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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Vasc Surg. Author manuscript; available in PMC Jun 1, 2006.
Published in final edited form as:
PMCID: PMC1249499
NIHMSID: NIHMS3259

Genetic analysis of polymorphisms in biologically relevant candidate genes in patients with abdominal aortic aneurysms

Toru Ogata, MD,a Hidenori Shibamura, MD, PhD,a Gerard Tromp, PhD,a Moumita Sinha, MStat,b Katrina A. B. Goddard, PhD,b Natzi Sakalihasan, MD, PhD,c Raymond Limet, MD, PhD,c Gerald L. MacKean, MD,d Claudette Arthur, BN, MBA,d Taijiro Sueda, MD, PhD,e Susan Land, PhD,a,f and Helena Kuivaniemi, MD, PhDa,g

Abstract

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 (χ2 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.

Clinical Relevance

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.

About 15,000 individuals die every year because of the rupture of abdominal aortic aneurysms (AAAs) in the United States.1,2 An estimated 1% to 6% of the population in the industrialized countries harbor aneurysms.1 Despite the major advances in surgical treatment, the survival rate after a ruptured AAA is low.1 Early diagnosis of AAA is therefore important for improving outcome. However, diagnosing AAAs is difficult because most AAAs are asymptomatic before rupture and ultrasonography screening can only tell if the person currently has an AAA but is not able to estimate the risk of developing an AAA later. If it were possible to predict who is at risk for developing an AAA, many lives and health care dollars would be saved. Finding a susceptibility gene for AAA could lead to a simple DNA test to identify individuals who are at risk for developing an AAA. Those individuals would then be screened routinely to detect an AAA before it reaches a critical size and ruptures.

It has been suggested that AAAs are a complex disease with both genetic and environmental risk factors.36 Two formal statistical analyses, so-called segregation studies, favored a genetic model in explaining the familial aggregation of AAA and suggested the presence of a major gene effect.3,4 Recently, we reported on a collection of 233 families with at least two individuals affected with AAA,7 and identified two genetic susceptibility loci for AAA on chromosomes 19q13 and 4q31.8

Several distinct processes contribute to the pathologic changes observed in AAAs. The most apparent of these are chronic inflammation, destructive remodeling of the extra-cellular matrix, and depletion of vascular smooth muscle cells.9 Our hypothesis was that genes involved in these events could be considered candidate genes for AAA.

The matrix metalloproteinases (MMPs) are a family of endopeptidases that degrade extracellular matrix proteins.10 The MMPs have been studied extensively and implicated in the pathogenesis of AAA.9,1120 Many studies have measured mRNA and protein levels of various MMPs in the aneurysmal wall and found them to be elevated.1114,21,see 15 We hypothesized that such elevated levels could be caused by genetic differences in the promoter sequences of these genes influencing transcription. Indeed, functional studies have shown that many of the promoter variants in MMP genes show differential binding of transcription factors.2227 In a previously published preliminary study, we described a suggestive genetic association between a 5A/6A polymorphism in the MMP3 gene and AAA, and found that the transcriptionally more active 5A allele was more common in AAA cases than in controls.15, 27 Other investigators found an association between a polymorphism in the MMP9 gene and AAA.16

Tissue inhibitors of metalloproteinases (TIMPs) are major inhibitors of MMPs.10 Downregulation of these inhibitors could lead to an increase in the activity of extra-cellular matrix degrading enzymes such as MMPs, and therefore could contribute to the pathogenesis of AAAs. In fact, two studies have shown decreased mRNA levels of TIMPs in AAA.21,28 Furthermore, the ratio of MMP mRNA to TIMP mRNA was higher in AAA than in normal aortas when assayed using competitive reverse-transcriptase polymerase chain reaction (RT-PCR).17 We analyzed previously the coding sequences of TIMP1 and TIMP2 genes in patients with AAA and observed a significant difference in the frequency of the nt+573 TIMP2 polymorphism between AAA patients and controls.29

We have now extended our genetic studies to the polymorphisms in genes for MMP1,23 MMP2,26 MMP3,15 MMP9,25 MMP10, MMP12,24 MMP13,22 TIMP1,29 TIMP2, TIMP3,30 transforming growth factor β-1 (TGFB1),31 elastin (ELN),32 and type III procollagen (COL3A1),33 and genotyped 387 AAA patients and 425 controls. Nine of the 14 polymorphisms under study were known to be functional based on previous studies.

