Association between gene polymorphisms of vitamin D receptor and pulmonary tuberculosis...

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Journal of Medical Colleges of PLA 26 (2011) 63–75

Association between gene polymorphisms of vitamin D receptor and pulmonary tuberculosis susceptibility:

a meta-analysisSu Qian1, 2, Ma Xiangyu1, Lin Hui1*, Li Ying3, Hu Daiyu2, Xiong

Hongyan1, Xu Rufu1, Li Yafei1

1Department of Epidemiology, College of Military Preventive Medicine, Third Military Medical University, Chongqing 400038, China

2Institute of Tuberculosis Prevention and Treatment of Chongqing, Chongqing 400050, China 3Department of Social Medicine and Health Service Management, College of Military Preventive Medicine, Third

Military Medical University, Chongqing, 400038, China

Received 13 February 2011; accepted 20 March 2011

Abstract

Background: The vitamin D receptor (VDR) gene is a primary candidate gene for tuberculosis susceptibility, but results of previous studies are somewhat contradictory and underpowered. Thus, it is essential to further explore the association between VDR gene polymorphisms and risk of pulmonary tuberculosis (PTB). Methods: A systematic review and meta-analysis about the association between FokI, TaqI, ApaI and BsmI polymorphisms and PTB susceptibility was conducted. Statistical Package for Social Science (Version 13.0) and Review Manager (Version 4.2, The Cochrane Collaboration) were used to analyze the data reported in studies. Results: A total of 13 studies with 2 262 cases and 2 833 controls were involved in the FokI polymorphism, and the results showed FokI polymorphism was associated with PTB susceptibility (allele f vs F: OR=1.12, 95% CI=[1.02, 1.23]; the additive effect model ff vs FF: OR=1.40, 95%CI=[1.10, 1.77]; the recessive genetic model ff vs Ff+FF: OR=1.39, 95%CI=[1.12, 1.71]). No significant associations were observed between TaqI (15 studies with 3 031 cases and 3 132 controls), ApaI (7 studies with 1 495 cases and 1 922 controls), BsmI (6 studies with 919 cases and 1 250 controls) variants and PTB susceptibility. Conclusion: We found variant FokI polymorphism of VDR gene may play a risky role in PTB development, and the genetic model was presumed to be recessive.

Keywords: Vitamin D receptor; Pulmonary tuberculosis; Polymorphism; Meta-analysis

Supported by the National Natural Science Foundation of China (30700685) and the Medical Science and Technology Research Project of Chongqing Municipal Health Bureau (2009-1-06)

* Corresponding author.

Tel.: 86-23-68752286E-mail address: [email protected] (Lin H.)

64 Su Qian et al. / Journal of Medical Colleges of PLA 26 (2011) 63–75

1. Background

Of late years, tuberculosis on a global scale

revived to become the first killer among infectious

diseases. It was estimated that about one third of

world’s population were infected with

Mycobacterium tuberculosis. The fact that only

10% of those infected developed the disease

suggested that genetic factors were involved in

pathogeny except for environmental factors (such

as poor economic conditions, malnutrition, stress,

overcrowding and so on) [1, 2]. Biological

experiments suggested that the active metabolite of

vitamin D-1, 25-dihydroxyvitamin D3 could

enhance the phagocytosis through the activation of

macrophages and adjust both innate and adaptive

immunity to resist M. tuberculosis infection [3–5].

Epidemiological data and meta-analysis also

confirm that the serum level of vitamin D is

associated with tuberculosis [6–9]. The VDR is a

crucial mediator for the cellular effects of vitamin

D, as vitamin D reacts by binding to VDR. Genetic

alterations of the VDR gene may lead to defects in

gene activation or changes in the protein structure

of the VDR, both of which could affect the cellular

functions of 1, 25-dihydroxyvitamin D3.

The VDR gene, which is located on

chromosome 12q12-14, is an intracellular hormone

receptor that specifically binds the active form of

vitamin D and interacts with target-cell nuclei to

produce a variety of biologic effects [10]. It

comprises 11 exons and spans approximately 75 kb.

