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00007632-201312010-0001600007632_2013_38_e1600_gu_polymorphism_25miscellaneous-article< 124_0_18_9 >Spine© 2013 by Lippincott Williams & WilkinsVolume 38(25)01 December 2013p E1600–E1607Aggrecan Variable Number of Tandem Repeat Polymorphism and Lumbar Disc Degeneration: A Meta-analysis[Epidemiology]Gu, Jiaao MD; Guan, Fulin MD; Guan, Guofa MD; Xu, Gongping MD; Wang, Xintao MD; Zhao, Wei; Ji, Ye MD; Yan, Jinglong MDFrom the Department of The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.Address correspondence and reprint requests to Jinglong Yan, MD, Department of The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng St, Nangang District, Harbin, Heilongjiang Province, People's Republic of China; E-mail: haerbinmed@yahoo.com.cn Acknowledgment date: November 12, 2012. First revision date: March 25, 2013. Acceptance date: May 19, 2013.The manuscript submitted does not contain information about medical device(s)/drug(s).Educational Commission of Heilongjiang Province, China (No. 12511280), funds were received to support this work.No relevant financial activities outside the submitted work.AbstractStudy Design. Data on the association between the ACAN (encoded for aggrecan core protein) variable number of tandem repeat (VNTR) polymorphism and lumbar disc degeneration are conflicting, so we performed a meta-analysis.Objective. Aggrecan is involved in the shock absorbing function of the lumbar disc; we performed a meta-analysis to assess the association between ACAN VNTR and lumbar degeneration.Summary of Background Data. To perform a meta-analysis, we searched for studies published until September 2012, using electronic databases (PubMed, EMBASE, and China National Knowledge Infrastructure). Eight studies involving 965 cases of lumbar disc degeneration and 982 control subjects were identified.Methods. Assessment for eligibility and extraction of data were performed by 2 independent investigators. We extracted allele frequency for each study. We calculated the pooled odds ratios (ORs) and 95% confidence intervals (CI) to assess the strength of the association between the ACAN VNTR polymorphism and lumbar disc degeneration risk.Results. Results from the allele model suggested an increased risk of lumbar disc degeneration for the shorter alleles carriers compared with the normal alleles and longer alleles (OR = 1.54, 95% CI: 1.04–2.30, P = 0.03). In subgroup analysis by ethnicity, significant increased risks were found among Asians with shorter alleles (OR=1.65, 95% CI: 1.17–2.33, P = 0.004).Conclusion. Our results suggest an increased risk of shorter alleles compared with normal alleles and longer alleles against lumbar disc degeneration among populations especially among Asian descent. Such association may not be statistically significant in European populations.Level of Evidence: N/AIn recent years, low back disorders have been the most common musculoskeletal problems in the industrialized societies.1,2 The disorders are a major source of disability and have a substantial impact on the cost of health care. Lumbar disc disease (LDD) is the main cause of low back disorders.Although the cause of LDD is still unknown, it has been suggested that some environmental factors, such as physical loading,3,4 driving motor vehicles,5 vibration,6 and smoking,7 may play a role. On the contrary, LDD is also affected by genetic factors and these genetic factors were noted as well for their important role in the degeneration process of musculoskeletal disorders.8–11LDDs such as disc degeneration and herniation are common problems that occur in adolescence, which had been traditionally regarded as a result of mechanical overloading and senescence.12,13 The intervertebral discs, separating the vertebrae of the spine, facilitate the bending and twisting motion to which the spine is subjected. These functions of disc are enabled by the unique structure: their outer annulus fibrosus and inner nucleus pulposus.14 The annulus is composed of lamellae of collagen fibrils that resist the tensile forces generated during bending or twisting.Aggrecan, a large aggregating proteoglycan, is one of the major structural components of intervertebral disc and cartilage.15,16 The localized high concentration of aggrecan provides the osmotic property that is necessary for common tissue function.17 This function is related to the structure of aggrecan, especially to the large number of chondroitin sulfate (CS) chains that present on their core protein. The CS chains are presented in 2 adjacent regions of the aggrecan core protein, termed the CS1 and CS2 domains. In humans, the region of the aggrecan gene encoding the CS1 domain exhibits size polymorphism, which can result in variation