CC BY-NC-ND 4.0 · Journal of Coloproctology 2021; 41(02): 182-187
DOI: 10.1055/s-0041-1726052
Original Article

Polymorphisms of the Vitamin D Receptor Gene in Crohn’s Disease

Polimorfismos do gene do receptor de vitamina D na doença de Crohn
1  School of Medical, Pharmaceutical and Biomedical Sciences, Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brazil
,
1  School of Medical, Pharmaceutical and Biomedical Sciences, Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brazil
,
2  Faculty of Biomedicine, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, GO, Brazil
,
1  School of Medical, Pharmaceutical and Biomedical Sciences, Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brazil
,
3  Nursing School, Universidade Federal de Goiás, Goiânia, GO, Brazil
,
1  School of Medical, Pharmaceutical and Biomedical Sciences, Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brazil
4  Graduate Program in Environmental Sciences and Health, Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brazil
› Institutsangaben
 

Abstract

Introduction Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions of the gastrointestinal tract. Studies have shown that polymorphisms of the vitamin D receptor (VDR) gene may help elucidate the pathogenesis of CD.

Objectives To analyze the role of VDR gene polymorphisms (ApaI, BsmI, FokI, and TaqI) in the development of CD.

Methods The present study is a systematic review with meta-analysis. a total of 50 articles in English and Portuguese published from 2000 to 2020 were selected from 3 databases. The relationship between CD and the VDR gene was addressed in 16 articles.

Results The TaqI polymorphism was analyzed in 3,689 patients and 4,645 control subjects (odds ratio [OR] = 0.948; 95% confidence interval [95%CI] = 0.851–1.056; p = 0.3467). The ApaI polymorphism was studied in 3,406 patients and 4,415 control subjects (OR = 1,033; 95%CI = 0.854–1.250; p = 0.7356). For FokI polymorphism, there were 2,998 patients and 4,146 control subjects (OR = 0.965; 95%CI = 0.734–1.267; p = 0.7958). Lastly, the BsmI polymorphism was analyzed in 2,981 patients and 4,477 control subjects (OR = 1,272; 95%CI = 0.748–2.161; p = 0.3743).

Conclusion These four VDR gene polymorphisms were not associated with CD. Therefore, further studies with larger samples are required to corroborate or rectify the conclusions from the present meta-analysis.


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Resumo

Introdução A doença de Crohn (DC) e a retocolite ulcerativa (RU) são condições inflamatórias crônicas do trato gastrointestinal. Estudos indicam que os polimorfismos do gene do receptor de vitamina D (RVD) são promissores para a patogênese da DC.

Objetivos Avaliar papel dos os polimorfismos do gene do RVD (ApaI, BsmI, FokI e TaqI) no desenvolvimento da DC.

Métodos Trata-se de uma revisão sistemática com metanálise. Foram identificados 50 artigos em inglês e português publicados entre 2000 a 2020 em 3 bases de dados. Destes, foram selecionados 16 artigos que contemplavam a relação entre a DC e o gene do RVD.

Resultados Para o polimorfismo TaqI, a amostra foi composta por 3.689 pacientes e 4.645 controles (razão de probabilidade [RP] = 0,948; intervalo de confiança de 95% [IC95%] = 0,851–1,056; p = 0,3467). Para o polimorfismo ApaI, 3.406 pacientes e 4.415 controles (RP = 1,033; IC95% = 0,854–1,250; p = 0,7356). Para o polimorfismo FokI, 2.998 pacientes e 4.146 controles (RP = 0,965; IC95% = 0,734–1,267; p = 0,7958). E, para o polimorfismo BsmI, 2.981 pacientes e 4.477 controles (RP = 1,272; IC95% = 0,748–2,161; p = 0,3743).

Conclusão Esses quatro polimorfismos do gene do RVD não apresentaram associação com a DC. Logo, sugere-se a realização de mais estudos com amostras maiores a fim de corroborar ou retificar a conclusão desta metanálise.


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Introduction

Inflammatory bowel diseases (IBDs) are chronic, recurrent inflammatory conditions of the gastrointestinal tract that affect genetically susceptible patients.[1] There are two IBD subtypes: Crohn’s disease (CD) and ulcerative colitis (UC),[2] with overlapping albeit distinct clinical and pathological features.[3] The etiology of CD remains unknown; this condition affects the entire gastrointestinal tract, from the mouth to the anus. It may be unifocal or multifocal, with varying intensity, and it is not curable by clinical or surgical treatments. In addition to its transmural nature, CD can result in complications such as fistulas in other organs or the abdominal cavity. The most frequently-involved sites are the small and large intestines, and perianal manifestations can affect more than 50% of the patients.[4] Crohn’s disease may cause manifestations outside the gastrointestinal tract, affecting the skin, joints, eyes, liver, and the genitourinary tract. Although CD can affect subjects from any age group, most diagnoses occur at the second and third decades of life.