Several polymorphisms in VDR gene have been

mostly investigated including TaqI (rs731236),

ApaI (rs7975232), BsmI (rs1544410) and FokI

(rs10735810). BsmI and ApaI are located in intron

8 of the VDR gene and TaqI is located in exon 9.

These three polymorphisms are at 3 end while

FokI is located in exon 2 of 5 end of VDR gene.

A series of studies on the association between

VDR gene polymorphisms and susceptibility of

PTB have been conducted, but the results are

somewhat contradictory and inconclusive. To

overcome the limitations of individual study and to

understand the real situation, now a meta-analysis

of all published case-control studies was performed

to get a more accurate estimate of effect size.

2. Materials and methods 2.1. Search strategy and selection criteria

A comprehensive search strategy was

performed towards the electronic databases

including MEDLINE (1966–2008), PubMed

(1950-November, 2009), EMBASE (1950-

November, 2009) and Chinese Biomedical

Literature database (CBM) using terms

“tuberculosis”, “TB”, “vitamin D”, “vitamin D

receptor”, “polymorphism”; “ApaI”; “BsmI”;

“FokI” and “TaqI”. Reference lists of the identified

articles were also examined and the literature

retrieval was performed in duplication by two

independent reviewers.

We reviewed titles and abstracts of all

citations and retrieved literatures. The studies

which met the following criteria were chosen: (1)

the publication was a population-based case-control

study (family-based study design with linkage

considerations was excluded) referring to the

association between VDR and PTB; (2) the articles

Su Qian et al. / Journal of Medical Colleges of PLA 26 (2011) 63–75 65

should clearly describe PTB diagnoses and the

sources of cases and controls; (3) the papers must

offer the size of the samples, odds ratios (ORs) and

their 95% confidence intervals (CI) or the

information that can help us infer the results; (4)

when multiple publications reported on the same or

overlapping data, we used the most recent or

largest population as recommended by Little et al

[11]; (5) cases with acquired immunodeficiency

syndrome or extra-PTB were excluded; (6)

genotype distribution of the control subjects must

confront to Hardy-weinberg equilibrium.

Accordingly, articles that could not offer the

source of cases and controls or other essential

information were excluded; reviews and repeated

literatures were also excluded.

2.2. Data extraction

Data was extracted from each study by two

reviewers (Su Qian and Ma Xiangyu) in-

dependently according to the pre-specified

selection criteria. Decisions were compared and

disagreements about study selection were resolved

by consensus or by involving a third reviewer. The

following information was extracted from the study:

first author, publishing year, studied poly-

morphisms, ethnicity of subjects, mean age,

male-female ratio, source of controls, distribution

of genotypes in case and control groups. In VDR

gene, the presence of a given restriction site was

assigned by lower case (i.e., f for FokI) and

absence by upper case (i.e., F); individuals were

scored as FokI-FF wild homozygote, FokI-ff

mutant homozygote, and FokI-Ff heterozygote,

respectively.

2.3. Statistical analysis

Summary ORs with their 95% CIs for alleles

and genotypes were used to assess the strength of

association between the VDR gene polymorphisms

and PTB. The pooled ORs were performed for

additive genetic model, dominant genetic model

and recessive genetic model, respectively.

Heterogeneity assumption was assessed by

Cochrane Q-test [12]. With lacking of

heterogeneity among studies, the pooled OR

estimate of the each study was calculated by the

fixed effect model (Mantel–Haenszel) [13].

Otherwise, the random effect model (DerSimonian

and Laird) was used [14]. In order to evaluate the

ethnicity-specific effect, subgroup analyses were

performed by ethnic group.

Publication bias was assessed by the funnel

plot, in which the standard error of log (OR) of

each study was plotted against its OR value. An

asymmetric plot suggested possible publication

bias by the method of the Egger’s linear regression

test. Fail-safe number for P=0.05 (Nfs0.05) was

also used to assess the publication bias.

A Montecarlo permutation procedure was used

to determine deviation from Hardy-Weinberg

equilibrium among control populations using the

Hardy-Weinberg Simulator programme (http://

krunch.med.yale.edu/hwsim). All of the statistical

analysis was performed by Statistical Package for

Social Science (Version 13.0) and Review Manager

(Version 4.2, The Cochrane Collaboration). And all

the tests were two-sided, a P value of 0.05 for any

test or model was considered to be statistically

significant.


