TY - JOUR
T1 - Genetic variants in SUSD2 are associated with the risk of ischemic heart disease
AU - Bruikman, Caroline S.
AU - Dalila, Nawar
AU - van Capelleveen, Julian C.
AU - Kroon, Jeffrey
AU - Peter, Jorge
AU - Havik, Stefan R.
AU - Willems, Martine
AU - Huisman, Laurens C.
AU - de Boer, Onno J.
AU - Hovingh, G. Kees
AU - Tybjaerg-Hansen, Anne
AU - Dallinga-Thie, Geesje M.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Background: Genetic factors partly determine the risk for premature myocardial infarction (MI). Objectives: We report the identification of a novel rare genetic variant in a kindred with an autosomal dominant trait for premature MI and atherosclerosis and explored the association of a common nonsynonymous variant in the same gene with the risk of ischemic heart disease (IHD) in a population-based study. Methods: Next-generation sequencing was performed in a small pedigree with premature MI or subclinical atherosclerosis. A common variant, rs8141797 A>G (p.Asn466Ser), in sushi domain–containing protein 2 (SUSD2) was studied in the prospective Copenhagen General Population Studies (N = 105,408) for association with IHD. Results: A novel heterozygous nonsense mutation in SUSD2 (c.G583T; p.Glu195Ter) was associated with the disease phenotype in the pedigree. SUSD2 protein was expressed in aortic specimens in the subendothelial cell layer and around the vasa vasorum. Furthermore, the minor G-allele of rs8141797 was associated with per allele higher levels of SUSD2 mRNA expression in the heart and vasculature. In the Copenhagen General Population Study, hazard ratios for IHD were 0.92 (95% CI: 0.87–0.97) in AG heterozygotes and 0.86 (0.62–1.19) in GG homozygotes vs noncarrriers (P-trend =.002). Finally, in meta-analysis including 73,983 IHD cases and 215,730 controls, the odds ratio for IHD per G-allele vs A-allele was 0.93 (0.90–0.96) (P = 4.6 × 10−7). Conclusions: The identification of a truncating mutation in SUSD2, which was associated with premature MI and subclinical atherosclerosis, combined with the finding that a common missense variant in SUSD2 was strongly associated with a lower risk of IHD, suggest that SUSD2 may alter the risk of atherosclerosis.
AB - Background: Genetic factors partly determine the risk for premature myocardial infarction (MI). Objectives: We report the identification of a novel rare genetic variant in a kindred with an autosomal dominant trait for premature MI and atherosclerosis and explored the association of a common nonsynonymous variant in the same gene with the risk of ischemic heart disease (IHD) in a population-based study. Methods: Next-generation sequencing was performed in a small pedigree with premature MI or subclinical atherosclerosis. A common variant, rs8141797 A>G (p.Asn466Ser), in sushi domain–containing protein 2 (SUSD2) was studied in the prospective Copenhagen General Population Studies (N = 105,408) for association with IHD. Results: A novel heterozygous nonsense mutation in SUSD2 (c.G583T; p.Glu195Ter) was associated with the disease phenotype in the pedigree. SUSD2 protein was expressed in aortic specimens in the subendothelial cell layer and around the vasa vasorum. Furthermore, the minor G-allele of rs8141797 was associated with per allele higher levels of SUSD2 mRNA expression in the heart and vasculature. In the Copenhagen General Population Study, hazard ratios for IHD were 0.92 (95% CI: 0.87–0.97) in AG heterozygotes and 0.86 (0.62–1.19) in GG homozygotes vs noncarrriers (P-trend =.002). Finally, in meta-analysis including 73,983 IHD cases and 215,730 controls, the odds ratio for IHD per G-allele vs A-allele was 0.93 (0.90–0.96) (P = 4.6 × 10−7). Conclusions: The identification of a truncating mutation in SUSD2, which was associated with premature MI and subclinical atherosclerosis, combined with the finding that a common missense variant in SUSD2 was strongly associated with a lower risk of IHD, suggest that SUSD2 may alter the risk of atherosclerosis.
KW - Epidemiology
KW - Genetics
KW - Human
KW - Myocardial infarction
KW - Premature atherosclerosis
KW - SUSD2
UR - http://www.scopus.com/inward/record.url?scp=85087343456&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jacl.2020.05.100
DO - https://doi.org/10.1016/j.jacl.2020.05.100
M3 - Article
C2 - 32620384
SN - 1933-2874
VL - 14
SP - 470
EP - 481
JO - Journal of clinical lipidology
JF - Journal of clinical lipidology
IS - 4
ER -