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 (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.
Shimizu
Chisato
C
Rady Children's Hospital and Departments of Pediatrics, UCSD School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Matsubara
Tomoyo
T
Onouchi
Yoshihiro
Y
Jain
Sonia
S
Sun
Shelly
S
Nievergelt
Caroline M
CM
Shike
Hiroko
H
Brophy
Victoria H
VH
Takegawa
Tsuyoshi
T
Furukawa
Susumu
S
Akagi
Teiji
T
Newburger
Jane W
JW
Baker
Annette L
AL
Burgner
David
D
Hibberd
Martin L
ML
Davila
Sonia
S
Levin
Michael
M
Mamtani
Manju
M
He
Weijing
W
Ahuja
Sunil K
SK
Burns
Jane C
JC
D016022:Case-Control Studies; D002648:Child; D003323:Coronary Aneurysm / Q000209:etiology* / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics*; D009080:Mucocutaneous Lymph Node Syndrome / Q000150:complications*; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide
D020782:Matrix Metalloproteinases
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