3. Results 3.1. Eligible studies

As revealed in Fig. 1, a total of 303 studies

were relevant to the search terms. After a

preliminary screening of titles and abstracts, 63

potentially relevant studies were identified. Then

the full texts were examined carefully according to

the inclusion criteria and the exclusion criteria. Of

these, 27 articles were reviews; 4 articles were

cohort studies; 15 articles were rejected by the

inclusion criteria, thus, a total of 17 case-control

studies, which were relevant to the association

between gene polymorphisms of VDR and

tuberculosis susceptibility, were selected finally (as

showed in Table 1).

Hardy Weinberg equilibrium test among

control populations induced that one study [27] for

FokI, one for ApaI [16], one for BsmI [27] and two

for TaqI [7, 26] were not suitable. Among the

eligible studies (Table 2), there were a total of 13

studies with 2 262 cases and 2 833 controls

concerning about the FokI polymorphism, 15

studies with 3 031 cases and 3 132 controls

concerning about the TaqI polymorphism, 7 studies

with 1 495 cases and 1 922 controls concerning

about the ApaI polymorphism, and 6 studies with

919 cases and 1 250 controls concerning about the

BsmI polymorphism.

3.2. Test of heterogeneity

Table 3 shows summary of ORs with

confidence intervals (CI) for allele and genotype

comparisons. The heterogeneity was demonstrated

by P value of Cochrane Q statistics test. The results

showed no heterogeneity including allele f vs F,

dominant genetic model (FF vs Ff+ff), additive

genetic model (ff vs FF) and recessive genetic

model (ff vs Ff+FF) for FokI. The situation of ApaI

is consistent with FokI, thus fixed effect model was

selected for meta-analysis. However, heterogeneity

was found in all comparisons for TaqI and BsmI,

therefore random effect model was elected.

3.3. Quantitative data synthesis

For FokI polymorphism, Fig. 2B showed the

allele comparison (f vs F), in which the overall OR

was 1.12 (95%CI=[1.02, 1.23]) and the Z value was

2.44 (P<0.05), thus it can be concluded that allele f

might have an association with susceptibility of

PTB; Fig. 2C showed the additive effect model (ff

vs FF) of F/f towards PTB, in which the overall OR

was 1.40 (95%CI=[1.10, 1.77]) and the Z value was

2.77 (P<0.05), we could also conclude that

genotype ff have an association with susceptibility

of PTB; Fig. 2A showed the recessive genetic

model (ff vs Ff+FF) of FokI polymorphism, in

which the carriers of mutant homozygote (ff) had a

1.39-fold elevated risk of PTB (95%CI=[1.12,

1.71], P<0.05) compared with the “FF+Ff”

genotype in a fixed effect model; however, as

showed in Table 3, the association was not

significant in the dominant genetic model (FF vs

Ff+ff) (OR=1.09, 95%CI=[0.97, 1.22], P=0.17).


n=303Relevant articles identified ( )

Table 1 Association between genetic polymorphism of VDR and PTB risk included in the meta-analysis

Mean age; male/female Studied polymorphisms

References PopulationCases controls

Control source

TaqI, FokI Roth et al, 2004 [15]

Peru 25.4±6.9; 62/41

25.5±7.3; 124/82

Age and gender matched for each case; randomly selected; no symptoms; TST+ and TST-; HIV(-)

TaqI, FokI, BsmI Lombard et al, 2006 [16]

South Africa

NA NA From Limpopo Province; unrelated individuals of patients and nurses without history of TB of participating hospitals

TaqI, FokI, ApaI, BsmI

Olesen et al, 2007 [17]

Guinea Bissau

37.246; 194/127

38.116; 173/174

Age, height and ethnics matched; from Guinea Bissau; no symptoms

TaqI, FokI, ApaI Søborg et al, 2007 [18]

Tanzania 35; 265/178 34; 209/217 Randomly selected from a community of Mwanza district; culture negative for M. tuberculosis; HIV(-)

TaqI, FokI Wilkinson et al, 2000 [19]

Gujaratis in London

45.5; 43/83 42.7; 62/53 TB contacts from contact clinic; no symptoms; TST+; normal chest radiograph