Vitamin D is a hormone that regulates serum calcium, and it is responsible for the balance of calcium between mineralized bone and the blood. It also has immunoregulatory effects and antiproliferative properties, mainly mediated by T cells, suppressing lymphocyte proliferation and immunoglobulin production. Vitamin D inhibits pro-inflammatory factors, including nuclear factor kappa B (NF-kB), and the production of cytokines such as interleukin (IL)-2, IL-12, and interferon.[5] At the intestine, vitamin D has additional functions such as promoting junctional integrity, increasing the absorption of epithelial folate, and activating intestinal cytochrome P450 3a4.[1]

Several lines of evidence support that vitamin D plays a role in the development of IBDs[6] because its effects are mediated by steroid receptors regulating the transcription of multiple cellular genes.[5] The vitamin D receptor (VDR) gene is expressed by macrophages, monocytes, B and T cells, and dendritic cells. Vitamin D binding to VDR triggers a cascade of intracellular molecular signaling that regulates the transcription of multiple genes.[7] The VDR gene has several polymorphic sites, and 4 polymorphisms recognized by restriction enzymes are reported: ApaI, BsmI and TaqI, which are found at the 3' end of the VDR gene, exon 8, and FokI, which is found at the 5' end of the VDR gene, exon 2.5

Thus, IBDs are more prevalent among populations living in geographic areas with reduced vitamin D synthesis by the skin due to lower exposure to sunlight. In addition, vitamin D deficiency often occurs in IBD patients though the disease may be in remission.[1] Previous studies have revealed an association between the VDR gene polymorphisms and prostate cancer, infectious diseases, type-1 diabetes mellitus, bone mineral disorders in postmenopausal women, skin melanoma, renal cell carcinoma, autoimmune hepatitis, Graves' disease, celiac disease, and CD.[5]


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Methods

The present is a cross-sectional, analytical, descriptive study. Three databases, namely the Virtual Health Library, PubMed and Microsoft Academic, were queried to identify studies published in journals specialized on the proposed theme, using the following descriptors: genetic polymorphism; vitamin D; and Crohn’s disease. The search resulted in 50 articles. The inclusion criteria were articles published in English or Portuguese between 2000 and 2020. Articles regarding VDR polymorphisms in diseases other than CD that did not fit the proposed time frame were excluded, along with those discussing polymorphisms in other receptors and with a different approach. Thus, 16 articles on CD and VDR receptors were retrieved.

The heterogeneity of studies grouped in a meta-analysis is defined by their diversity, which can strongly influence results. Such diversity can be assessed by the Chi-squared test for heterogeneity. The frequencies of polymorphisms from all articles were grouped in a single table. Diversity was assessed using the Chi-squared test in 2 × 2 contingency tables to compare the different odds ratios (ORs) and 95% confidence intervals (95%CIs) of each study.

A Chi-squared test for heterogeneity revealing a p-value > 0.05 confirms the null hypothesis, indicating that the studies are homogeneous. In this case, fixed-effect tests, which assume that all studies point in the same direction, are recommended, such as the Mantel-Haenszel test, which is the most used test in this category. On the other hand, a Chi-squared test resulting in p < 0.05 indicates heterogeneity among studies; therefore, a random-effects test, such as the DerSimonian-Laird test, is recommended.

Next, global association tests were used to assess the significance of the correlation between polymorphisms and CD; to do so, values from each study were combined and submitted to both fixed- and random-effects tests using the BioEstat (Manuel Ayres, Belém, Pará, Brazil) software, version 5.3.


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Results and Discussion

The present meta-analysis evaluated the following VDR gene polymorphisms: TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570), and BsmI (rs1544410). In total, 13 scientific articles on these polymorphisms were included, with 9,301 subjects; 4,161 (44.7%) had CD (case group) and 5,140 (55.3%) were healthy subjects (control group).

The TaqI polymorphism (rs731236) was analyzed in 11 articles, with a total sample of 8,334 subjects (3,689 patients and 4,645 controls); this polymorphism was not statistically signficant for CD (OR = 0.948; 95%CI = 0.851–1.056; p = 0.3467) ([Figure 1]; [Table 1]).

Zoom Image
Fig. 1 Forest plot for the TaqI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.

The ApaI polymorphism (rs7975232) was analyzed in 8 articles, with 7,821 subjects (3,406 patients and 4,415 controls); this polymorphism was not associated with CD (OR = 1.033; 95%CI = 0.854–1.250; p = 0.7356) ([Figure 2]; [Table 2]).

Zoom Image
Fig. 2 Forest plot for the ApaI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.

