vascular calcification; Vascular Calcification - genetics; Vascular Calcification - pathology
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148731

[Display omitted] •Vascular calcification is prevalent in chronic kidney disease patients.•ABCC6 is a candidate gene for vascular calcification seen in kidney disease.•ABCC6 variants cause a pseudoxanthoma elasticum phenotype with calcification.•Pathogenic ABCC6 variants are more common in calcification patients than controls.•ABCC6 and ENPP1 in the ectopic calcification pathway may be digenic. Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10–20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality.