Inflammatory Bowel Diseases:
Original Clinical Articles
Associations Between Vitamin D Receptor Polymorphisms and Susceptibility to Ulcerative Colitis and Crohn's Disease: A Meta-analysis
Xue, Le-Ning MD*; Xu, Ke-Qun MD, PhD*; Zhang, Wei MD*; Wang, Qiang MD*; Wu, Jia MD†; Wang, Xiao-Yong MD, PhD*
*Department of Gastroenterology
†Department of Gynecology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China.
Reprints: Xiao-Yong Wang, MD, PhD, Department of Gastroenterology, Changzhou No. 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province 213000, China (e-mail: firstname.lastname@example.org).
The first two authors contributed equally to this work.
Supported by a grant from the Natural Science Funds of Jiangsu Province, China (No. BK2010194).
Received February 25, 2012
Accepted March 05, 2012
Background: Several polymorphisms have been identified in the vitamin D receptor (VDR) gene, while their roles in the incidence of ulcerative colitis (UC) and Crohn's disease (CD) are conflicting. This meta-analysis was designed to clarify the impact of these polymorphisms on UC and CD risk.
Methods: The PubMed, Embase, and Cochrane electronic databases were searched from February 1995 to August 2011 for studies on the four VDR polymorphisms: TaqI, BsmI, FokI, and ApaI. Data were extracted and pooled odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Results: Nine studies were included. In Asians, the ff genotype of FokI was associated with increased UC risk (OR = 1.65; 95% CI, 1.11– 2.45). The “a” allele carrier status of ApaI appeared to be a protective factor for CD (OR = 0.81; 95% CI, 0.67–0.97). The tt genotype increased the risk of CD in Europeans (OR = 1.23; 95% CI, 1.02–1.49). Moreover, the tt genotype of TaqI in males had a moderate elevated risk of UC (OR = 1.56; 95% CI, 1.02–2.39) and CD (OR = 1.84; 95% CI, 1.19–2.83).
Conclusions: The meta-analysis reveals a significant increase in CD risk for Europeans carrying TaqI tt genotype and a significant decrease in CD risk for all carriers of the Apal “a” allele. For Asians, the VDR FokI polymorphism appears to confer susceptibility to UC. For males, the TaqI tt genotype is associated with susceptibilities to both UC and CD. Our study explored the genetic risk prediction in UC and CD, and may provide valuable insights into IBD therapy.
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic disorders caused by aberrant inflammation of the gastrointestinal tract. UC is a continuous inflammatory condition that begins in the rectum and extends for a varying distance proximally through the colon, specifically involving the mucosal and submucosal layers. In contrast, CD occurs as a transmural discontinuous inflammation that may affect any region of the gastrointestinal tract.
The IBD incidence rate has gradually increased over the past decade and currently represents one of the most common health problems worldwide.1,2 However, the etiology and pathogenesis of IBD are still uncertain. Extensive studies have suggested that IBD is a multifactorial disease, and a number of contributing factors have been identified, including genetic predisposition, environmental insults, intestinal microbial flora, and aberrant immune responses.3 Due to the inflammatory character of IBD, much research has focused on the immune response. It has been found that many IBD patients have a dysregulated intestinal mucosal T-cell-mediated immune response, specifically involving the CD4+T helper type-1 (Th1) lymphocytes. This impairment leads to production of Th1-associated proinflammatory cytokines, such as interferon-γ (IFN-γ), interleukin (IL)-2, and tumor necrosis factor-alpha (TNF-α).4,5
Although the primary function of vitamin D is believed to be the regulation of bone mineral homeostasis, accumulating evidence has indicated that vitamin D plays a role in regulating immune function.6 Vitamin D has been demonstrated to suppress both lymphocyte proliferation and immunoglobulin synthesis. In addition, it can inhibit the action of the proinflammatory transcription factor, nuclear factor kappa B (NF-κB), and the production of various cytokines, including IL-2, IL-12, and IFN-γ.7,8 As such, it is conceivable that vitamin D may influence the pathogenesis of IBD through its functional interactions with various immune system processes.
