TY - JOUR
T1 - Genotype-phenotype correlation in pseudoxanthoma elasticum
AU - Bartstra, Jonas W.
AU - Risseeuw, Sara
AU - de Jong, Pim A.
AU - van Os, Bram
AU - Kalsbeek, Lianne
AU - Mol, Chris
AU - Baas, Annette F.
AU - Verschuere, Shana
AU - Vanakker, Olivier
AU - Florijn, Ralph J.
AU - Hendrikse, Jeroen
AU - Mali, Willem
AU - Imhof, Saskia
AU - Ossewaarde-van Norel, Jeannette
AU - van Leeuwen, Redmer
AU - Spiering, Wilko
N1 - Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.
AB - Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.
KW - ABCC6
KW - Arterial calcification
KW - Choroidal neovascularization
KW - Genotype-phenotype
KW - Peripheral arterial disease
KW - Pseudoxanthoma elasticum
KW - Genetic Association Studies
KW - Humans
KW - Middle Aged
KW - Peripheral Arterial Disease/diagnostic imaging
KW - Genotype
KW - Phenotype
KW - Pseudoxanthoma Elasticum/diagnosis
UR - http://www.scopus.com/inward/record.url?scp=85104724751&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2021.03.012
DO - 10.1016/j.atherosclerosis.2021.03.012
M3 - Article
C2 - 33812167
AN - SCOPUS:85104724751
SN - 0021-9150
VL - 324
SP - 18
EP - 26
JO - Atherosclerosis
JF - Atherosclerosis
ER -