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Human Molecular Genetics Advance Access originally published online on May 20, 2007
Human Molecular Genetics 2007 16(14):1676-1681; doi:10.1093/hmg/ddm115
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Meta-analysis of association between the ASPN D-repeat and osteoarthritis

Takahiro Nakamura1, Dongquan Shi3, Maria Tzetis4, Julio Rodriguez-Lopez5, Yoshinari Miyamoto2, Aspasia Tsezou6, Antonio Gonzalez5, Qing Jiang3, Naoyuki Kamatani1,7, John Loughlin8 and Shiro Ikegawa2,*

1 Laboratory for Statistical Analysis and 2 Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, Tokyo 108-8639, Japan, 3 The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, Jiangsu, China, 4 Department of Medical Genetics, University of Athens Medical School, Athens, Greece, 5 Laboratorio de Investigacion 2, Hospital Clinico Universitario de Santiago, 15706-Santiago de Compostela, Spain, 6 Department of Biology, University of Thessalia Medical School, Larissa, Greece, 7 Division of Statistical Genetics, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan and 8 Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Institute of Musculoskeletal Sciences, Headington, Oxford X3 7LD, UK

* To whom correspondence should be addressed at: Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Tel/Fax: +81 354495393; Email: sikegawa{at}ims.u-tokyo.ac.jp

Received March 26, 2007; Accepted April 26, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 REFERENCES
 
Osteoarthritis (OA) is the most common form of human arthritis. Genetic factors have been implicated in OA. It was reported that an aspartic acid (D)-repeat polymorphism in the gene encoding asporin (ASPN) was associated with OA of knee and hip joints in Japanese; in the three independent studies performed, the D14 allele of the ASPN polymorphism was over-represented and the D13 allele was under-represented. Subsequently, four replication studies, three in Europeans and one in Chinese populations, have been reported; however, they showed inconsistent results. To evaluate between-study heterogeneity and to estimate the common genetic effect of the D-repeat polymorphism on OA, we performed a meta-analysis of the five reports that include seven association studies, using the DerSimonian–Laird procedure. We detected association between knee OA and the susceptible D14 allele [P = 0.003, summary odds ratio (OR) = 1.46] with significant heterogeneity (P = 0.047) among the studies. We also detected positive association between knee OA and the protective D13 allele (P = 0.026, summary OR = 0.84) with significant heterogeneity (P = 0.040) among the studies. Because of significant heterogeneity, we stratified the studies by ethnicity. We detected positive association between knee OA and the D14 allele (P = 0.0000013, summary OR = 1.95) with non-significant heterogeneity (P = 0.535) in Asian populations. In hip OA, significant heterogeneity was identified and there was no positive association for any allele in any comparison. The present results suggest that the association of the ASPN D14 allele and knee OA has global relevance, but that its effect has ethnic differences.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 REFERENCES
 
Osteoarthritis (OA) is one of the most common joint diseases. Epidemiological studies suggest that genetic factors strongly affect the onset and development of OA (1–3). Several susceptibility genes have been reported, which is consistent with the polygenic nature of the disease (4–10). Kizawa et al. (11) reported an association between OA and the gene encoding asporin (ASPN) in Japanese: using a cohort sample, they found a positive association between knee OA and the D14 allele of the aspartic acid (D)-repeat polymorphism in ASPN [P = 0.0013, odds ratio (OR) = 2.49]. The association was replicated in a separate case–control sample of knee OA (P = 0.018, OR = 1.66). Furthermore, they replicated the association of the polymorphism in a case–control study of hip OA (P = 0.0078, OR = 1.70). Subsequent functional analyses presented compelling evidence for causality of asporin in OA (11).

