Lack of association of matrix metalloproteinase 3 (MMP3) genotypes with ankylosing spondylitis susceptibility and severity

L. Jin1, M. Weisman2, G. Zhang1, M. Ward4, J. Luo1, J. Bruckel5, R. Inman11, M. A. Khan6, H. R. Schumacher7, W. P. Maksymowych12, M. Mahowald8, T. Martin9, J. T. Rosenbaum9, D. T. Y. Yu2, M. Stone11, J. Watson1, E. Dickman1, J. Davis3 and J. D. Reveille10

1 University of Cincinnati, Cincinnati, OH, 2 University of California-Los Angeles, Los Angeles, 3 University of California-San Francisco, CA, 4 National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 5 Spondylitis Association of America, Sherman Oaks, CA, 6 Case-Western Reserve University, Cleveland, OH, 7 University of Pennsylvania, Philadelphia, PA, 8 University of Minnesota, Minneapolis, MN, 9 Oregon Health and Science University, Portland, OR, 10 University of Texas-Houston Health Science Center, Houston, TX, USA, 11 University of Toronto, Toronto, ON and 12 University of Alberta, Edmonton, AL, Canada.

Correspondence to: J. D. Reveille, University of Texas-Houston Health Science Center, MSB 5.270, 6431 Fannin, Houston, TX 77030, USA. E-mail: john.d.reveille{at}uth.tmc.edu


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To study the linkage and association of ankylosing spondylitis (AS) with genotypes for matrix metalloproteinase 3 (MMP3), a gene located at chromosome 11q22.3 and lying within the 101–124 cM region observed in a recent genome-wide scan as a region associated with AS susceptibility.

Methods. MMP3 genotypes were examined in 229 pedigrees with AS, 131 sporadic AS cases and 87 Caucasian controls. Eight single-nucleotide polymorphisms (SNPs) were selected and genotyped using Taqman. Non-parametric linkage (NPL) analysis was conducted between the eight MMP3 SNPs and AS using the NPL-all statistic and two-point parametric linkage analysis using GeneHunter Plus. Unrelated AS cases and controls were compared using {chi}2 statistics, and family-based controls using the transmission disequilibrium test and pedigree disequilibrium test.

Results. None of the eight MMP3 SNPs were significantly associated with AS, either using the 131 sporadic cases alone or in analyses which combined these cases with the 226 unrelated affected AS patients derived from the pedigrees. Analysis of linkage disequilibrium (LD) demonstrated that seven of the eight SNPs studied were in strong LD except for rs626750, which is about 6 kb upstream of the 5' end of the gene. No significant linkage was observed using NPL and LODs in the families. No association was seen of any of the MMP3 SNPs with disease severity (defined by patient functioning), as measured either by the Bath Ankylosing Spondylitis Functional Index or the modified Health Assessment Questionnaire.

Conclusion. These data suggest that MMP3 genotypes are not involved in AS susceptibility or severity.

KEY WORDS: Ankylosing spondylitis, Genetics, Single-nucleotide polymorphisms, Matrix metalloproteinase 3, Disease severity


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Although HLA-B27 is probably the primary mediator of genetic susceptibility to ankylosing spondylitis (AS), evidence is accumulating that suggests that genes outside the major histocompatibility complex (MHC) also contribute to disease risk. Modelling studies estimate that the MHC explains less than 50% of the total genetic risk for AS [1, 2]. Furthermore, prior genome-wide linkage scans implicate numerous non-MHC genomic regions, including 1p, 2p, 2q, 3p, 9q, 10q, 11p, 16q and 19q [3, 4]. Thus, the genetic dissection of AS may be contingent upon the identification and characterization of non-MHC susceptibility genes.

Matrix metalloproteinase 3 (MMP3, also known as human fibroblast stromelysin) is a secreted metalloprotease produced predominantly by connective tissue cells. Together with other metalloproteases, it can synergistically degrade the major components of the extracellular matrix [5] and is also capable of degrading proteoglycan, fibronectin, laminin and type IV collagen [6]. In a recent report, high levels of MMP3 expression in synovial biopsies on microarray analysis were the best predictor of disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index [7]) in patients with AS [8]. Moreover, another study described an association between a polymorphism in the MMP3 gene promoter and the severity and progression of RA, but not RA susceptibility [9].