in the degree of CS substitution of aggrecan in different individuals.18 The human ACAN gene (encoded for aggrecan core protein), locating on the chromosome 15q26, is unique among species analyzed to date in possessing variable number of tandem repeat (VNTR) polymorphism.19 The polymorphism has repeating of 57 nucleotides, encoding each 19 amino acid unit. Alleles have been identified with CS1 repeat numbers ranging from 13 to 33. The most common alleles possess 26, 27, or 28 repeats.19,20,21Some studies proved that the A13-25 were risk factors for the lumbar disc degeneration,20,22–26 some found that A26-27 alleles were associated with lumbar disc degeneration,21,23 whereas one obtained no relationship between the ACAN polymorphism and lumbar disc degeneration.27Considering the inconsistent results, we sought to summarize the current data on the association between the ACAN VNTR polymorphism and lumbar disc degeneration by systematically reviewing the literature and performing a meta-analysis.MATERIALS AND METHODSSelection of StudiesThe investigators included published observational studies of lumbar disc degeneration including ACAN VNTR as a primary or secondary exposure. They followed the guidelines for systematic reviews of genetic association studies.28 Jiaao Gu is an orthopedist and Fulin Guan is a neurologist. The 2 investigators (Jiaao Gu, Fulin Guan) independently searched PubMed, EMBASE, and China National Knowledge Infrastructure from 1995 to April 2013. They identified the publications using the keywords ACAN (“ACAN” or “AGC1” or “aggrecan”) and disc degeneration (“disc degeneration” or “disc” or “disc heriation” or “intervertebral disc degeneration” or “spinal stenosis”) in combination with genetic variations (“gene polymorphism” or “genetic variation”). They considered full articles without language restrictions. In addition, they manually searched the reference list of all primary articles and review articles.The investigators defined the following criteria for inclusion: (1) Studies must have a cross-sectional, case-control, or cohort design and they must have been published as full articles. (2) Lumbar disc degeneration was diagnosed according to the magnetic resonance imaging. (3) Authors must provide information on allele frequency of the ACAN VNTR polymorphism or sufficient data to calculate odds ratio (OR) and 95% confidence interval (CI). Accordingly, the exclusion criteria were defined as: (1) reviews, abstracts, or animal studies; (2) useless data reported, genotype frequency not reported; (3) repeat or overlapping studies. Larger and latest data were selected for the duplicate publications. (4) Studies with overlapping cases and/or controls, the largest with extractable data was included. (5) A family-based design study was not accepted.Data ExtractionGuofa Guan is an orthopedist, and the 2 investigators (Jiaao Gu, Guofa Guan) independently extracted the data from the published studies and entered them in a customized database. Disagreements were resolved by consensus. The following characteristics of each study were collected: the first author, year of publication, country of origin, ethnicity of investigated population, study design, genotyping method, numbers of case and control, and allele frequency. If not given, allele frequencies were calculated where possible. DNA were isolated and purified from leucocytes of peripheral blood from the cases and controls.Statistical AnalysisComparing with single-nucleotide polymorphisms, which are characterized by 2 alleles and 3 genotypes, the ACAN VNTR polymorphism is characterized by 13 alleles.19For each study, we divided alleles into 3 groups: A13-25 (shorter alleles), A26-A27 (common alleles), and A28-A32 (longer alleles), as done in the previous research.19,20,21 This approach investigated whether an excess of alleles in 1 of the 3 groups altered the risk for lumbar disc degeneration. On the contrary, we divided the whole population into 2 groups according to the ethnicity—Asian and European. After dividing, we evaluated the risk of lumbar disc degeneration of the 3 groups in populations of European and Asian descent.The ORs and 95% CIs for each study were calculated to evaluate the association between the alleles of ACAN VNTR polymorphism and lumbar disc degeneration. In this analysis, P < 0.05 was defined as statistically significant. We performed the Laird Q test for heterogeneity and also calculated the I2 statistic for each analysis.29 If the P value was 0.05 or less, indicating obvious heterogeneity between studies, a random-effects (the DerSimonian and Laird method) model was used to calculate the pooled OR30; otherwise, a fixed-effects (the Mantel-Haenszel method) model was performed.31 Potential publication bias was evaluated