In total, 6 articles analyzed the FokI polymorphism (rs2228570), with 7,144 subjects (2,998 patients and 4,146 controls); this polymorphism was not positively associated with the susceptibility to develop CD (OR = 0.965; 95%CI = 0.734–1.267; p = 0.7958) ([Figure 3]; [Table 3]).

Zoom Image
Fig. 3 Forest plot for the FokI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.

Lastly, 6 articles analyzed the BsmI polymorphism (rs1544410), with 7,458 subjects (2,981 patients and 4,477 controls); this polymorphism was not associated with CD (OR = 1.272; 95%CI = 0.748–2.161; p = 0.3743) ([Figure 4]; [Table 4]).

Zoom Image
Fig. 4 Forest plot for the BsmI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.

The present study aimed to determine the relationship between the FokI, BsmI, ApaI, and TaqI VDR gene polymorphisms and the increased risk of developing CD in both a homogeneous and heterogeneous manner in populations from different countries. However, we found no significant associations regarding the heterozygous or homozygous alleles of the VDR gene and the risk of developing CD.[16]

Consistent with our study, Hughes et al.[4] in 2011, in a cohort of 1,359 Irish subjects, observed no significant association for any variant when analyzing data from 413 patients with CD separately.[16] Moreover, in a meta-analysis regarding VDR polymorphisms associated CD development, Xue et al.[7] found no significant association between the TaqI, FokI and BsmI polymorphisms and the general risk of developing CD.

Bentley et al.[17] investigating the association of 3 single nucleotide polymorphisms (SNPs) of the VDR gene in a cohort of 897 Caucasian patients with IBD, found 449 subjects with CD. Therefore, they concluded that these three SNPs were not associated with CD or its subphenotypes. However, among studies regarding the relationship with CD in cases and controls with reduced receptors with FokI polymorphism in Iranian homozygotes, Naderi et al.[10] reported that 80 CD patients were more likely to present polymorphic FokI allele compared to controls (n = 150) (p < 0.001, OR = 2.68, 95% CI = 1.79–4.01).

Similarly, in a meta-analysis including 27 case-control studies, Cho et al.[16] showed that the FokI polymorphism at the f allele was positively associated with the risk of developing IBDs, including CD. In a genetic analysis of 240 subjects with CD, Limketkai et al.[18] found an association between the TaqI polymorphism and CD. Xue et al.[7] also reported that, in a subgroup analysis by ethnicity, the TaqI polymorphism was associated with CD among Europeans (OR = 1.23; 95%CI = 1.02–1.49); in the gender stratification, men were considered genotype carriers, with a moderately high risk of developing CD (OR = 1.84; 95%CI = 1.19–2.83) compared to the TT genotype.[7]

A limitation of the present study is the low statistical power to detect small effects of the VDR polymorphisms on the risk of developing CD.[15] [16] However, Naderi et al.[10] in a study conducted in Iran, reported that their 80 CD patients were more likely to present the polymorphic FokI allele compared to controls (n = 150) (p < 0.001; OR = 2.68; 95%CI = 1.79–4.01).


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Conclusion

We could not find an association between the risk of developing CD (or any protection against it) and the 4 VDR gene polymorphisms analyzed: TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570), and BsmI (rs1544410). Further studies using larger samples with the same CD-related polymorphisms are required to corroborate or rectify the conclusion of the present meta-analysis. The assessment of nutritional interactions with SNPs of the VDR gene, 25-hydroxy-vitamin D levels, analyses of ethnic groups with a high incidence of CD, and investigations on the relationships with these polymorphisms are also suggested to elucidate this association.

Table 1

Metanalysis data for the TaqI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls)

N

Authors and year

Cases (n)

TaqI

Controls (n)

TaqI

OR

95%CI

Weight

Negative

Positive

Negative

Positive

Inferior

Superior

1

Chen et al.,[8] 2008

167

147

20

40

36

4

0.817

0.263

2.538

2.99

2

Gisbert-Ferrándiz et al.,[3] 2018

103

44

59

72

31

41

0.986

0.537

1.812

10.38

3

Hughes et al.,[4] 2011

413

148

265

699

250

449

1.003

0.778

1.293

59.68

4

Luo et al.,[5] 2013

122

109

13

19

18

1

0.466

0.057

3.782

0.88

5

Martin et al.,[9] 2002

95

37

58

119

31

88

1.811

1.013

3.238

11.38

6

Naderi et al.,[10] 2008

80

39

41

150

67

83

1.178

0.684

2.030

12.99

7

Noble et al.,[11] 2008

286

173

113

250

156

94

0.923

0.651

1.308

31.57

9

Szymczak-Tomczak et al.,[12] 2019

85

71

14

39

36

3

0.423

0.114

1.566

2.24

10

Wang et al.,[13] 2014

1,796

296

1,500

2,647

502

2,145

0.843

0.720

0.988

153.77

11

Xia et al.,[14] 2016

297

272

25

446

381

65

1.856

1.141

3.020

16.21

Total

3,689

1,420

2,269

4,645

1,572

3,073

0.948

0.851

1.056

p  = 0.3467

Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.