In this report, we investigated the role of MMP3 in AS susceptibility using a large cohort collected by the North American Spondylitis Consortium (NASC; referred to hereafter as the NASC cohort), which includes 229 pedigrees with AS and 131 sporadic cases of AS with disease duration (from the onset of inflammatory back pain) of >20 yr. We have recently identified a susceptibility region for AS on chromosome 11q in a genome-wide scan of 244 affected sibling pairs from 180 multiplex AS families in which the MMP3 gene is located [10]. However, in the present study, both case–control and family-based association studies failed to reveal any significant association between genetic variation in MMP3 and AS, and no association was found with disease severity (as indicated by functional impairment).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
The families were recruited by the Spondylitis Association of America (SAA) and the investigators of the NASC. Only families with two or more siblings both meeting the modified 1984 New York criteria [11] for AS with available radiographs for review were included. Informed consent was obtained from each family member, and this study was approved by the Committee for the Protection of Human Subjects at the University of Texas-Houston Health Science Center in accordance with the Declaration of Helsinki. In total, 229 pedigrees with at least one affected individual with AS were included in this study, all of which were included in analyses based on the transmission disequilibrium test (TDT) after removing the individuals without genetically confirmed paternity. These included 244 affected sib pairs derived from 180 pedigrees of European ancestry that were studied in linkage analyses, and an additional 49 pedigrees with a proband with AS and both parents available.

For the case–control studies, 131 unrelated AS patients without a known family history of the disease were used (case 1). These, in addition to six of the probands in the families study, were enrolled in a study of outcome (the Prospective Study of Outcomes in Ankylosing Spondylitis or PSOAS study). These patients have disease duration of >20 yr, dated from the onset of inflammatory low back pain. The 226 unrelated affected probands derived from the pedigrees constituted another case group (case 2). The total number of cases is therefore 357 (case T). Eighty-seven unrelated unaffected North Americans of European ancestry were used as controls in the case–control studies (control). Patient functioning was measured using the Bath Ankylosing Spondylitis Functional Index (BASFI) [12] and by the Health Assessment Questionnaire (HAQ) modified for the spondyloarthropathies [13].

SNP genotyping
Eight single-nucleotide polymorphisms (SNPs) (rs4754884, rs639752, rs520540, rs476762, rs591058, rs679620, rs522616 and rs626750) were selected from dbSNP Build 116 (based on NCBI Human Genome Build 33) and genotyped using Taqman (Applied Biosystems, Foster City, CA, USA).

The primers and probes were ordered through Assay-on-Demand (Applied Biosystems) and the genotyping was conducted following the manufacturer's instruction. Detailed information on the eight SNPs is presented in Table 1.


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TABLE 1. Association analyses of MMP3 SNPs and susceptibility to AS

 
Statistical analysis
Single-locus association analyses were performed by standard {chi}2 statistics on both allele (2 x 2 table) and genotype (2 x 3 table) frequencies. Family-based tests of linkage disequilibrium (LD) were conducted using the TDT [14] and pedigree disequilibrium test (PDT) [15], which were implemented in Unphased software [16]. Mendelian inconsistencies and likely genotyping errors were identified using Pedcheck software [17]. Two-point non-parametric linkage (NPL) analysis was conducted using the NPL-all statistic in GeneHunter Plus [18]. Two-point parametric linkage analysis was also conducted using GeneHunter Plus [18]. Differences in the BASFI and the modified HAQ among subjects with different genotypes were tested using analysis of variance, with adjustment for duration of AS, number of comorbid conditions and years of formal education.

Haplotype inference
Individual genotypes for 24 African Americans and 23 European Americans were obtained from the SeattleSNPs study funded as part of the National Heart Lung and Blood Institute's (NHLBI) Programs for Genomic Applications (referred to as PGA hereafter). These genotypes were used to examine the LD of the SNPs at the MMP3 gene and to infer the genotypes of the 5a deletion/insertion polymorphism located approximately 1600 bp upstream to the start of the transcription. Phase v. 2.0.2 was used to estimate the haplotype frequencies [19]. The LD between any of the two markers was measured as D' [20].


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
AS patients and families
In total, 244 sib pairs concordant for AS, sampled from 180 pedigrees, were included in this study, including 602 family members. AS occurred more frequently in men than in women in these families (data not shown). Ninety-four per cent of the families were Caucasian, the rest being either of mixed Caucasian/native American or Caucasian/Eastern Asian heritage. Sixty-three families had affected sibs and both parents available, 25 had affected sibs and one parent available, and 92 had affected sibs only (Table 2). One hundred and fifty-two families had one affected sibling pair, one family had two affected sib pairs in different generations, 24 had three affected siblings and three families had four affected siblings. For the case–control studies, 131 unrelated AS patients without a known family history of the disease were used (case 1). These, in addition to six of the probands in the families, were enrolled in a study of outcome (the PSOAS study). Clinical and demographic characteristics of the PSOAS cohort are shown in Table 3.


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TABLE 2. Composition of families studied

 

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TABLE 3. Disease severity in AS: the PSOAS cross-sectional study (n = 137)

 
Association of MMP3 with AS susceptibility
None of the eight MMP3 SNPs were significantly associated with AS, either using 131 cases (case 1) or combined cases by adding 226 unrelated affected AS patients derived from the NASC pedigrees (case 2) (Table 1).

