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

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease 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 8 polymorphisms in 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 Kawasaki disease patients (aneurysm+: n=111, aneurysm−: n=371) and tested our findings in an independent cohort of 200 Japanese Kawasaki disease 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= 2-4 × 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 Kawasaki disease. The region encompassing these risk haplotypes is a prime candidate for re-sequencing to look for rare genetic variation that may influence aneurysm formation.