Despite the strong evidence indicating association between OA and ASPN in Japanese populations, subsequent studies of other populations showed inconsistent results. Mustafa et al. (12) assessed the association in UK cases (ascertained by hip or knee total joint replacement for primary OA) and controls, but did not detect significant association. They found only marginal evidence of association to the D14 allele in male patients with hip OA (P = 0.025, OR = 1.41). A Greek case–control study (13), comprising OA cases ascertained by total knee joint replacement, indicated that the D13 allele decreased the risk of knee OA (P = 0.002, OR = 0.62), but that the D14 allele did not increase risk (P = 0.65, OR = 1.1). In a Spanish case–control study (14), comprising cases with hand OA or with hip or knee OA ascertained by total joint replacement, no significant associations were detected between the ASPN D-repeat and OA (all P > 0.05). In a Chinese case–control study (15), comprising cases with symptomatic and radiographically defined knee OA, significant association was detected between the D14 allele and OA (P = 0.0013, OR = 2.04). However, the association with the D13 allele was not replicated (P = 0.4, OR = 1.11). The discrepant results may be due to differences in inclusion criteria. The Japanese and Chinese studies used patients with symptomatic hip or knee OA ascertained radiographically, whereas the three European studies recruited hip or knee OA patients who had undergone joint replacement. Alternatively, the discrepancy may be due to ethnic differences.

Meta-analysis is a widely accepted tool for summarizing different studies beyond the between-study variance (16,17). Its main objective is to assess heterogeneity and association. Meta-analysis can assess the significance of observed heterogeneity. It can exclude differences in allele frequencies and affection rates between studies that can be confounding factors in genetic association studies. Exclusion of confounding factors increases the quality of the evidence. For example, Iwamoto et al. (18) used meta-analysis to summarize several studies of association between PADI4 and rheumatoid arthritis. They found that the discrepancies between the studies were not significant, and that overall association was significant.

The purpose of the present study is to evaluate between-study heterogeneity of the association studies on the ASPN D-repeat polymorphism and OA and to estimate the common genetic effect of the polymorphism. Using meta-analysis of the genotyping data, we integrated the previous association studies and evaluated the global significance of the association. We found strong association between the D14 allele of the ASPN D-repeat and knee OA in Asian populations.


   RESULTS
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 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 REFERENCES
 
Genotyping data and patient clinical data of a total of 5446 subjects from the five participating groups (Japan, China, UK, Spain and Greece) were obtained from the original researchers. There were 1370 cases and 2296 controls in the knee OA study and 1800 cases and 1416 controls in the hip OA study.

Allelic and genotypic counts were evaluated for the D14 and D13 alleles, respectively (Table 1 and Supplementary Material, Table S1). The frequencies of the D14 allele and of the D13 allele differed between the Asian and European studies (Table 1). The differences of the allele frequencies between the Asian and European studies were tested by chi-square test using 2 x 3 tables, Asian/European and D13/D14/others, in case and control samples separately. The P-values for the tests were significant (P < 0.0001). The variation of the frequencies of the D13 allele between studies was larger than those of allele D14, particularly in the case groups. The frequency of the D14 allele in the control groups was very similar between Japanese and Chinese (Asian) studies and between the European studies. The frequency of the D14 allele was higher in OA cases than in control individuals in all studies, except for the Spanish hip OA cases; the frequency of the D13 allele was lower in OA cases than in control individuals in all studies, except for the Chinese study.


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  		Table 1. Allele counts for the D-repeat polymorphisms in ASPN in the six studies from five articles

 
Because differences of the clinical covariates related to OA between the different genotype groups might cause a spurious association, we compared the age, sex and body mass index (BMI) status between the D13 and the D14 genotypes for each study (Supplementary Material, Tables S2–S4). There were no differences (all nominal P > 0.05) in these analyses except for the age and the D14 genotype in the Japanese cohort study (P = 0.002 in a dominant model) and sex and the D13 genotype in the Japanese case–control study (P = 0.035). Neither difference would remain significant if the results were subjected to Bonferroni correction for multiple testing [corrected P = 0.0007 (0.05/72)].