visually by examining for possible skewness in funnel plots32 and further evaluated with the methods described by Begg and Egger.33 Sensitivity analysis was performed by omitting each study in turn to assess the results stability. All statistical tests were 2 sided. All analyses were performed by Review Manager 4.2 (Cochrane Collaboration, Oxford, England) and STATA 10.1 (Stata, College Station, TX). Because we only used previously published data, we did not obtain approval of an ethics committee or written informed consent. All authors had access to all of the data.RESULTSThe process of identifying eligible studies was shown in Figure 1. After title and abstract evaluation, 13 candidate studies were identified. We excluded 5 more studies after evaluating the full article versions of the remaining articles due to unsuitable controls, lack diagnosis of lumbar disc degeneration, data replication, especially insufficient information about the allele frequency for OR calculation. Finally, 8 studies with a total of 965 cases and 982 controls entered this meta-analysis.20–27Figure 1. Flow diagram of the selection of eligible studies.Study CharacteristicsTable 1 summarizes the characteristics of the 8 included studies. Four studies were performed on populations of European descent21,23–25 and the other 4 on population of Asian descent.20,22,26,27 All studies were hospital-based case-control studies. They all investigated mixed female and male populations, and used standard polymerase chain reaction genotyping methods. All the cases were diagnosed according to the magnetic resonance imaging. The allele frequencies of the ACAN VNTR polymorphism in lumbar disc degeneration and controls in each of the included studies are summarized in Table 2.TABLE 1. Characteristics of Included Studies Investigating the Association Between the Aggrecan VNTR Polymorphism and Lumbar Disc DegenerationTABLE 2. Allele Frequencies for the Aggrecan VNTR PolymorphismQuantitative SynthesisAssociation Between the ACAN VNTR Polymorphism and Lumbar Disc DegenerationOn the basis of the allele model, the pooled ORs among all study populations for the shorter alleles versus common and longer alleles of 1.54 (95% CI = 1.04–2.30; P = 0.03, Pheterogeneity = 0.01) demonstrated a 54% increased risk for lumbar disc degeneration among carriers of the shorter alleles. The common alleles and longer alleles had no effect on increasing the lumbar disc degeneration risk (common alleles: OR = 0.84, 95% CI = 0.70–1.01, P = 0.07, Pheterogeneity = 0.16; longer alleles: OR = 0.80, 95% CI = 0.57–1.13, P = 0.21, Pheterogeneity = 0.08).We also performed subgroup analysis stratified by ethnicity. In the Asian population, the carrier of shorter alleles would increase the risk for lumbar disc degeneration (OR = 1.65; 95% CI = 1.17–2.33; P = 0.004; Pheterogeneity = 0.27). No statistical significance in Asians was obtained for the common and longer alleles distribution (common alleles: OR = 0.93; 95% CI = 0.69–1.25; P = 0.64; Pheterogeneity = 0.23; longer alleles: OR = 0.75; 95% CI = 0.39–1.44; P = 0.39; Pheterogeneity = 0.06). The distribution of the 3 allele groups showed no significant association between ACAN VNTR polymorphism and lumbar disc degeneration in populations of European descent (shorter alleles: OR = 1.48; 95% CI = 0.75–2.92; P = 0.26; Pheterogeneity = 0.003; common alleles: OR = 0.78; 95% CI = 0.62–1.00; P = 0.05; Pheterogeneity = 0.14; longer alleles: OR = 0.90; 95% CI = 0.69–1.18; P = 0.44; Pheterogeneity = 0.26; Figures 2–4).Figure 2. Forest plot of lumbar disc degeneration risk associated with the aggrecan polymorphism (shorter alleles vs. common and longer alleles) in overall populations. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study specific weight (inverse of the variance). Diamonds represent the pooled OR and 95% CI. OR indicates odds ratio; CI, confidence interval.Figure 3. Forest plot of lumbar disc degeneration risk associated with the aggrecan polymorphism (common alleles vs. shorter and longer alleles) in overall populations. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study specific weight (inverse of the variance). Diamonds represent the pooled OR and 95% CI. OR indicates odds ratio; CI, confidence interval.Figure 4. Forest plot of lumbar disc degeneration risk associated with the aggrecan polymorphism (longer alleles vs. shorter and common alleles) in overall populations. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study specific weight (inverse of the variance). Diamonds represent the pooled OR and 95% CI. OR indicates odds ratio; CI, confidence interval.Sensitivity AnalysesSensitivity analyses indicated that one independent study conducted by Mashayekhi et al24 was the main origin of heterogeneity for the ACAN VNTR polymorphism in the overall population. The heterogeneity was effectively decreased or removed after exclusion of the study (shorter alleles: P = 0.06 for heterogeneity, I2= 64.1%; common alleles: P = 0.93 for heterogeneity, I2= 0%; longer alleles: P = 0.17 for heterogeneity, I2= 44.2%). No single study influenced the pooled OR qualitatively, as indicated by sensitivity analyses. Pooled ORs were consistently significant in Asian populations or European populations by omitting one study at a time under allele comparison, suggesting robustness of our results (data not shown).Bias DiagnosticsFunnel plots were generated to assess publication bias. The Egger test was performed to evaluate funnel plot symmetry. The results showed no evidence of publication bias (P = 0.910, 0.479, 0.596; showed in Figures 5–7).Figure 5. Begg funnel plot of the Egger test for publication bias of aggrecan VNTR polymorphism and lumbar disc degeneration (shorter alleles vs. common and longer alleles). Sloping lines indicate the expected 95% CI for a given SE. CI indicates confidence interval; SE, standard error; VNTR, variable number of tandem repeat.Figure 6. Begg funnel plot of the Egger test for publication bias of aggrecan VNTR polymorphism and lumbar disc degeneration (common alleles vs. shorter and longer alleles). Sloping lines indicate the expected 95% CI for a given SE. CI indicates confidence interval; SE, standard error; VNTR, variable number of tandem repeat.Figure 7. Begg funnel plot of the Egger test for publication bias of aggrecan VNTR polymorphism and lumbar disc degeneration (longer alleles vs. common and shorter alleles). Sloping lines indicate the expected 95% CI for a given SE. CI indicates confidence interval; SE, standard error; VNTR, variable number of tandem repeat.DISCUSSIONWe performed a comprehensive review of the literature on the association between the ACAN VNTR polymorphisms and lumbar disc degeneration risk. This article is the first systemic review that investigated the relationship between single-nucleotide polymorphisms and lumbar disc degeneration.Degeneration of the intervertebral disc is a process that begins early in life, with a consequence of various intrinsic and extrinsic factors contributing to the process. Environmental factors seem to be involved in only a minor part of individual variation in pathological changes in the disc, whereas the major part remains unclear.34–36 After reviewing the substantial genetic influence on intervertebral disc degeneration,37 the mechanisms of the genetic effect should be considered. It is still not certain whether a specific gene effect of relatively large importance exists or the genetic contribution is because of small effects of many genes. However, it seems that disc degeneration may be characterized as a common, oligogenic, and multifactorial genetic process.38Aggrecan is the major protein in the nucleus pulposus, which involved in the shock absorbing function of the intervertebral disc.15,39,40 Humans are unique in owning VNTR polymorphism and single-nucleotide polymorphism within the ACAN CS1 domain.19This meta-analysis including 965 cases and 982 controls from 8 published case-control studies examined the association between the VNTR polymorphism of the ACAN gene and lumbar disc degeneration susceptibility. The main results from this meta-analysis were that shorter alleles seemed to be a risk factor among populations compared with common and longer alleles. The carriers of shorter alleles would increase about 55% risk for lumbar disc degeneration. The longer alleles and common alleles carriers would neither increase nor decrease the risk of the disease.We found a 65% increase in lumbar disc degeneration in populations of Asian descent, but the ACAN VNTR showed no association with lumbar disc degeneration in Europeans. This difference might contribute to the different frequencies of alleles of different ethnicity. For example, the shorter alleles frequency among controls was 0.305 in Asian populations and 0.195 in European populations, which suggested a possible ethnic difference.Heterogeneity is a potential problem when interpreting the results of all meta-analysis. Significant between-study heterogeneity existed in shorter allele comparisons. After subgroups were analyzed by ethnicity, heterogeneity had effectively decreased after removing one article,24 the heterogeneity had disappeared in populations of European descent. The reason might be that genetic background and the environment are different among different ethnicities.An important issue that is often raised in a meta-analysis is publication bias. In this meta-analysis, Begg funnel plot was carried out to assess the potential publication bias of literatures, and no evidence