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Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype.

ABSTRACT: Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ САТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart.

SUBMITTER: Goncharova IA

PROVIDER: S-EPMC8761574 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe rise in Gastro-Esophageal Reflux Disease (GERD) prevalence appears to have coincided with a simultaneous increase in the prevalence of diabetes mellitus, hypertension and bronchial asthma amongst the Indian population. Despite being evaluated extensively for their role as a risk factor for GERD, till date this relationship has remained a debatable one. Moreover, literature available on such studies conducted within Indian population remains scarce.AimThe aim of the present study was to examine the risk of developing GERD in patients suffering from diabetes mellitus, hypertension and asthma in a Southern Indian population. The present retrospective, triple cohort and hospital based study was conducted by accessing the patient records from the medical records department of a tertiary care hospital in Southern India.Materials and MethodsThe patient’s records were accessed from the year 2011 onwards. Relative Risk (RR) was calculated to determine the risk of development of GERD with every disease. Chi-square test was used to determine the statistical significance of the relationship between each disease and the development of GERD. A p-value of <0.05 was considered statistically significant.ResultsIn view of the time constraints as well as the limitations of the inclusion and exclusion criteria, data pertaining to only 40, 71 and 53 patients in Cohort 1 (diabetics), 2 (hypertensives) and 3 (bronchial asthmatics) respectively could be analyzed in the present study. The relative risk of GERD development was greater than 1 for patients belonging to Cohort 2 and 3, suggesting that the risk of GERD development is higher amongst hypertensives and asthmatics. Surprisingly, the diabetics (Cohort 1) were not associated with a high risk of GERD development. However, the relationship between any of the disease and GERD development was not statistically significant.ConclusionThe present study found an increased risk of GERD development amongst patients suffering from hypertension and bronchial asthma, but not with diabetes mellitus.

Project description:BackgroundRNA-binding proteins are master orchestrators of gene expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs. Thus, characterizing RNA-binding proteins targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RNA-binding protein targets, limiting our understanding of their function. In cancer, the RNA-binding protein HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1; A2B1) promotes the pro-proliferative/anti-apoptotic phenotype. The same phenotype in pulmonary arterial smooth muscle cells (PASMCs) is responsible for the development of pulmonary arterial hypertension (PAH). However, A2B1 function has never been investigated in PAH.MethodThrough the integration of computational and experimental biology, the authors investigated the role of A2B1 in human PAH-PASMC. Bioinformatics and RNA sequencing allowed them to investigate the transcriptome-wide function of A2B1, and RNA immunoprecipitation and A2B1 silencing experiments allowed them to decipher the intricate molecular mechanism at play. In addition, they performed a preclinical trial in the monocrotaline-induced pulmonary hypertension rat model to investigate the relevance of A2B1 inhibition in mitigating pulmonary hypertension severity.ResultsThey found that A2B1 expression and its nuclear localization are increased in human PAH-PASMC. Using bioinformatics, they identified 3 known motifs of A2B1 and all mRNAs carrying them. In PAH-PASMC, they demonstrated the complementary nonredundant function of A2B1 motifs because all motifs are implicated in different aspects of the cell cycle. In addition, they showed that in PAH-PASMC, A2B1 promotes the expression of its targets. A2B1 silencing in PAH-PASMC led to a decrease of all tested mRNAs carrying an A2B1 motif and a concomitant decrease in proliferation and resistance to apoptosis. Last, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats.ConclusionsThrough the integration of computational and experimental biology, the study revealed the role of A2B1 as a master orchestrator of the PAH-PASMC phenotype and its relevance as a therapeutic target in PAH.

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Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype.

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