Role of genetic variants of Vitamin D receptor, Toll-like receptor 2 and Toll-like receptor 4 in extrapulmonary tuberculosis

Bilal Ahmad Wani; Faheem Shehjar; Sonaullah Shah; Ajaz Koul; Adfar Yusuf; Muzamil Farooq; Mohmad Iqbal Mir; Rajni Singh; Dil Afroze

doi:10.1016/j.micpath.2021.104911

Role of genetic variants of Vitamin D receptor, Toll-like receptor 2 and Toll-like receptor 4 in extrapulmonary tuberculosis

Microb Pathog. 2021 Jul:156:104911. doi: 10.1016/j.micpath.2021.104911. Epub 2021 May 13.

Authors

Bilal Ahmad Wani¹, Faheem Shehjar², Sonaullah Shah³, Ajaz Koul³, Adfar Yusuf⁴, Muzamil Farooq⁴, Mohmad Iqbal Mir⁴, Rajni Singh⁵, Dil Afroze⁶

Affiliations

¹ Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India; Amity Institute of Microbial Technology, Amity University, Noida, Uttar Pradesh, India.
² Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India.
³ Department of Internal & Pulmonary Medicine, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India.
⁴ Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India.
⁵ Amity Institute of Microbial Technology, Amity University, Noida, Uttar Pradesh, India. Electronic address: rsingh3@amity.edu.
⁶ Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, J&K, India. Electronic address: afrozedil@gmail.com.

PMID: 33991642
DOI: 10.1016/j.micpath.2021.104911

Abstract

Background: Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB). Vitamin D deficiency and vitamin D receptor (VDR) gene abnormalities confer susceptibility to tuberculosis. Toll-like receptors (TLRs), such as TLR-2, are also important mediators of inflammatory response against Mycobacterium tuberculosis. We evaluated VDR, TLR-2 and TLR-4 gene polymorphisms in patients with extrapulmonary tuberculosis (EPTB).

Objectives: To find out a possible association of Vitamin D receptor (VDR) (rs731236), TLR-2 (196-174 Ins > Del) and TLR-4 (Thr399Ile) gene polymorphisms with extrapulmonary tuberculosis in ethnic Kashmiri population.

Methods: A total of 100 extrapulmunary tuberculosis cases and 102 healthy controls were analyzed for Vitamin D receptor (VDR) (rs731236), TLR-2 (196-174 ins > del) and TLR-4 (Thr399Ile) gene polymorphisms using PCR-RFLP and Allele-Specific PCR methods.

Results: We found increased frequency of TLR-4 Thr/Ile heterozygous genotype in cases as compared with healthy controls (22% vs 5.8%). Thus acting as a risk factor for extrapulmonary tuberculosis, as was elucidated from statistical analysis [OR, 4.5; 95% CI (1.74-11.68); P < 0.001]. In case of TLR-2 (196-174 ins > del) we observed significant differences in the homozygous variant (Del/Del) genotype of cases and controls (28% in cases & 2.94% in controls). Thus, TLR-2 (Del/Del) genotype acts as a strong risk factor for extrapulmonary tuberculosis predisposition [OR, 12.2; 95% CI (3.5-42.69); P < 0.001]. We did not find any significant differences in the genotypic distribution of (VDR) (rs731236) T > C SNP between cases and controls (P > 0.05).

Conclusion: TLR-4 (Thr/Ile) and TLR-2 (Del/Del) act as significant risk factors for extrapulmonary tuberculosis predisposition in ethnic Kashmiri population.

Keywords: Extrapulmonary tuberculosis; Mycobacterium tuberculosis (MTB); Single nucleotide polymorphism; Toll-like receptors (TLRs); Vitamin D receptor (VDR).

MeSH terms

Case-Control Studies
Gene Frequency
Genetic Predisposition to Disease
Genotype
Humans
Mycobacterium tuberculosis*
Polymorphism, Single Nucleotide
Receptors, Calcitriol / genetics
Toll-Like Receptor 2 / genetics
Toll-Like Receptor 4 / genetics
Tuberculosis* / genetics

Substances

Receptors, Calcitriol
TLR2 protein, human
TLR4 protein, human
Toll-Like Receptor 2
Toll-Like Receptor 4
VDR protein, human