Several studies have investigated the role of vitamin D-mediated inflammatory pathways in IBD pathogenesis. Intriguingly, vitamin D deficiency has been linked to the development of a number of different autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Genome-based studies of IBD patients have determined that individuals with a genetic predisposition in which they are not able to maintain adequate vitamin D levels have an increased likelihood of developing the disease.9,10 Joseph et al. found that CD activity correlated negatively with the serum levels of 25-hydroxy vitamin D (25OHD), the major circulating vitamin D metabolite.11 Furthermore, vitamin D supplementation may have therapeutic potential for IBD.12,13 However, we cannot rule out the possibility that vitamin D deficiency is merely a consequence of these disorders, as some patients may become housebound and not get adequate sun exposure.
The vitamin D receptor (VDR) is a member of the steroid nuclear receptor superfamily, and it is required for most known biological effects of vitamin D. It is highly expressed on macrophages, monocytes, B and T lymphocytes, and dendritic cells. Binding of vitamin D to the VDR triggers an intracellular molecular signaling cascade that ultimately regulates the transcription of multiple genes.14 The VDR gene is located on chromosome 12, within one of the IBD candidate regions, as determined by linkage analysis.15,16 Four common polymorphisms recognized by restriction enzymes have been reported within this region: ApaI (rs7975232) and BsmI (rs1544410) at the 3' flanking end in intron 8; TaqI (rs731236) at the 3' flanking end in exon 9; and FokI (rs2228570) at the 5' end in exon 2.17
Numerous case-control studies across multiethnic groups have assessed the association between VDR polymorphisms and IBD18–26; however, the results have been inconsistent and inconclusive. Several possible explanations have been proposed for the disparity, including small sample sizes, low statistical power, and subjects from different ethnic backgrounds. Therefore, in order to overcome the limitations of these individual studies, resolve inconsistencies, and reduce the likelihood that random errors are responsible for false-positive or false-negative associations, we conducted a meta-analysis of the previously published studies. Here, we describe our findings of whether the four common polymorphisms of VDR confer susceptibility to IBD.
MATERIALS AND METHODS
The PubMed, Embase, and Cochrane databases were searched for studies focused on the relationship between the four common polymorphisms of VDR and the risk of IBD from February 1995 to August 2011. Searching was carried out by two independent reviewers (X.-Y.W. and K.X.). The key words and subject terms used were as follows: “Crohn's disease” or “CD,” “ulcerative colitis” or “UC,” “inflammatory bowel disease” or “IBD,” “vitamin D receptor” or “VDR,” and “polymorphism.” The reference lists in the identified studies were also investigated to identify additional studies of interest. Only articles published in English were retrieved.
Inclusion and Exclusion Criteria
Inclusion in the meta-analysis was based on the following criteria: 1) the study assessed the association between IBD and at least one of the four polymorphisms of interest; 2) controls of included studies were from a healthy population or were subjects without diseases related to IBD; 3) the genotype distribution of the control population was in Hardy–Weinberg (H-W) equilibrium; and 4) the study reported sufficient data to calculate the number of each allele identified. For those articles with overlapping data of the same population source, only the latest and largest report was included. Studies were excluded if: 1) the design was based on family data; 2) the genotype frequency was not reported; 3) the article was a review; 4) there was insufficient information to support integrity of the data upon extraction; 5) the article was composed of case studies only; or 6) the research did not study any of the ApaI, BsmI, TaqI, and FokI polymorphisms.
The information extracted from each study included the following: name of the first authors; year of publication; ethnicity of subjects; type of diseases; sample sizes; and H-W equilibrium of control. For studies including subjects of different ethnicities, data were extracted separately for each race whenever possible. Baseline information and data were extracted by two reviewers (X.-Y.W. and K.X.) independently using the same standard. The results were compared and disagreements were resolved by consensus.
Variant genotype frequencies were compared between cases and controls. The odds ratio (OR) and 95% confidence interval (CI) for the heterozygote and variant homozygote were calculated as compared with the wildtype homozygote. In addition to overall comparisons, a subgroup analysis was performed based on ethnicity and sex when adequate data were available. Between-study heterogeneity was estimated using the χ2 -based Q statistic. Heterogeneity was considered statistically significant when P < 0.1. A P < 0.10 was chosen in lieu of the conventional cutoff point of P < 0.05 since the test is known to be insufficiently powered to detect heterogeneity when there are few studies.27 I2 was also tested, and if I2 = 0 then heterogeneity was absent, and data were subsequently analyzed using a fixed effects model. If I2 > 50%, heterogeneity was considered present, and data were subsequently analyzed using a random effects model. We could not construct a funnel plot for each meta-analysis due to small numbers of studies, and Egger's regression test was used to assess the publication bias.28 A χ2 test was performed to examine H-W equilibrium, and P < 0.05 was considered statistically significant.
All analyses were performed by the Review Manager 5.1 and Stata 11 (Statsoft, Tulsa, OK) software packages.
Studies Included in the Meta-analysis
A total of 15 articles were identified that were relevant to the search words.18–26,29–34 Six of these articles were excluded for the following reasons: three were reviews29–31; two were case only studies, without controls32,33; and one did not study any of the ApaI, BsmI, TaqI, and FokI polymorphisms.34 As a result, nine studies were included in the current meta-analysis (Table 1). One of the eligible studies contained data on two different ethnicities.23 In UC, eight studies examined the VDR TaqI polymorphism,18–22,24–26 six studied the VDR ApaI poly-morphism,18,20–22,25,26 five studied the VDR FokI polymorphism,18,19,21,25,26 and five studied the BsmI polymorphism.18,20,21,23,26 In CD, six studies examined the VDR TaqI polymorphism,19,21,22,24–26 four studied the VDR ApaI polymorphism,21,22,25,26 four studied the VDR FokI polymorphism,19,21,25,26 and three studied the BsmI polymorphism.21,23,26
Associations Between VDR Polymorphisms and UC
A summary of the meta-analysis findings concerning associations between VDR polymorphisms and UC is shown in Table 2. The VDR TaqI polymorphism was investigated in eight series,18–22,24–26 which were comprised of 1500 cases and 2132 controls. We did not find any significant association between the TaqI variants and overall UC risk (Tt vs. TT, OR = 1.00, 95% CI, 0.87–1.15; tt vs. TT, OR = 1.21, 95% CI, 0.99–1.47; tt+Tt vs. TT, OR = 1.11, 95% CI, 0.96–1.28). Some studies indicated that consideration of sex is warranted in studies of single nucleotide polymorphisms (SNPs) of the VDR gene,19,22 and when the data were stratified by sex, it was found that males carrying the TaqI tt genotype had a moderately elevated UC risk, as compared with males carrying the TT genotype (OR = 1.56; 95% CI, 1.02–2.39) (Fig. 1). For five of the total eight studies, sex stratification of the data was not possible, even after the respective authors were contacted for further inquiry. Therefore, only three studies were included in the sex stratification analysis.
The VDR FokI polymorphism was investigated in five series. No association was found between the FokI variants and overall UC risk (Table 2) (Ff vs. FF, OR = 1.01, 95% CI, 0.87–1.18; ff vs. FF, OR = 1.10, 95% CI, 0.89–1.36; Ff+ff vs. FF, OR = 1.08, 95% CI, 0.81–1.44). The importance of ethnic background has been raised in bio-medical research and clinical practice.35 Genetic variation that predisposes to IBD appears to vary between different ethnic groups.36 In a subgroup analysis by ethnicity, we found that the ff genotype of FokI was associated with increased UC risk for the Asian population (OR = 1.65; 95% CI, 1.11–2.45) (Fig. 2). In terms of ApaI and BsmI polymorphisms, no associations were found with UC by meta-analyses (Table 2) (ApaI: Aa vs. AA, OR = 1.07, 95% CI, 0.90–1.26; aa vs. AA, OR = 0.92, 95% CI, 0.75–1.12; Aa+aa vs. AA, OR = 1.00, 95% CI, 0.82–1.22; BsmI: Bb vs. bb, OR = 1.05, 95% CI, 0.88–1.26; BB vs. bb, OR = 1.16, 95% CI, 0.90–1.49; BB+Bb vs. bb, OR = 1.14, 95% CI, 0.94–1.37).