Knee OA
We analyzed six studies of association between knee OA and the ASPN D-repeat alleles. The summary OR for the contingency table of the D14 allele versus other alleles combined and its 95% CI exceeded 1 (Table 2; Fig. 1), indicating a significant association. The same result was obtained in the analysis for the contingency table of the D13 allele versus other alleles combined. D14 was over-represented, and D13 was under-represented; the P-values for the summary OR of D14 and D13 were 0.003 and 0.026, respectively (Table 2). Furthermore, the ORs of each of the six studies all exceeded 1 in the contingency table of D14 (Fig. 1). Under the null hypothesis, the probability that the OR exceeds 1 in a single study is 1/2. Therefore, the P-value for the sign test (two-sided test) is 1/32 (<0.05), also supporting a positive association between the D14 allele and knee OA.


Figure 1
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  		Figure 1. A meta-analysis for association between OA and the ASPN D-repeat in the comparison of the D14 allele versus other alleles combined. Bar, 95% CI of OR; diamond, OR and its 95% CI for the summary study. In knee OA (left panel), the summary ORs except for the European studies do not include 1, indicating the positive association between D14 and knee OA. In hip OA (right panel), the summary ORs include 1.

 


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  		Table 2. Summary OR of six studies and summary studies regarding the association of knee OA and the asporin D-repeat polymorphisms

 
To exclude the possible publication and selection bias of the first study (the Japanese knee cohort study), we excluded this study and analyzed the remaining five knee case–control studies (the ‘replication’ studies). The summary OR of D14 versus other alleles combined was lower for the replication studies than for all six studies, but still exceeded 1, as did its 95% CI (Table 2). The P-value for D14 for the replication studies was significant (P = 0.009). The summary OR of D13 versus other alleles combined exceeded 1 in the replication studies, but its 95% CI also intercepted 1, generating a non-significant P-value of 0.085 (Fig. 2; Table 2).


Figure 2
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  		Figure 2. A meta-analysis for association between OA and the ASPN D-repeat in the comparison of the D13 allele versus other alleles combined. ORs for the Jiang's study (China) for knee OA and for the Rodrigues's study (Spain) for hip OA are above 1. Summary ORs except for all studies of knee OA include 1.

 
Significant heterogeneity was detected among the studies in the analysis of association of the D14 allele versus other alleles combined (P = 0.047, Table 2). Because of this, we stratified the studies by ethnicity, into Asian and European groups (Table 2). We detected association between knee OA and the D14 allele (P = 0.0000013, OR = 1.95) with non-significant heterogeneity (P = 0.54) in the Asian group. In contrast, the D14 allele was not associated in the European group (P = 0.2, OR = 1.14) with non-significant heterogeneity (P = 0.90). D13 was not associated in the Asian group (P = 0.26) or in the European group (P = 0.081).

We analyzed genotype data with the assumption of the inheritance modes of dominant or recessive. A stronger association was not found with the assumption of mode of inheritance. The tendency found in the analysis of allele count data was maintained in the analysis with the assumption of dominance of the D14 allele for all studies (P = 0.006), the replication studies (P = 0.02) and for Asians (P = 0.0000014) but not for Europeans (P = 0.32) (Supplementary Material, Table S5; Fig. 3). An association with the D13 allele was detected in the recessive mode for all studies (P = 0.009), for the replication study (P = 0.038) and for Europeans (P = 0.049) but not for Asians (P = 0.14). (Supplementary Material, Table S6; Fig. 3).


Figure 3
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  		Figure 3. A meta-analysis of knee OA under the assumption of the inheritance mode. Left: knee OA in the dominant mode of the D14 allele. Summary ORs do not include 1 except for the European studies. Right: knee OA in the recessive mode of the D13 allele. Summary ORs do not include 1 except for the Asian studies.