METHODS

Study population

AAA was defined as an infrarenal aortic diameter of 3.0 cm or greater.34 Altogether, 387 unrelated AAA cases (male subjects: n = 316, 81.7%), 180 Belgian admitted to the University Hospital of Liège in Liège and 207 Canadian admitted to Dalhousie University Hospital in Halifax, were included in the study. Seventeen patients were admitted for emergency repair of ruptured AAA, and 335 patients were admitted for elective surgery. Thirty-five patients were diagnosed with AAA using ultrasonography and did not undergo surgery because of old age or because the size of the aneurysm was relatively small. Altogether, 152 cases (39.3%) had a family history of AAA. All patients were white.

Control samples were obtained from 425 white subjects (male subjects: n = 217, 51.1%), 269 Belgian and 156 Canadian, and included spouses of AAA patients (n = 113) and individuals admitted to the same hospitals as the AAA patients for reasons other than AAA (n = 312).

The study was approved by the Institutional Review Boards of Wayne State University School of Medicine and of each patient recruiting center. All subjects gave informed written consent to participate in the study.

Genotyping

We isolated genomic DNA from peripheral blood using a Puregene kit (Gentra Systems, Minneapolis, Minn). Before performing genotyping using PCR-based methods, a whole-genome amplification using primer extension preamplification (PEP) was carried out to increase the amount of template DNA available for genotyping and to ensure that limited resources were used cost effectively.35 The PEP products were diluted 100-fold and used for genotyping.

The PCR conditions and methods used to assay the 14 polymorphisms (Table I) are summarized in Table II, online only. Five microliters of 100-fold diluted PEP products were used for each genotyping reaction. The genotyping assays for MMP1,23 MMP3,15 MMP9,25 MMP12,24 MMP13,22 TIMP1(+434),29 TIMP3,30 TGFB1,31 ELN,32 and COL3A133 were carried out as described previously. Allele-specific PCR was used to genotype MMP226 polymorphism (Table II, online only). Three polymorphisms, dbSNP rs486055 in MMP10 (MMP10 nt+180), rs2070584 in TIMP1, and rs2009196 in TIMP2, were identified from the National Center for Biotechnology Information LocusLink database (www.ncbi.nih.gov/LocusLink). Two polymorphisms, rs2070584 and rs2009196, were genotyped by 5′-nuclease assay (TaqMan Assay; Applied Biosystems, Foster City, Calif). Allele-specific TaqMan minor groove binder (MGB) probes and PCR primers were designed by using Primer Express version 1.5 software (Applied Biosystems). Reactions were carried out in 5-μL volumes in an ABI PRISM Sequence Detection System 7900 (SDS; Applied Biosystems). The results were analyzed using SDS software version 1.7 (Applied Biosystems).

Table I
Polymorphisms used in this study
Table II, online only
Genotyping assays used in the study

Power calculations

Power calculations were performed using the Genetic Power Calculator (http://statgen.iop.kcl.ac.uk/gpc/cc2.html).36 To compute the power, we assumed that the polymorphism and the disease locus were in complete linkage disequilibrium with the same allele frequencies, ie, the polymorphism was the disease locus. The population prevalence of AAA was taken as 5%.1 Power was computed for different values of several different model parameters including mode of inheritance, allele frequency, and genotype relative risk.36