Associations Between VDR Polymorphisms and CD
Meta-analysis findings for associations of BsmI, TaqI, ApaI, and FokI polymorphisms in the VDR gene and the risk of CD are presented in Table 3. The “a” allele carrier status appeared to be a protective factor for CD (OR = 0.81; 95% CI, 0.67–0.97) (Fig. 3), as compared with the AA genotype. We did not find any significant association between the TaqI variants and overall CD risk (Tt vs. TT, OR = 0.95, 95% CI, 0.83–1.09; tt vs. TT, OR = 1.19, 95% CI, 0.99–1.43; tt+Tt vs. TT, OR = 1.05, 95% CI, 0.91–1.21). In a subgroup analysis by ethnicity, we found TaqI polymorphism was associated with CD for the European population (tt vs. TT: OR = 1.23; 95% CI, 1.02–1.49) (Fig. 4). When stratifying by sex, we found that, in males, the tt genotype carrier status produced a moderately elevated CD risk (OR = 1.84; 95% CI, 1.19–2.83) (Fig. 5), as compared with the TT genotype. No significant difference was found for any of the FokI and BsmI genotypes (FokI: Ff vs. FF, OR = 1.02, 95% CI, 0.87–1.20; ff vs. FF, OR = 1.46, 95% CI, 0.88–2.42; Ff+ff vs. FF, OR = 1.22, 95% CI, 0.80–1.84; BsmI: Bb vs. bb, OR = 0.95, 95% CI, 0.79–1.14; BB vs. bb, OR = 1.17, 95% CI, 0.93–1.48; BB+Bb vs. bb, OR = 1.05, 95% CI, 0.87–1.27).
Test of Heterogeneity and Publication Bias
Heterogeneity of the included studies pertaining to each polymorphism is presented in Table 2. There was significant heterogeneity for the comparison of FokI Ff+ff genotype with FF genotype in the total analysis of UC (χ2 = 11.92, I2 = 66%, P = 0.02). According to the results of the various stratification analyses, we explored the source of heterogeneity from the subgroup analyses of Europeans (χ2 = 7.04, I2 = 72%, P = 0.03) (Fig. 6). For the meta-analysis of CD, heterogeneity was found for FokI ff vs. FF (χ2 = 12.63,I2 = 76%, P = 0.005) and FokI Ff+ff vs. FF (χ2 = 14.82, I2 = 80%, P = 0.002) in the total analysis. As indicated by Egger's test, there was a possibility of publication bias for the comparison of TaqI tt vs. TT (P = 0.03) and BsmI BB+Bb vs. bb (P = 0.001) in the total analysis of CD. We found no evidence of publication bias for any polymorphism with UC risk.
It has been suggested that vitamin D deficiency is independently associated with lower health-related quality of life and greater disease activity in CD but not UC,37 whereas the underlying mechanism remains to be elucidated. The current meta-analysis of nine studies is the first quantitative evaluation of the potential association of VDR gene polymorphisms with the susceptibility to IBD. The first major finding revealed by this comprehensive approach is that the tt genotype of TaqI was associated with CD in Europeans. The mechanism by which the tt genotype influences the susceptibility to CD in Europeans remains unclear, however. The TaqI polymorphism represents a synonymous T–C base substitution at codon 352 in exon 9 at the 3' end of the VDR gene, and does not produce an amino acid coding change since both codon sequences encode an isoleucine. The 3' untranslated region of this gene, which is close to the polymorphism site, is known to be involved in the regulation of gene expression, especially by affecting mRNA stability.38 Some investigators have shown that the tt genotype of the TaqI polymorphism seems to be associated with a lower VDR mRNA level.39,40 As a result, there is a less efficient VDR-induced inhibition effect of 1,25(OH)2 vitamin D3 on the production of IL-12,7,8 a cytokine central to the immune activation seen in CD lesions.41 This modification, then, may give rise to an enhanced Th1 immune response and consequently increase the susceptibility to CD. Alternatively, it is also possible that the TaqI polymorphism may be in linkage disequilibrium (LD) with another yet unidentified marker that may be the true causative factor increasing CD risk.
The second major finding of this meta-analysis is that the variant homozygote tt of TaqI was significantly associated with UC and CD risk in males. However, this result should be interpreted cautiously, because only three studies (for UC) and two studies (for CD) were included in the meta-analysis, due to the incomplete data of other studies. The mechanisms by which this polymorphism may contribute to a sex-specific effect on IBD susceptibility remain unknown.