 
Hip OA
We analyzed three case–control studies of association between hip OA and ASPN D-repeat alleles: one in Japanese and two in European subjects (UK and Spain). The tests for the D14 allele versus other alleles combined and for the D14 allele versus the D13 allele showed significant heterogeneity (Supplementary Material, Table S7). The 95% CI for the summary OR included 1 when all studies were analyzed together (Japanese, UK and Spain) and when the replication studies (UK and Spain) were analyzed together (Fig. 1), indicating that there was no positive association between ASPN and hip OA. The same tendency was observed in the analysis of genotype data assuming inheritance modes of dominant or recessive except for the assumption of a recessive mode for the D13 allele in all three hip studies (P = 0.026, summary OR = 1.20) (Supplementary Material, Table S8).

Other alleles
Kaliakatsos et al. (13). reported that the D15 allele of the D-repeat also associated with knee OA (P = 0.018, OR = 1.54). We performed a meta-analysis for this allele as well as for additional common alleles of the repeat other than D13 and D14. No significant association was detected for any allele (Supplementary Material, Table S9).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 REFERENCES
 
This report represents the first comprehensive meta-analysis of OA-associated genes. We enrolled a large number of subjects for the ASPN D-repeat association from Europe and Asia. There were two objectives of the study. The first was to assess heterogeneity among the association studies so far published. The OR of association between OA and ASPN D-repeat alleles in the studies examined showed significant heterogeneity. These results suggest that there are ethnic differences in the effect of the ASPN on OA susceptibility.

The second objective was to test association by summarizing allele and genotype information. The summary OR of the D14 allele for knee OA showed a significant association and was greater than 1. The sensitivity analysis also indicated significance, despite use of the conservative DerSimonian–Laird (DSL) procedure. These results, together with evidence from functional analyses (11), enhance the evidence for the association of the D14 allele of the ASPN D-repeat with knee OA. However, the effect is heterogeneous. The lower effect of this allele in Europeans may be caused by the influence of other genes or by environmental effects that vary between Europeans and Asians. We detected strong association between knee OA and the D14 allele with non-significant heterogeneity in Asian populations. These results suggest that the genetic effect of the ASPN D-repeat in the Asian population is stronger than in the European population.

In contrast, the summary OR for hip OA did not indicate a significant association. Allelic frequencies differed greatly between the two European studies (UK and Spain). These results may indicate either lack of association, population differences or a lack of power to detect minor associations. The OR for association of hip OA was substantially lower than that of knee OA, even in the Japanese studies.

The recessive protective effects was observed for the D13 allele in knee and hip European populations (Supplementary Material, Tables S6 and S8), which is inconsistent with the previous in vitro functional study where the inhibitory effect of the D13 allele on TGF-ß induction on cartilage marker gene is similar to those of the D16 and D17 alleles (11). The effect of the D13 allele may just be a reflection of the absence of the D14 allele that has a dominant positive effect.

Our conclusion is that the D-repeat of ASPN is globally associated with knee OA, but its effect size has ethnic difference: strong in Eastern Asians and weaker in Europeans. The heterogeneity of genetic effects between Asian and European suggests the existence of gene–gene interaction or gene–environmental interaction. The summary ORs presented here are marginal effects of ASPN polymorphism for knee OA. The combination of ASPN D-repeat and the other polymorphisms that are common in Asian and uncommon in European may increase the risk of knee OA. Otherwise, the polymorphism of ASPN may increase the risk of knee OA with the other environmental factors. The meta-analysis using ORs corrected by the other information, clinical parameters and the other polymorphisms that are associated with knee OA, is efficient. Further replication studies are required in order to detect the true effects of the ASPN.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
SUPPLEMENTARY MATERIAL
 REFERENCES
 
Data collection
To find articles about association between ASPN and OA, the first author (Takahiro Nakamura) searched the PubMed database for articles containing the terms ‘asporin’ and ‘osteoarthritis’. Five relevant articles were published between February 2005 and October 2006 and are described in Introduction (11–15). Under the initiative of the corresponding author (Shiro Ikegawa), the authors of the five articles joined together to form a collaborative group. The genotype data and clinical covariates, age, sex and BMI of each study were collected together.

