Date of Award

3-3-2026

Thesis Type

Masters

Document Type

Dissertation

Divisions

Institute for Advanced Studies

Institution

Universiti Malaya

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe respiratory failure and death. While advanced age, sex, and comorbidities are recognised risk factors, these alone do not fully account for interindividual variability. Host genetic factors and immune dysregulation are increasingly acknowledged as key determinants of disease severity, yet data from Southeast Asian populations remain limited. This study aimed to investigate the role of host genetic polymorphisms in predisposing individuals to severe COVID-19 and to assess the potential immunological consequences in recovered patients, focusing on memory T and B lymphocyte subsets. A total of 409 recovered COVID-19 patients were recruited in Malaysia, comprising 381 non-severe and 28 severe cases. Genomic DNA was extracted from peripheral blood and sequenced using a custom 100-gene Ion AmpliSeq panel targeting immune and inflammatory genes. Variant annotation was performed using Ion Reporter software, and deleterious variants were filtered with SIFT (≤0.05). Statistical association testing was conducted using Fisher’s exact test, and in silico analyses (ESEfinder, PROMO, ConSurf, and STRING) were applied to predict functional effects. In parallel, peripheral blood mononuclear cells (PBMCs) from a subset of patients were analysed by flow cytometry to quantify CD4⁺ and CD8⁺ T cell subsets under unstimulated, PHA-stimulated, and SARS-CoV-2 peptide–stimulated conditions, as well as to assess antigen-specific memory B cells. In total, 6,367 variants in non-severe and 2,786 variants in severe cases were identified, from which five significant SNPs were associated with severe COVID-19: HLA-C, IFNL3, SLC6A4, and two sites in MUC5B. The strongest association was observed for SLC6A4 rs6352 (OR = 29.23), implicating serotonin-mediated immune modulation. Functional analyses suggested potential impacts on protein function, splicing regulation, and transcription factor binding. Flow cytometry analyses of memory T- and B-lymphocyte subsets showed that in the non-severe group, CD137 expression was significantly upregulated following stimulation, increasing fromunstimulated to PHA-stimulated (p < 0.05) and peptide pool-stimulated conditions (p < 0.0001), consistent with the presence of SARS-CoV-2–specific memory CD8⁺ T cells. CD134 expression was also enhanced under PHA stimulation (p < 0.05), reflecting mitogen-driven activation of memory CD4⁺ T cells. These results indicate more prominent activation of both CD8⁺ and CD4⁺ memory T-cell subsets in non-severe individuals, highlighting immune response differences associated with COVID-19 severity. This study provides evidence of population-specific genetic variants associated with severe COVID-19 in a Malaysian cohort, highlighting the roles of antigen presentation, interferon signalling, serotonin pathways, and mucin biology. Immune cell profiling further indicated differential activation of memory T-cell subsets between severity groups, supporting the relevance of immune response patterns alongside genetic factors. Collectively, these findings advance understanding of host genetic contributions to severe disease and emphasise the importance of including underrepresented populations in COVID-19 host genetics.

Initial

khm

Additional Information

Dissertation (M.A.) – Institute for Advanced Studies, Universiti Malaya, 2026.

Download

Share

COinS