期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 92, 期 3, 页码 366-374出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.01.012
关键词
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资金
- British Heart Foundation
- William Harvey Research Foundation
- Chinese Scholarship Council
- British Heart Foundation Intermediate Basic Science Research Fellowship [FS/09/044/28007]
- National Institute for Health Research
- MRC [G0600237, G9521010] Funding Source: UKRI
- British Heart Foundation [FS/09/044/28007, PG/11/40/28891, FS/12/82/29736, FS/11/28/28758] Funding Source: researchfish
- Medical Research Council [G0600237, G9521010, MR/K006584/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10113] Funding Source: researchfish
Recent genome-wide association studies have revealed an association between variation at the ADAMTS7 locus and susceptibility to coronary artery disease (CAD). Furthermore, in a population-based study cohort, we observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a Ser-to-Pro substitution in the prodomain of the protease ADAMTS7. In light of these data, we sought a mechanistic explanation for this association. We found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) of the GIG genotype for rs3825807 had reduced migratory ability, and conditioned media of VSMCs of the GIG genotype contained less of the cleaved form of thrombospondin-5, an ADAMTS7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration. Furthermore, we found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by VSMCs of the GIG genotype and that the Ser-to-Pro substitution affected ADAMTS7 prodomain cleavage. The results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD rendering a reduction in ADAMTS7 function.
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