Statistical analysis

The two populations (Belgians and Canadians) were tested separately to determine whether the genotypes were in Hardy-Weinberg equilibrium by comparing the observed genotype frequencies in AAA cases and controls with their expected frequencies at equilibrium based on the χ2 test. Odds ratios (ORs) and P values adjusted for gender and country of origin using logistic regression and stratified by family history of AAA were calculated to test the association between genotype and AAA. Next, possible interactions between the polymorphism, country of origin, and gender were included in the model. We modified the input files for the HAPFREQS program37 to estimate haplotype frequencies via the expectation-maximization algorithm for two X-linked polymorphisms (TIMP1 polymorphisms [nt+434 and rs2070584]). In this case, female subjects who are heterozygous and have two different alleles at both polymorphisms have ambiguous phase, whereas all homozygous female subjects and all male subjects (who have only one X chromosome and therefore only one TIMP1 allele) have known haplotypes. Haplotype frequencies were estimated separately for cases (stratified by family history of AAA) and controls, and then compared using the χ2 test. Empirical P values were also obtained using a permutation test, as implemented in the CLUMP program.38 Linkage disequilibrium (which means nonrandom segregation of polymorphisms in a population) between the two TIMP1 gene polymorphisms used in the study was estimated by computing the squared correlation coefficient (r2).39

RESULTS

The observed genotype counts and their frequencies are shown in Table III, online only. All results, except TIMP3 in the Belgian cases, were in Hardy-Weinberg equilibrium. The minor allele frequencies varied from 0.12 to 0.46 in the study population (Table III, online only). The allele frequencies of both Belgian and Canadian controls in our study were remarkably similar to those reported in previous studies or public databases, suggesting that the control groups used in our study were representative of the general population (Table IV, online only).

Table III, online only
Genotype and allele counts and frequencies in cases and controls with odds ratios and P values for tests of association between genotype and AAA adjusted for gender and country of origin using logistic regression
Table IV, online only
Comparison of minor allele frequencies between controls in the current study and other studies

Our power calculations indicated that in general, the power was high (>90%) for common alleles (frequency >0.2). For alleles with lower frequency, a higher genetic relative risk was required to maintain high power. The dominant model had the greatest power of the modes of inheritance that were tested (not shown).

ORs and P values adjusted for gender and country of origin using logistic regression were calculated (Table III, online only). This analysis was performed for all polymorphisms except TIMP1 (nt+434) and TIMP1 (rs2070584), which are X-linked, and which genotypes were analyzed separately for each gender. None of the polymorphisms were associated significantly with risk of AAA (Table III, online only).

We stratified the AAA cases based on family history of AAA and repeated the analyses. Interestingly, the two polymorphisms located in TIMP1 were significantly associated with AAA in male cases without family history (n = 235) of AAA (nt+434, P = .0047; rs2070584, P = .015; Table V).

Table V
Odds ratios and P values for tests of association between genotype and AAA adjusted for gender and country of origin using logistic regression, and stratified by family history of AAA

We then proceeded to carry out a haplotype analysis using the results of the two polymorphisms in the TIMP1 gene (Table VI). The TT haplotype was more common in the AAA cases without family history than in controls, whereas the CG haplotype was more common in controls than AAA cases without family history (TT: AAA 60% vs control, 47%; CG: AAA 37% vs control, 51%). There was a significant difference between the AAA cases without family history and controls (χ2 P = .014, and empirical P = .009). CT and TG haplotypes were rare in both AAA cases and controls. The two polymorphisms in the TIMP1 gene were linked together tightly using r2 as a measure of linkage disequilibrium (Belgians, r2 = .892; Canadians, r2 = .778; total, r2 = .827).