of publication bias was detected, indicating that the pooled results were robust.Our study provided some evidence to support an association between ACAN VNTR polymorphisms and lumbar disc degeneration. Advantages in our meta-analysis should be acknowledged. First, a substantial number of cases and controls were pooled from different studies; this significantly increased the statistical power of the analysis. Second, no publication bias was detected, indicating that the pooled results were reliable. Third, the quality of case-control studies included in the meta-analysis was found to be satisfactory based on our selection criteria. However, some limitations of this meta-analysis should be addressed. First, the number of published studies was not sufficiently large for a comprehensive analysis, which limited statistical power. Second, because of the data limitation, we did not perform stratification analysis by age, sex, smoking status, drinking status, obesity, physical load, or other variables. This might have caused serious confounding bias. Third, failing to get the original data for the reviewed studies limited our evaluation of potential gene-gene, gene-environment, or even different polymorphism loci of the same gene, which may affect lumbar disc degeneration risk. Studies with large sample sizes of lumbar disc degeneration and controls seem warranted. Studies should not just be carried out on populations of European and Asian descent, but also on other populations. Besides, further results should also be presented stratified by sex, age, and physical load.There are important clinical relevance between the aggrecan polymorphism and intervertebral disc or cartilage degeneration. If an association is present, then ACAN VNTR analysis early in one's life can be used to, so that one can be advised on how his/her future lifestyle may impact on tissue degeneration. An ACAN VNTR analysis will also be necessary if donors of allogenic tissue or cells were used for intervertebral disc or cartilage repair because there seems little point in repairing a lesion with a tissue that itself is at a risk for degeneration.CONCLUSIONThe shorter alleles of ACAN VNTR polymorphism would increase a 56% risk for lumbar disc degeneration. By ethnicity, we found that the shorter alleles would increase nearly 65% risk for lumbar disc degeneration in Asians, but not in populations of European descent. Because of limitations of this study, replication studies on homogenous subgroups with larger sample size as well as consideration of gene-gene or/and gene-environmental interactions are needed before reaching definite conclusions.Key Points * Aggrecan is involved in the shock absorbing function of the lumbar disc. * Association between ACAN VNTR and lumbar disc degeneration is conflicting. * Meta-analysis is used to evaluate such association. * We found that ACAN VNTR polymorphism is associated with lumbar disc degeneration.AcknowledgmentsJiaao Gu and Fulin Guan contributed equally to this article.References1. Andersson GB. Epidemiological features of chronic low-back pain. Lancet 1999;354:581–5. [CrossRef] [Full Text] [Medline Link] [Context Link]2. Frymoyer JW. Epidemiology. Magnitude of the problem. In: Wiesel SW, Weinstein JN, Herkowitz HN, Dvorak J, Bell GR, eds. The Lumbar Spine. 2nd ed. Philadelphia: WB Saunders; 1996:8–16. [Context Link]3. 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[CrossRef] [Medline Link] [Context Link]lumbar disc degeneration; meta-analysis; VNTR polymorphismovid.com:/bib/ovftdb/00007632-201312010-0001600005531_1999_354_581_andersson_epidemiological_|00007632-201312010-00016#xpointer(id(R1-16))|11065213||ovftdb|00005531-199908140-00045SL00005531199935458111065213P73[CrossRef]10.1016%2FS0140-6736%2899%2901312-4ovid.com:/bib/ovftdb/00007632-201312010-0001600005531_1999_354_581_andersson_epidemiological_|00007632-201312010-00016#xpointer(id(R1-16))|11065404||ovftdb|00005531-199908140-00045SL00005531199935458111065404P73[Full Text]00005531-199908140-00045ovid.com:/bib/ovftdb/00007632-201312010-0001600005531_1999_354_581_andersson_epidemiological_|00007632-201312010-00016#xpointer(id(R1-16))|11065405||ovftdb|00005531-199908140-00045SL00005531199935458111065405P73[Medline 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degeneration. Eight studies were identified. Our result suggested an increased risk of shorter alleles compared with normal alleles and longer alleles against lumbar disc degeneration among populations, especially among populations of Asian descent.Aggrecan Variable Number of Tandem Repeat Polymorphism and Lumbar Disc Degeneration: A Meta-analysisGu, Jiaao MD; Guan, Fulin MD; Guan, Guofa MD; Xu, Gongping MD; Wang, Xintao MD; Zhao, Wei; Ji, Ye MD; Yan, Jinglong MDEpidemiology2538