The third major finding of this meta-analysis is that the ff genotype of FokI was significantly associated with increased risk of UC in Asians (by 1.65-fold), as compared with Asian subjects carrying the FF genotype. Again, this result should be interpreted with caution since only two studies were included in this meta-analysis. Fok1 is located in the 5′ promoter region of the VDR and can be considered an independent marker in the VDR gene since there is no LD with any of the other VDR polymorphisms, and the LD area surrounding this polymorphism seems to be very small.42 Therefore, LD with another polymorphism is not a likely explanation for the associations, and functional studies should focus on the polymorphism itself. The mechanism by which the FokI polymorphism might influence the susceptibility to UC is not completely understood, although several explanations have been postulated. The T–C transition polymorphism (ATG to ACG) in exon 2 of the VDR gene alters the translation initiation sites and results in proteins of different lengths. Functional studies have suggested that the ff genotype results in a longer protein with three extra amino acids, which is less transcriptionally active and has a lower capacity to transactivate VDR target genes.17,43,44 This suggests that people with the ff genotype have a less active VDR. As the VDR protein is believed to play a role in many inflammatory disorders, including IBD, alteration in VDR function is likely to affect IBD susceptibility.
The fourth major finding of this meta-analysis is that the “a” allele carrier status (Aa + aa genotypes) of ApaI may be associated with decreased CD susceptibility, as compared with the AA genotype. The ApaI polymorphism is located in intron 8 at the 3' end of the VDR gene. Although the effects of the ApaI polymorphisms on any splicing or transcription factor binding site are not presently known,45 it is possible that this polymorphism might be linked to true disease-causing genetic variation(s) in the VDR gene itself or in nearby polymorphic gene(s).
The available data support the characterization of FokI and TaqI polymorphisms as ethnic population-specific risk factors, although the small number of studies available to date reduces our confidence in this conclusion. The finding of the association according to ethnicity is somewhat surprising; however, many underlying factors may contribute to this difference. First, genetic heterogeneity for UC and CD may exist in different ethnic populations. Second, clinical heterogeneity may be involved, and the differences in diagnoses and the classification of UC and CD populations may cause different results. Third, different LD patterns may contribute to the discrepancy. This polymorphism may be in LD with a nearby causal variant in one ethnic group, but not in another. Fourth, the difference might arise from chance, representing a type I error.
In conclusion, we found a significant increase in CD risk for European carriers of the TaqI tt genotype, as compared to carriers of the TT genotype, and a significant decrease in CD risk for all “a” allele carriers (Aa + aa), as compared with AA carriers. Furthermore, associations were found between the VDR TaqI polymorphism and susceptibility to UC and CD in males. The VDR FokI polymorphism may confer susceptibility to UC in Asians. This meta-analysis summarizes the previous literature to help define the potential risk factors for UC and CD. However, our results should be interpreted with caution, due to the small number of studies included in the overall analysis. Unfortunately, very few published studies are available in this field, and current evidence remains limited. Therefore, the necessity to conduct large studies with adequate methodological quality should be emphasized in order to obtain more significant and informative results. In view of UC and CD being multifactorial diseases, the polymorphisms of VDR cannot be viewed as the unique crucial factor of pathopoiesis. Future studies are expected to give further insights into the etiology of UC and CD by considering all relevant interactions.
By combining the data of individual studies, we increased the statistical power to detect subtle associations; however, there are still some limitations to this approach. Only studies published in the English language were included in this meta-analysis; therefore, publication bias may have occurred. It is also possible that studies yielding negative results may not have been published or may have been missed by our search.
Another limitation of our study is the fact that it was designed to analyze single polymorphisms; a haplotype analysis may have provided more information and been more powerful for finding significant associations with UC and CD. In addition, the numbers of subjects and studies included in the meta-analysis was very small, and may not have been sufficient to reveal an association between the VDR polymorphisms and the diseases. Finally, meta-analysis is inherently a retrospective method that is subject to the methodological deficiencies of the included studies. We attempted to minimize the likelihood of bias by developing a detailed protocol before initiating the study, but we most certainly could not completely abolish it.
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vitamin D receptor; polymorphism; ulcerative colitis; Crohn's disease; meta-analysis
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