Dataset Information

Association of human leukocyte antigens-DQB2/DPA1/DPB1 polymorphism and pulmonary tuberculosis in the Chinese Uygur population.

ABSTRACT:

Background

Tuberculosis (TB) is the second-leading cause of death globally. Genetic polymorphisms in human leukocyte antigens (HLA)-DQB2, HLA-DPA1, and HLA-DPB1 may partly explain individual differences in TB susceptibility.

Methods

We performed a hospital-based case-control study to assess the genetic influence of single-nucleotide polymorphisms (SNPs) in the HLA (HLA-DPA, HLA-DPB, and HLA-DQB) on the development of TB. There were 248 TB-infected cases and 340 healthy controls in this study.

Results

The HLA-DQB2 rs7453920 genotype GG was applied as the reference group, the GA genotype was related to a considerably magnified risk of TB (GA vs. GG: adjusted OR = 1.547, 95% CI = 1.039-2.304, p = 0.032). Nevertheless, the other two SNPs were not associated with TB risk. Stratified analyses suggested that tobacco was associated with an increased risk of TB in HLA-DQB2 rs7453920 G>A.

Conclusion

These results suggested that the functional HLA-DQB2 rs7453920 G>A polymorphism may contribute to the genetic susceptibility to TB. Nevertheless, the results were based on a limited sample size, and larger well-designed studies are expected to confirm these preliminary findings.

SUBMITTER: Wang X

PROVIDER: S-EPMC6418356 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Association of human leukocyte antigens-DQB2/DPA1/DPB1 polymorphism and pulmonary tuberculosis in the Chinese Uygur population.

Wang Xue X Cao Xudong X Zhang Wanjiang W Zhang Le L Lu Lijun L Li Xinyue X El-Ashram Saeed S Wu Jiangdong J Chen Chuangfu C

Molecular genetics & genomic medicine 20190101 3

<h4>Background</h4>Tuberculosis (TB) is the second-leading cause of death globally. Genetic polymorphisms in human leukocyte antigens (HLA)-DQB2, HLA-DPA1, and HLA-DPB1 may partly explain individual differences in TB susceptibility.<h4>Methods</h4>We performed a hospital-based case-control study to assess the genetic influence of single-nucleotide polymorphisms (SNPs) in the HLA (HLA-DPA, HLA-DPB, and HLA-DQB) on the development of TB. There were 248 TB-infected cases and 340 healthy controls in ...[more]

PMID: 30600606

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Project description:Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA-DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele-specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele-imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP-binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium (r2>0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele-specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA-DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA-DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele-specific binding of ACTN4 and controlling expression of the neighboring HLA-DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4-HLA-DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mechanistic explanation for the association between this SNP and PAH outcomes.

Project description:Tuberculosis (TB) is an infectious disease caused by a mycobacterial infection, with high morbidity and mortality worldwide. The pathogenesis of TB is still unclear; however, a growing body of evidence suggests that host genetic factors may play important roles in susceptibility to TB, and different gene polymorphisms in different ethnic and genetic backgrounds may lead to different effects. In view of the above theories, our research group used bioinformatics to screen for 12 single nucleotide polymorphisms (SNPs), including rs1045481, rs1045491, rs2740349, rs10719, rs642321, rs3744741, rs7813, rs3742330, rs3757, rs14035, rs720012, and rs4961280, which are derived from 6 main genes (i.e., GEMIN4, DICER1, DROSHA, DGCR8, AGO2, and RAN) acting in the microRNA-machinery pathway. We then analyzed the correlations between TB patients of Uygur in Xinjiang China and the above SNPs using a case-control study. The results showed that the genotypic distributions of rs720012 (from gene DGCR8) and rs4961280 (from gene AGO2) were not in accordance with the Hardy-Weinberg equilibrium (P < .05), so they were deleted. Subjects carrying the rs3742330 AG/GG genotype, rs1045481 GA genotype, rs1045491 CT genotype, and rs7813 AG genotype, respectively, had an increased risk of TB than individuals carrying rs3742330 AA genotype, rs1045481 GG/AA genotype, rs1045491 CC/TT genotype, and rs7813 AA/GG genotype between different groups. Expression quantitative trait loci analysis found that rs3744741 and rs2740349 from gene GEMIN4 had a regulatory effect, while rs3742330 from gene DICER1 had a reverse regulatory effect. Finally, according to the results of Linkage Disequilibrium between SNPs, the haplotype analysis showed that the haplotype of GCTAC from gene GEMIN4 had statistical differences when compared with active and inactive TB. The current experimental results provide a direction for our future research, and the research team will conduct more in-depth studies on the correlation between miRNA and TB.

Dataset Information

Association of human leukocyte antigens-DQB2/DPA1/DPB1 polymorphism and pulmonary tuberculosis in the Chinese Uygur population.

Background

Methods

Results

Conclusion

Publications

Association of human leukocyte antigens-DQB2/DPA1/DPB1 polymorphism and pulmonary tuberculosis in the Chinese Uygur population.

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