In addition to case–control-based association analysis, family-based LD studies including the TDT and PDT were performed. TDT and PDT analyses were employed to examine the association of the SNPs and the susceptibility to AS by eliminating the possible presence of population stratification. In particular, 226 pedigrees from the NASC study were included. Neither the TDT nor the PDT approach showed a significant P value except for rs626750, which showed marginal significance (P = 0.048; Table 1), which will diminish with correction for multiple testing.

Linkage disequilibrium, haplotypes and haplotype tagging SNPs in MMP3
Analysis of LD showed that seven of the eight SNPs studied were in strong LD except for rs626750, which is about 6 kb upstream of the 5' end of the gene. The minimum absolute values of the pairwise D' between any two of the 7 SNPs were 0.91, 0.97, 0.92 and 0.95 for control, case 1, case 2, and case T, respectively; the maximum coefficient of LD, |D'|, was 1 for each of the four groups.

The genetic variation of MMP3 was carefully characterized by PGA, a collaboration between the University of Washington and the Fred Hutchinson Cancer Research Center (http://pga.mbt.washington.edu). In the PGA samples, six of the seven SNPs mentioned above that were in strong LD were genotyped (rs4754884 was not included in PGA). European Americans (n = 23) showed complete LD (|D'| = 1) between all of them, forming one single haplotype block [20, 21]. However, in the African Americans (n = 24), complete LDs were only found in rs591058, rs476762, rs520540 and rs639752 (group 1). The value of |D'| between group 1 SNPs and rs679620 was about 0.7 while that between rs679620 and rs522616 was about 0.8; both values are above the threshold of 0.5 which was used to define the haplotype blocks [22]. A similar observation was made using all 17 SNPs found in the PGA study, with the frequency of the minor allele above 0.05. Therefore, all genetic variations in MMP3 gene are in strong LD.

The haplotypes of the MMP3 SNPs were inferred using Phase v. 2.0.2 [19] and are listed in Table 4 along with the frequencies in all four groups in this study. The five most frequent haplotypes accounted for 93.9, 92, 94.5 and 94% of all haplotypes in the control, case 1, case 2 and case T, respectively. Therefore, even with the inclusion of rs626750, which did not show strong LD with the other SNPs, all eight SNPs are located in one single haplotype block [21, 23]. Four SNPs can be chosen as the haplotype-tagging SNPs (htSNPs) for the MMP3 gene. They are rs476762, rs522616, rs626750 and any one of the other five SNPs (rs4754884, rs639752, rs520540, rs591058, rs679620). Since rs626750 is not a part of the MMP3 gene, the four most frequent haplotypes (ACATTTT, GAGTCCCC, GAGACCT, GAGTCCT) would account for at least 98% of the genetic variation of the MMP3 gene in all four groups mentioned above, and three htSNPs (removing rs626750 from the above htSNP list) are sufficient to represent the gene.


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TABLE 4. Haplotype distribution of MMP3 SNPs

 
Association of haplotypes with AS susceptibility
The LD and haplotype analyses in the previous section laid a firm ground for a haplotype-based association analysis, given that the eight SNPs selected in this study contain sufficient information to represent the entire MMP3 gene. Using the haplotype frequencies listed in Table 4, we conducted the case–control association study by comparing the haplotype frequencies between case 1 and control (P = 0.69), case 2 and control (P = 0.86), and case T and control (P = 0.90). None of the comparisons were statistically significant.

Furthermore, TDT and PDT analyses were conducted on the haplotypes, and again no significant association were found between MMP3 and AS susceptibility (P = 0.409 for TDT and P = 0.515 for PDT).

Inference of genotypes of 5A/6A polymorphism and its association with AS susceptibility
An insertion/deletion polymorphism in the promoter region of the MMP3 gene about 1600 bp upstream from the start of transcription was identified with 6A for one allele and 5A for the other (referred to as the 5A/6A site hereafter) [24]. This polymorphism has been found to be associated with the atherosclerotic plaque instability [24–27] in patients with cardiovascular disease and it causes variation of expression of the gene in vitro [28]. Because of its functional importance, an association study of this site and AS susceptibility was performed.

Although 5A/6A was not typed in this study, the genotypes at this locus can be inferred since we have shown that genetic variations at MMP3 are in strong LD. Before we inferred genotypes at this locus, we examined the LD between the 5A/6A site and the other SNPs, again using the genotype data from the PGA project. The |D'| values between the 5A/6A site and the six SNPs typed in both PGA and this study (not including rs626750 and rs4754884) were 1 in both African Americans and European Americans, indicating that the 5A/6A site is in complete LD with the MMP3 SNPs.