Statistical analysis
We used the software R (http://www.R-project.org) (19) for all the calculations of statistical analysis. We compared the difference of the clinical covariates between the genotypes of the ASPN D-repeat polymorphisms using Mann–Whitney and Kruskal–Wallis tests. We used OR as a measure of the effect of the genetic factor. There are two major models for meta-analysis: the fixed-effect model and the random-effect model (16,17). The fixed-effect model interprets variations in genetic effects between studies as just errors, whereas the random-effect model interprets variations as the sum of errors and heterogeneity. We principally used the DSL procedure (20) for the analysis. The DSL procedure is based on the random-effect model and contains two tests. One is a test of heterogeneity for testing the null hypothesis that all the populations in the studies have a common OR; the other is a test of significance for testing the null hypothesis that the common OR is equal to 1.

We performed the tests for three comparisons of the allele count data: the D14 allele versus other alleles combined, the D13 allele versus the D14 allele and the D13 allele versus the other alleles combined. If the onset of OA depends on the mode of inheritance then a test assuming the mode of inheritance (dominant or recessive) would be more powerful. Therefore, we also performed the tests using the genotype data. There was a tendency for the Japanese knee cohort study to have a high OR (21), which may have been caused by the selection of major significant genes from among multiple candidates, as well as by the publishing bias. Therefore, in addition to the analyses using all seven studies (Japanese knee cohort, Japanese knee case–control, Japanese hip case–control, Chinese, UK, Spanish and Greek), we performed a sensitivity analysis in which the Japanese knee cohort study was excluded. Furthermore, we examined the data following stratification by ethnicity (Asian or European) and by joint site (hip or knee) for the meta-analysis.


   SUPPLEMENTARY MATERIAL
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
REFERENCES
 
Supplementary Material is available at HMG Online.


   ACKNOWLEDGEMENTS
 
We would like to thank Atsushi Takahashi (SNP Research Center, RIKEN). This work was supported by The Arthritis Research Campaign (to J.L.), Research into Ageing (to J.L.), Grant PI02/0713 form the Instituto de Salud Carlos III (Spain) with participation of funds from FEDER (European Union) (to J.R.-L. and A.G.), National Nature Science Foundation of China (3057874) (to D.S. and Q.J.), Programme of Technology Development of Nanjing (200603001) (to D.S. and Q.J.) and The Ministry of Education, Science, Sports and Culture Grant-in-Aid for Young Scientists (B) 18700283 (2006) (to T.N.).

Conflict of Interest statement. The authors declare that they have no competing financial interests.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 SUPPLEMENTARY MATERIAL
 REFERENCES
 

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  12. Mustafa Z., Dowling B., Chapman K., Sinsheimer J.S., Carr A., Loughlin J. Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population. Arthritis Rheum. (2005) 52:3502–3506.[CrossRef][Web of Science][Medline]

  13. Kaliakatsos M., Tzetis M., Kanavakis E., Fytili P., Chouliaras G., Karachalios T., Malizos K., Tsezou A. Asporin and knee osteoarthritis in patients of Greek origin. Osteoarthritis Cartilage (2006) 14:609–611.[CrossRef][Web of Science][Medline]

  14. Rodriguez-Lopez J., Pombo-Suarez M., Liz M., Gomez-Reino J.J., Gonzalez A. Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case-control studies in Spanish Caucasians. Arthritis Res. Ther. (2006) 8:R55.[CrossRef][Medline]

  15. Jiang Q., Shi D., Yi L., Ikegawa S., Wang Y., Nakamura T., Qiao D., Liu C., Dai J. Replication of the association of the aspartic aciD-repeat polymorphism in the asporin gene with knee-osteoarthritis susceptibility in Han Chinese. J. Hum. Genet. (2006) 51:1068–1072.[CrossRef][Web of Science][Medline]

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