Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms.
BACKGROUND
Abdominal aortic aneurysms (AAAs) are characterized by histologic signs of chronic inflammation, destructive remodeling of extracellular matrix, and depletion of vascular smooth muscle cells. We investigated the process of extracellular matrix remodeling by performing a genetic association study with polymorphisms in the genes for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and structural extracellular matrix molecules in AAA. Our hypothesis was that genetic variations in one or more of these genes contribute to greater or lesser activity of these gene products, and thereby contribute to susceptibility for developing AAAs.


METHODS
DNA samples from 812 unrelated white subject (AAA, n = 387; controls, n = 425) were genotyped for 14 polymorphisms in 13 different candidate genes: MMP1(nt-1607), MMP2(nt-955), MMP3(nt-1612), MMP9(nt-1562), MMP10(nt+180), MMP12(nt-82), MMP13(nt-77), TIMP1(nt+434), TIMP1(rs2070584), TIMP2(rs2009196), TIMP3(nt-1296), TGFB1(nt-509), ELN(nt+422), and COL3A1(nt+581). Odds ratios and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test for association between genotype and disease status. Haplotype analysis was carried out for the two TIMP1 polymorphisms in male subjects.


RESULTS
Analyses with one polymorphism per test without interactions showed an association with the two TIMP1 gene polymorphisms (nt+434, P = .0047; rs2070584, P = .015) in male subjects without a family history of AAA. The association remained significant when analyzing TIMP1 haplotypes (chi 2 P = .014 and empirical P = .009). In addition, we found a significant interaction between the polymorphism and gender for MMP10 ( P = .037) in cases without a family history of AAA, as well as between the polymorphism and country of origin for ELN ( P = .0169) and TIMP3 ( P = .0023) in cases with a family history of AAA.


CONCLUSIONS
These findings suggest that genetic variations in TIMP1, TIMP3, MMP10, and ELN genes may contribute to the pathogenesis of AAAs. Further work is needed to confirm the findings in an independent set of samples and to study the functional role of these variants in AAA. It is noteworthy that contrary to a previous study, we did not find an association between the MMP9 (nt-1562) polymorphism and AAA, suggesting genetic heterogeneity of the disease.


CONCLUSIONS
Abdominal aortic aneurysms (AAAs) are an important cardiovascular disease, but the genetic and environmental risk factors, which contribute to individual's risk to develop an aneurysm, are poorly understood. Histologically, AAAs are characterized by signs of chronic inflammation, destructive remodeling of the extracellular matrix, and depletion of vascular smooth muscle cells. We hypothesized that genes involved in these events could harbor changes that make individuals more susceptible to developing aneurysms. This study identified significant genetic associations between DNA sequence changes in tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP3, matrix metalloproteinase 10 (MMP10) and elastin (ELN) genes, and AAA. The results will require confirmation using an independent set of samples. After replication it is possible that these sequence changes in combination with other risk factors could be used in the future to identify individuals who are at increased risk for developing an AAA.
Ogata
Toru
T
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Shibamura
Hidenori
H
Tromp
Gerard
G
Sinha
Moumita
M
Goddard
Katrina A B
KA
Sakalihasan
Natzi
N
Limet
Raymond
R
MacKean
Gerald L
GL
Arthur
Claudette
C
Sueda
Taijiro
T
Land
Susan
S
Kuivaniemi
Helena
H
D017544:Aortic Aneurysm, Abdominal / Q000235:genetics*; D004549:Elastin / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D053506:Matrix Metalloproteinase 10; D008666:Metalloendopeptidases / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*
C088390:TIMP3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D004549:Elastin; D008666:Metalloendopeptidases; D053506:Matrix Metalloproteinase 10