Functional characterization of key genetic markers involved in allergic rhinitis among Chinese population

Teh, Keng Foo (2021) Functional characterization of key genetic markers involved in allergic rhinitis among Chinese population. Masters thesis, Sunway University.

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Allergic rhinitis is an IgE-mediated inflammation of the nasal membranes that occurs upon allergen exposure. It results in nasal symptoms such as itchy or runny nose and can impact the quality of life and be a significant economic burden to its sufferers. AR is caused by both genetic and environmental risk factors. Previous genetic studies found that genetic variants associated with AR were population- and ethnicity-specific. In this study, we investigated the genetic risk factors of AR among the individuals of Chinese ethnicity. There has been only one previous study conducted on this ethnic group, but it had a small sample size which did not allow for sufficient discovery of significant genetic variants. This thesis aims to (1) identify the genetic variants that are risk factors of AR; (2) predict and characterize the functions of these genetic variants, and (3) evaluate the putative effects of the variants on the functions of the genes to investigate AR susceptibility. In this study, 2,146 cases and 2,039 controls were recruited and 5,215,687 genotyped and quality checked SNPs were employed for GWAS. Functional prediction was conducted to identify the potential molecular influence by the associated susceptibility variants from GWAS using bioinformatic tools. Dual luciferase reporter assay was conducted to characterize the predicted function of transcription factor binding sites (TFBS) of the target SNPs using HEK293T cell lines. 278 RNA samples from peripheral blood mononuclear cells (PBMCs) were collected for in vivo expression analysis using genetic model to study genotypic effect on the expression of target gene transcript, along with literature review for evaluation of candidate genetic variants. In this study, GWAS on AR individuals of Chinese ethnicity revealed two genome-wide significantly associated susceptibility variants (p<5×10-8; rs3135390 and rs10506953) and six suggestively associated quantitative trait locus (QTL) regions (p<1×10-5; CABP1, BMPR1B, SMAD2, LINC0036, LOC105378397 and NR5A2). Functional prediction identified the TFBS by CABP1, BMPR1B, SMAD2 and LINC0036. Dual luciferase reporter assay revealed that the haplotype of risk alleles (T allele and G allele) from the SNP rs12228187 and rs110655189 of CAPB1 isoform XM_005253994.2 demonstrated a significant lower promoter activity compared to the haplotype of protective alleles (C allele and A allele) at 24 hours and 48 hours post transfection (P<0.001 and P<0.0001, respectively). Based on literature findings, the lower expression levels of XM_005253994.2 isoform might lead to an increase in the HLA-DM expression level, and ultimately an increase in antigen presentation pathways causing increased IgE production and AR manifestation. However, the in vivo expression analysis revealed that the haplotype of risk alleles did not significantly decrease the expression level of XM_005253994.2 isoform, but was deemed as inconclusive, due to the natural low expression of this gene in PBMC. More accurate in vivo studies should be conducted in cells lines with higher innate expression levels of the target genes in the future for optimal characterization of this gene. The understanding of the involvement of these candidate genetic variants in the AR pathogenesis would provide a basis for earlier diagnosis and new therapeutic targets of this disease.

Item Type: Thesis (Masters)
Uncontrolled Keywords: allergic rhinitis; genetic; genome-wide association study; single nucleotide polymorphisms; CABP1.
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine
Divisions: Sunway University > School of Medical and Life Sciences [formerly School of Healthcare and Medical Sciences until 2020] > Dept. Biological Sciences
Depositing User: Ms Yong Yee Chan
Date Deposited: 08 Oct 2023 23:55
Last Modified: 08 Oct 2023 23:55

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