Table 2

Metanalysis data for the ApaI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls)

N

Authors and year

Cases (n)

ApaI

Controls (n)

ApaI

OR

95%CI

Weight

Negative

Positive

Negative

Positive

Inferior

Superior

1

Chen et al.,[8] 2008

167

117

50

40

28

12

1.020

0.486

2.144

6.97

2

Hughes et al.,[4] 2011

413

151

262

699

226

473

1.207

0.935

1.557

59.04

3

Luo et al.,[5] 2013

122

68

54

19

12

7

0.754

0.285

1.995

4.06

4

Naderi et al.,[10] 2008

80

37

43

150

50

100

1.716

0.988

2.980

12.59

5

Noble et al.,[11] 2008

286

156

130

250

133

117

1.056

0.751

1.483

33.27

6

Simmons et al.,[15] 2000

245

128

117

164

88

76

0.945

0.637

1.404

24.59

7

Wang et al.,[13] 2014

1796

700

1096

2647

1179

1468

0.795

0.704

0.898

258.51

8

Xia et al.,[14] 2016

297

153

144

446

223

223

1.110

0.829

1.486

45.06

Total

3,406

1,510

1,896

4,415

1,939

2,476

1.033

0.854

1.250

p  = 0.7356

Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.


Table 3

Metanalysis data for the FokI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls)

N

Authors and year

Cases (n)

FokI

Controls (n)

FokI

OR

95%CI

Weight

Negative

Positive

Negative

Positive

Inferior

Superior

1

Chen et al.,[8] 2008

167

151

16

40

34

6

1.730

0.649

4.610

4.00

2

Hughes et al.,[4] 2011

413

159

254

699

285

414

0.910

0.709

1.167

62.06

3

Naderi et al.,[10] 2008

80

22

58

150

81

69

0.328

0.183

0.587

11.34

4

Simmons et al.,[15] 2000

245

141

104

164

93

71

1.035

0.695

1.542

24.20

5

Wang et al.,[13] 2014

1796

698

1098

2647

971

1676

1.097

0.970

1.241

252.03

6

Xia et al.,[14] 2016

297

78

219

446

93

353

1.352

0.958

1.907

325.45

Total

2,998

1,249

1,749

4,146

1,557

2,589

0.965

0.734

1.267

p  = 0.7958

Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.


Table 4

Metanalysis data for the BsmI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls)

N

Authors and year

Cases (n)

BsmI

Controls (n)

BsmI

OR

95%CI

Weight

Negative

Positive

Negative

Positive

Inferior

Superior

1

Chen et al.,[8] 2008

167

153

14

40

36

4

1.305

0.427

3.990

3.08

2

Dresner-Pollak et al.,[2] 2004

228

83

145

495

190

305

0.920

0.665

1.273

36.53

3

Hughes et al.,[4] 2011

413

140

273

699

260

439

0.867

0.672

1.118

59.21

4

Naderi et al.,[10] 2008

80

16

64

150

38

112

0.748

0.389

1.436

9.01

5

Wang et al.,[13] 2014

1796

1083

713

2647

1031

1616

2.380

2.105

2.690

255.59

6

Xia et al.,[14] 2016

297

275

22

446

380

66

2.140

1.295

3.537

15.21

Total

2,981

1,750

1,231

4,477

1,935

2,542

1.272

0.748

2.161

p  = 0.3743

Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.



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Die Autoren geben an, dass kein Interessenkonflikt besteht.


Address for correspondence

Antonio Márcio Teodoro Cordeiro Silva, D.Sc.
Escola de Ciências Médicas, Farmacêuticas e Biomédicas, Pontifícia Universidade Católica de Goiás, Avenida Universitária
1.440, Setor Universitário, Campus 1, Área 4, Goiânia, Goiás, 74605-010
Brazil   

Publikationsverlauf

Eingereicht: 10. August 2020

Angenommen: 07. September 2020

Publikationsdatum:
24. Mai 2021 (online)

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Zoom Image
Fig. 1 Forest plot for the TaqI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.
Zoom Image
Fig. 2 Forest plot for the ApaI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.
Zoom Image
Fig. 3 Forest plot for the FokI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.
Zoom Image
Fig. 4 Forest plot for the BsmI polymorphism among patients with Crohn’s disease (cases) and healthy subjects (controls). Abbreviations: 95%CI, 95% confidence interval; OR, odds ratio.