Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease

Chisato Shimizu, Tomoyo Matsubara, Yoshihiro Onouchi, Sonia Jain, Shelly Sun, Caroline M. Nievergelt, Hiroko Shike, Victoria H. Brophy, Tsuyoshi Takegawa, Susumu Furukawa, Teiji Akagi, Jane W. Newburger, Annette L. Baker, David Burgner, Martin L. Hibberd, Sonia Davila, Michael Levin, Manju Mamtani, Weijing He, Sunil K. AhujaJane C. Burns

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31 Citations (Scopus)

Abstract

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4×10-5) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation.

Original languageEnglish
Pages (from-to)779-784
Number of pages6
JournalJournal of Human Genetics
Volume55
Issue number12
DOIs
Publication statusPublished - Dec 1 2010

Keywords

  • Kawasaki disease
  • coronary artery aneurysm
  • haplotype
  • matrix metalloproteinase

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Shimizu, C., Matsubara, T., Onouchi, Y., Jain, S., Sun, S., Nievergelt, C. M., Shike, H., Brophy, V. H., Takegawa, T., Furukawa, S., Akagi, T., Newburger, J. W., Baker, A. L., Burgner, D., Hibberd, M. L., Davila, S., Levin, M., Mamtani, M., He, W., ... Burns, J. C. (2010). Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease. Journal of Human Genetics, 55(12), 779-784. https://doi.org/10.1038/jhg.2010.109