Table VI
Haplotypes for the TIMP1 gene in male subjects

The final analyses examined possible interactions between the polymorphisms, country of origin, and gender. We found a significant interaction between the polymorphism and gender for MMP10 (P = .037) in cases without a family history of AAA. For male subjects, the adjusted ORs were 1.97 and 1.40 for the GG and AG genotypes compared with the AA genotype, respectively, and for female subjects, the adjusted ORs were .377 and .614 for the GG and AG genotypes compared with the AA genotype, respectively. We also found a significant interaction between the polymorphism and country of origin for ELN (P = .0169) in cases with a family history of AAA. For Belgians, the adjusted ORs were .933 and .966 for the GG and AG genotypes compared with the AA genotype, respectively, and for Canadians, the adjusted ORs were 4.15 and 2.04 for the GG and AG genotypes compared with the AA genotype, respectively. Finally, there was a significant interaction between the polymorphism and country of origin for TIMP3 (P = .0023) in cases with a family history. For the Belgians, the adjusted ORs were 2.19 and 1.48 for the CC and CT genotypes compared with the TT genotype, respectively, and for the Canadians, the adjusted ORs were .31 and .56 for the CC and CT genotypes compared with the TT genotype, respectively.

DISCUSSION

We selected polymorphisms from genes encoding for proteins important as structural molecules of the aortic wall or involved in the process of extracellular matrix remodeling. Many of these proteins had been implicated in the pathogenesis of AAA previously based on protein and mRNA expression.9,1120

Few genetic association studies between polymorphisms in MMPs and AAA have been reported.15,16,19 Jones et al16 found an association between AAA and MMP9 (nt−1562) polymorphism in the population of New Zealand, and we previously reported a borderline association between AAA and MMP3 (nt−1612) polymorphism.15 Our current study was designed to replicate these previous observations, and it was therefore somewhat surprising that we did not find an association between these polymorphisms and AAA. There was no significant difference between the allele frequencies of the MMP9 polymorphism in controls in the study by Jones et al16 and our study, and both studies had about the same number of cases and controls. One possible explanation of the differences in the results may be ethnic variations, although as pointed out in a recent review article by Colhoun et al,40 other explanations also exist.

Our results showed a significant difference in the frequencies of both two TIMP1 polymorphisms and haplo-types between AAA cases without a family history and controls in male subjects. This observation supports the hypothesis that genetic variations responsible for down-regulation of TIMPs contribute to the pathogenesis of AAAs.5,6,14,17 These two TIMP1 polymorphisms, which have haplotypes that were found to be associated with AAA, are unlikely to be the causative changes because one of them is at the third position of a codon and does not change the amino acid and the other lies within an intron. It is therefore likely that this haplotype is in linkage disequilibrium with other functional sequence changes that contribute to the disease.

Intriguing findings were the significant interactions between the MMP10 (nt+180) polymorphism, gender, and AAA; between the ELN (nt+422) polymorphism, country of origin, and AAA; and between the TIMP3 (nt−1296) polymorphism, country of origin, and AAA. The biological significance of these statistical interactions has yet to be defined.

Because the power of detecting an association was high, we can exclude the polymorphisms, which did not show an association with AAA in the study, as important for AAA. A limitation of our study was that we analyzed only one polymorphism in most of the genes and could have missed an association that was to a specific polymorphism not studied here. It should also be emphasized that the results obtained here require confirmation in an independent set of samples before the information can be considered definitive and useful for estimating an individual’s risk for developing an AAA.

In conclusion, we investigated 14 polymorphisms in 13 biologically relevant candidate genes for AAA and found evidence for an association between TIMP1 polymorphisms and AAA in male subjects without a family history of AAA. In addition, we identified significant interactions between MMP10 (nt+180) polymorphism and gender as well as between TIMP3 (nt−1296) polymorphism or ELN (nt+422) polymorphism and country of origin and AAA. If the results are confirmed in another study, further work will be needed to explain the functional role of these variants in the pathogenesis of AAA.

Acknowledgments

We thank Dr. Jane M. Olson for her invaluable input in the design of the study before she died.

Footnotes

Supported in part by grants from the National Heart, Lung, and Blood Institute (HL064310 to H.K.), the National Human Genome Research Institute (HG01577 to K.G.), and the National Center for Research Resources (RR03655).

Detroit, Mich; Cleveland, Ohio; Liège, Belgium; Halifax, Canada; and Hiroshima, Japan

Competition of interest: none.

Additional material for this article may be found online at www.mosby.com/jvs.

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