(Table 1 continued in next page)

Excluded by screening of titles and abstracts (n=240)

Review (n=27); exclusion criteria (n=15); not case control studies (n=4)

Case control studies on VDR and PTB (n=17)

Included studies in meta-analysis for Fok (n=13) Included studies in meta-analysis for Taq (n=15) Included studies in meta-analysis for Apa (n=7); Included studies in meta-analysis for Bsm (n=6);

Potentiall n=63y relevant studies ( )

Test of Hardy-Weinberg equilibrium ( =0.05)

Fig. 1. Flow chart of included and excluded studies. VDR: Vitamin D receptor; PTB: pulmonary tuberculosis.


(Continued Table 1)

Studied polymorphisms

References PopulationMean age; male/female

Control source

TaqI, FokI,

ApaI, BsmI

Selvaraj et al, 2004 [20]

South Indian

35.4± 1.7; 36/10

29.1±1.3; 32/32

Staffs and students of Tuberculosis Research Centre; no symptoms; HIV(-); ethnics matched

TaqI, FokI, ApaI Babb et al, 2007 [21]

South Africa

NA NA From clinics, households and places of work; no symptoms of TB; socio-economic status, ethnic matched; HIV(-)

TaqI, FokI, BsmI Banoei et al, 2009 [22]

Iran 45.8±11; 30/30

41±9; 36/26 Randomly selected from blood donor centers; HIV(-); no history of TB

TaqI, FokI, ApaI, BsmI

Bornman et al, 2004 [23]

West African

34.7 ±12.60; 280/137

32.6 ±10.97; 380/342

Healthy community subjects; age, ethnic; no history of TB

TaqI, FokI Chen et al, 2006 [24]

China 28.8±10.1; 60/80

30.1±8.9; 62/77

Randomly selected from same districts; no TB symptoms, TST+; age and gender matched; HIV(-)

TaqI, FokI Liu et al, 2008 [25]

China 40±6; 40/20 37±6; 20/10 Unrelated healthy examination persons from the same hospitals; no history of TB; gender, age matched, TST+

FokI, ApaI, BsmI Selvaraj et al, 2009 [7]

South Indian

36.0±8.06; 52/13

29.9±7.74; 40/20

Staffs and trainees of Tuberculosis Research Centre; no symptoms; HIV(-)

FokI Liu et al, 2004 [26]

China 27.65±12.72; 120/0

27.26±9.21; 240/0

Unrelated male servicemen from Beijing; free from PTB by X-ray examination; HIV(-) and diabetes(-)

TaqI, ApaI Vidyarani et al, 2009 [27]

South Indian

35.5±10.6; 25/15

30±8; 34/15 No symptom; volunteers from Chennai, India; HIV(-)

TaqI Delgado et al, 2002 [28]

Cambodia 42.2±12.1; 134/224

37.5±12.9; 46/60

Unrelated patients from the same hospitals; TST+, HIV(-); no TB symptoms; monitored 7 years

TaqI Bellamy et al, 1999 [29]

Gambia 34.7±13.2; 275/133

30.3±7.5; 414/0

Males only; age, ethnic matched; HIV(-); no TB symptoms

TaqI Selvaraj et al, 2000 [30]

South Indian

39.4±2.1; 155/47

37.7±2.2; 48/61

Age and ethnic matched; no TB symptoms; not consanguineous

NA: not applicable; TST: tuberculin skin test; HIV: human immunodeficiency virus; TB: tuberculosis.


Table 2 Distribution of VDR allele frequency of individual studies (cases vs controls)

TaqI FokI ApaI BsmI References

T t F f A a B b

Roth et al, 2004 [15]

196 379 10 33 51 108 155 304- - - - - - - -

Lombard et al, 2006 [16]]

129 128 39 36 107 150 25 22 - - - -

41 38 129 138

Delgado et al, 2002 [28]

680 202 36 10 - - - - - - - - - - - -

Olesen et al, 2007 [17]

445 472 195 218 502 532 138 156 300 368 332 306 207 228 433 456

Søborg et al, 2007 [18]

666 628 210 222 704 662 166 170 634 592 242 260 - - - -

Wilkinson et al, 2000 [19]