The genotypes of the 5A/6A site in the four groups in this study were therefore inferred based on the haplotypes of the six SNPs mentioned above (Table 4). However, such inference cannot be accomplished with three rare haplotypes, which were probably derived from historical recombination crossovers. In the association study, we can either assign them as D (5A) or I (6A). Regardless of the assignment, no statistically significant association was found between the 5A/6A site and AS susceptibility.

Linkage of analyses of MMP3 SNPs
Non-parametric linkage analysis was also conducted between the eight MMP3 SNPs and the AS using the NPL-all statistic in GeneHunter Plus [18]. Two-point parametric linkage analysis was also conducted using GeneHunter Plus [18]. No significant linkage was observed using NPL and LODs (Table 5). The LOD scores were below –2 for seven out of eight markers (Table 5).


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TABLE 5. Results of linkage analyses of MMP3 SNPs

 
MMP3 polymorphisms and disease severity in AS
In a study of 138 patients with AS with disease duration of >20 yr (from the onset of inflammatory back pain), no association was seen of any of the MMP3 SNPs identified here with disease severity [defined by patient functioning as measured by the BASFI [12] (Table 6) or the modified HAQ [13] (Table 7)].


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TABLE 6. Lack of association of MMP3 genotypes with functional impairment in AS (as measured by the BASFI)

 

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TABLE 7. Lack of association of MMP3 genotypes with functional impairment in AS (as measured by the HAQ)

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In a recent genome-wide scan project, strong positive linkage was observed at 98.89–121.08 cM on chromosome 11q [10]. The NPL and LOD scores [18] are shown in Fig. 1. Furthermore, on TDT analysis we also observed a strong association between D11S4090 (105.74 cM) and AS susceptibility (P = 6.2 x 10–5). The MMP3 gene is located at 99.91 cM and was chosen as a candidate gene based on its location and its involvement in previous studies on AS and RA [8, 9]. Given its role in disease severity and progression in RA [9] and in the light of preliminary data showing an association of MMP3 mRNA levels with disease activity in AS [8], it is reasonable to study MMP3 SNPs and disease severity. We chose function as a measure of disease severity, as in other studies [29], and focused on AS patients with disease activity of greater than 20 yr in order to examine a ‘fully expressed’ disease phenotype. Although this study does not rule out an impact of MMP3 genotypes on other aspects of disease severity in AS (e.g. radiographic), no association was seen with functional severity, defined either by the BASFI (Table 6) or by the HAQ (Table 7).



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FIG. 1. Multipoint linkage analysis results of AS in a chromosome 11q region.

 
Brown et al. [29] extended data from their genome-wide scan [3, 4] to examine disease severity in 188 affected sibling pair families with 454 affected individuals. Maximum linkage with the functional impairment (defined here by the BASFI) was seen at chromosome 2q (LOD score 2.9). No linkage was seen with chromosome 11q.

MMP3 genotypes have been found to be relevant in other connective tissue diseases. In one study of 31 women with scleroderma (SSc) and 65 age-matched controls, the frequency of heterozygotes and homozygotes for the 6A allele (5A/6A and 6A/6A) of MMP3 was significantly higher in 31 SSc patients (93.5%) than in 65 age-matched controls (70.8%, P<0.02) [30]. Levels of MMP3 have also been associated with disease severity in SSc [31] as well as with activity of lupus nephritis in one study [32], but not another [33].

Using TDT, we expect to achieve 80% power ({alpha} = 0.0001) in detecting any locus with a relative risk of the order of 1.5, given a sample of 244 sib pairs with one-third of the pedigrees having both parents genotyped. This estimation was calculated by following Bacanu et al. [34] and assuming perfect linkage disequilibrium between the disease mutation locus and the marker (D' = 1 with matched allele frequencies). Given the level of LD of the SNPs typed within the MMP3 gene (|D'| = 1 for all pairs of SNPs), this estimate is considered to be reasonably accurate.

These data suggest that the MMP3 is not involved in AS susceptibility or severity. Further research and examination of other candidate genes in this region is therefore warranted.


    Acknowledgments
 
We would like to express our sincere appreciation to the families who participated in this study and have supported the NASC project, as well as to Patricia Newman and Myriam Bianco, the Clinical Coordinators for this study at the Spondylitis Association of American, who were responsible for the recruitment of many of the families in this study, and to Laura Diekman and Jo McClain at the University of Texas-Houston Health Science Center, the Program Manager for this project. This work was supported by NIH grants RO1-AR46208. Additional support was provided by a grant from the National Eye Institute-EY13139 (TM, principal investigator) as well as by University Clinical Research Center Grants M01-RR02558 (UTHSC) and M01RR000425 (Cedars-Sinai).

The authors have declared no conflict of interest.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 2 January 2004; revised version accepted 7 September 2004.



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