Characterizing MHC Ancestral Haplotypes of Arabian Origin: A resource for the identification of disease genes and improved histocompatibility matching for transplantation

Student thesis: Doctoral Thesis

Abstract

The Major Histocompatibility Complex (MHC) or the Human Leukocyte Antigen (HLA), on the short arm of chromosome 6 is of particular interest because of its role in determining the compatibility of organs or tissues for transplantation and immunity. The high level of genetic polymorphism in the classical HLA class I (HLA-A, HLA-C, and HLA-B) and II genes (HLA DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1) reflect their direct engagement as antigen-presenting molecules against a wide range of diseases experienced by mankind throughout history. The MHC system has been extensively studied to improve clinical histocompatibility assay precision and accuracy in Caucasians, Africans, and Asians. Conversely, there is a scarcity of genomic information on ethnic groups of Arabia. This knowledge gap has an impact on the region's healthcare system's ability to translate genetic research into clinical practice, particularly in critical clinical assays such as histocompatibility matching, where donors are often limited to nuclear family members. Specific HLA class I and HLA class II variants exist in specific combinations with other nonclassical MHC genes in long stretches of conserved sequences known as Ancestral Haplotypes (AHs) and/or Conserved Extended Haplotypes (CEHs). Those conserved sequences are useful as markers for autoimmune disease association, anthropology, and immune response. This dissertation utilizes Next Generation Sequencing (NGS) high-resolution HLA typing techniques to characterize classical HLA class I and class II alleles and haplotypes in the United Arab Emirates (UAE). This objective is attained by distinct parts detailed in separate chapters within the current dissertation, including studies of a cohort of healthy families and families with an autoimmune disorder (i.e., Type 1 Diabetes), as well as a cohort with a communicable disease (i.e., Coronavirus Disease). First, a review of the current literature on MHC associations with diseases in ethnic groups of the Arabian Peninsula was conducted to highlighted and discuss the scarcity of data, the limitations of current studies, and the demand for additional efforts into characterizing the MHC and associated diseases in the populations of Arabian Peninsula. Next, common CEHs in the UAE population were identified and characterized through segregation analysis of high-resolution, pedigree-defined, MHC haplotypes derived from 41 healthy UAE families. The results of this study indicated that the contemporary UAE population exhibits a high degree of gene flow with neighboring ethnic groups. Notably, alleles and haplotypes previously associated with autoimmune diseases (e.g., Type 1 Diabetes). This study demonstrated that an appreciation for ethnic differences can provide insight into disease specific MHC polymorphisms in populations, an endeavor that motivated the establishment of a study with a specific reference to Type 1 Diabetes (T1D), an autoimmune disease that is becoming more prevalent in the populations of the Arabian Peninsula. In the second instance, the association of MHC alleles and haplotypes to Type 1 Diabetes Mellitus was investigated in families with Type 1 Diabetes proband by first conducting a study on 5 families to provide examples of MHC haplotype analysis in pedigrees and to improve our understanding of the genetics of T1D the population of the UAE. The incomplete concordance of the disease among individuals that are, genetically, at risk, in these families motivated the hypothesis that there might have been certain non-genetic environmental factors that have possibly triggered the rise of childhood T1D cases in patients with risk-associated genotypes, considering the substantial changes to the environmental and socioeconomic conditions (especially dietary intake patterns, healthcare, sanitation, and lifestyle) in the country since the 1990s. In this regard, an appreciation of the genetic risk factors is essential to understand the process leading to the disease. Subsequently, we sought to first improve our understanding of the disease in the population by examining the association of MHC alleles and haplotypes in 13 families with T1D patients from the UAE using family-based association as well as case-control analysis methods. The results of this study demonstrated that T1D diabetics from the UAE share susceptible MHC haplotype blocks with other world populations, which could be argued to have resulted from ancient genetic admixture between populations of central south Asia and the Middle East and that factors such as consanguinity, and first-cousin marriages might have enhanced susceptibility to T1D in these children by favoring the transmission of risk HLA haplotypes. This project is important as it provides a framework for understanding this major public health burden, particularly in a nation where consanguineous marriages are common. The third part of the dissertation investigates the association of HLA alleles and haplotypes on the severity of the Novel Coronavirus Disease (COVID-19) in the UAE, a communicable disease that is caused by the severe acute respiratory syndrome coronavirus (SARS-cov-2). This study was conceived during the first outbreak of the SARS-cov-2 infection in 2019, when there were many uncertainties regarding the pathogenesis of the disease. In response to global efforts toward characterizing the immunogenetic factors that contribute to the pathogenesis of SARS-cov-2 infection, the association between the HLA and COVID-19 severity in the UAE was investigated. The study included infected individuals in UAE hospitals with different levels of infection severity including mild, moderate, and severe. NGS-based case-control analysis was conducted to study the associations of HLA alleles and haplotypes of the patients. Two case-control studies were conducted. The cohort was divided into two groups, hospitalized (patients with moderate to severe conditions) and non-hospitalized (patients who were asymptotic or had very mild symptoms). The two groups were then compared for their HLA allelic and haplotypic variations using the Bridging immunogenomic Data-Analysis Workflow Gaps (BIGDAWG) R package for case-control association analyses of individual HLA loci. The first case-control study examined the HLA repertoire of 115 UAE nationals with COVID 19. The second case-control study included 92 COVID-19 infected individuals from 15 different nationalities that reside in the UAE and reported a significant association between HLA-B*35 genotype and HLA-C*04-B*35 haplotype with the severity of the COVID-19. Interestingly, this haplotype was observed in 11 of the 15 different nationalities and was repeatedly reported in previous studies on different populations. Consequently, the results support the potential use of HLA testing to differentiate between patients who require specific clinical management strategies. In conclusion, with the UAE recently launching its national organ registry program, and national genome strategy, this dissertation contributes to these efforts by improving the definition of Arabian MHC and the extent of HLA diversity in the local Arabian population of the UAE. This, in turn, shall improve the selection of bone marrow donors as well as provide the knowledge for future fine mapping studies to identify the genetic factors that are associated with a plethora of autoimmune diseases as well as communicable diseases.
Date of AwardMay 2022
Original languageAmerican English

Keywords

  • Human Leukocyte Antigens
  • Major Histocompatibility Complex
  • ancestral haplotypes
  • conserved extended haplotypes
  • Type 1 Diabetes
  • SARS-cov-2
  • United Arab Emirates.

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