248 148 116 84 270 187 94 45 - - - - - - - -

Vidyarani et al, 2009 [27]

48 72 32 26 - - - -

50 53 30 45 - - - -


49 81 43 47 71 99 21 29 51 78 37 50 56 63 36 65

Bellamy et al, 1999 [29]

585 553 231 275 - - - - - - - - - - - -

Babb et al, 2007 [21]

366 520 132 184 368 535 130 169 310 405 188 299 - - - -

Banoei et al, 2009 [22]

49 90 71 34 81 85 39 39 - - - -

53 88 67 36

Bornman et al, 2004 [23]

480 915 206 353 654 1130 178 306 457 824 229 444 148 286 538 982

Chen et al, 2006 [24]

277 273 3 5 176 200 104 78 - - - - - - - -

Liu et al, 2008 [25]

113 54 7 6 57 39 63 21 - - - - - - - -


248 144 152 72 - - - - - - - - - - - -


- - - - 95 92 35 28 79 71 51 49 76 55 54 65

Liu et al, 2004 [26]

- - - - 121 290 119 190

- - - - - - - -


For TaqI polymorphisms, associations of the allele (t vs T) and genotypes with PTB were estimated using dominant (TT vs Tt+tt), additive (tt vs TT), and recessive (tt vs Tt+TT) genetic models in random effect model according to the heterogeneity Q test in Table 3. No association was found between TaqI polymorphisms and susceptibility of PTB. Subgroup analysis also showed no significant association (data not shown).

For ApaI polymorphisms, only 7 studies have investigated its association with PTB to date. No association was found among four types of

comparisons. For BsmI polymorphisms, we did not find any

significant association with PTB in overall and subgroup analysis.

Sensitive analysis was conducted by altering corresponding variables and analysis models. No influence towards FokI, ApaI and TaqI was found. Notably, significant association between BsmI polymorphism and PTB would be found when analysis model changed from random effect to fixed effect in overall and subgroup analysis.

Table 3 Summary of odds ratios (ORs) with confidence intervals (CI) for allele and genotype comparisons

Fixed effects model Random effects model Comparisons

OR (95%CI) P value OR (95%CI) P value

P value

(heterogeneity)

FokI

f vs F 1.12 (1.02, 1.23) 0.01 - - 0.11

ff vs FF 1.40 (1.10, 1.77 ) 0.006 - - 0.09

ff vs (Ff+FF) 1.39 (1.12, 1.71) 0.002 - - 0.15

(ff+Ff) vs FF 1.09 (0.97, 1.22) 0.17 - - 0.47

TaqI

t vs T - - 1.07 (0.90, 1.27) 0.44 <0.01

tt vs TT - - 1.27 (0.82, 1.95) 0.28 <0.01

tt vs (Tt+TT) - - 1.09 (0.77, 1.55) 0.61 <0.01

(tt+Tt) vs TT - - 1.05 (0.87, 1.28) 0.59 <0.01

BsmI

b vs B - - 1.02 (0.73, 1.43) 0.91 <0.01

bb vs BB - - 1.10 (0.05, 2.20) 0.79 <0.01

bb vs (Bb+BB) - - 0.97 (0.64, 1.46) 0.89 <0.01

(bb+Bb) vs BB - - 1.47 (0.74, 2,93) 0.27 <0.01

ApaI

a vs A 0.97 (0.87, 1.07) 0.49 - - 0.05

aa vs AA 0.90 (0.63, 1.29) 0.56 - - 0.05

aa vs (Aa+AA) 0.94 (0.77, 1.15) 0.55 - - 0.24

(aa+Aa) vs AA 0.96 (0.83, 1.10) 0.54 - - 0.05


Fig. 2. Results of the published studies of the association between FokI polymorphism and PTB. A: represents comparison of the genotype ff against the genotype Ff+FF (recessive genetic model); B: represents comparison of the allele f against the allele F; C: represents comparison of the genotype ff against the allele FF (additive effect model).


3.4. Bias diagnosis

Publication biases were assessed by funnel

plots firstly. For FokI gene polymorphism, the

funnel plot appeared to be approximately

symmetrical (Fig. 3). Furthermore, fail-safe

number was found to be 56 (Nfs0.05) for FokI allele

F/f associated with PTB, which suggested that

biases from publications and other factors may not

have a significant influence on the results of

current meta-analysis for the association between

FokI polymorphism of VDR gene and PTB.

4. Discussion

The historical impression that tuberculosis

was an inherited disorder has come full circle and

substantial evidence now exists of the human

genetic contribution to susceptibility to tubercu-

losis. Many candidate genes have been reported to

be involved in PTB susceptibility, including VDR,

SLC11A1 (formerly NRAMP1), mannose-binding

lectin (MBL), some cytokine genes (such as TNF- ,

TGF- , IFN- , IL-1b, IL-1RA, IL-12, IL-10 and so

on), Toll-like receptors and nitric oxide synthases

[31]. VDR is the primary candidate gene among

these candidate genes. Extensive data indicate that

there are two mechanisms of action. One involves

the activation of nuclear VDR and transcriptional

regulation of many vitamin D-responsive genes.

The other involves activation of non-genomic

signal transduction pathways in target cells [32].

The vitamin D endocrine system is involved in a

wide variety of biological processes including

modulation of the immune response, bone

metabolism, and regulation of cell proliferation and

differentiation [33]. The role of Vitamin D and

VDR in innate immunity, especially for the

development of tuberculosis, is a subject of intense

debate [19, 34]. Though series of case-control

studies were performed to assess the importance of

VDR polymorphisms in PTB, there have been no

consistent associations of VDR gene poly-

morphisms with PTB susceptibility.

A previous meta-analysis about the association

between FokI and TaqI polymorphisms of VDR

gene and PTB susceptibility was performed by

Lewis et al [35] with the data up to August 2004,

and the result was confirmed to be inconclusive and

studies to be underpowered. During this study, only

6 studies are included for FokI polymorphism and 8

studies for TaqI polymorphism, also the data has

been age-old. As time goes by, new findings

continue to emerge and the data are also

continually updated. In this situation, in order to

better evaluate research findings, we carried out a

more comprehensive systematic review and

meta-analysis about FokI, TaqI, ApaI and BsmI

polymorphisms of VDR gene. A large number of

research data from August 2004 onwards has been

Fig. 3. Funnel plot of FokI polymorphism for

publication bias.


taken into account areas to provide support for the

results of more objective.

Basing on the 13 case-control studies focused

on FokI polymorphism of VDR gene and PTB, our

meta-analysis provided evidence that variant FokI

polymorphism of VDR gene was significantly

associated with susceptibility of PTB. In addition,

the recessive genetic model (ff vs Ff+FF) of FokI

polymorphism confirmed that carriers of mutant

homozygote (ff) was significantly associated with a

1.39-fold elevated risk of PTB compared with

subjects carrying Ff+FF genotypes. However, for

the rest three polymorphisms, we did not find any

significant association with PTB in overall and

subgroup analysis. During the meta-analysis, we

did not perform subgroup analysis for FokI

polymorphism, because the data showed an absence

of heterogeneity among the include studies. For

TaqI and BsmI polymorphisms, subgroup analysis

was done for the reason of heterogeneity.

To some extent, some limitations have

affected the objectivity of the conclusions and

should be considered when interpreting the results.

Firstly, the sample sizes of several included studies

are rather small and underpowered [7, 20, 25].

Secondly, the baseline information of several

studies [16, 21] is so meager that we can not

recognize the comparability between the cases and

the controls. Thirdly, the controls of several studies

were hospital-based normal individuals or patients

of other diseases, even the staffs and trainees of the

institute [7]. Furthermore, the VDR gene contains

many more SNPs than the four mentioned in this

article. Given the limited evidence available on

other VDR gene polymorphisms, this review was

restricted to the four most investigated

polymorphisms described above.

5. Conclusion

We found variant FokI polymorphism of VDR

gene may play a risky role in PTB development,

and the genetic model was presumed to be

recessive. No significant associations were

observed between TaqI, ApaI, BsmI variants and

PTB susceptibility. Large well-designed

epidemiological studies will be necessary to

validate the risk identified in the current

meta-analysis.

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(Editor Guo Jianxiu)

Association between gene polymorphisms of vitamin D receptor and pulmonary tuberculosis...

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