APHIA Oral Presentation Asia-Pacific Histocompatibility and Immunogenetics Association Meeting 2023

MHC Conserved extended haplotypes in families from the Middle East: implications for disease association and transplantation in an admixed population. (95825)

Halima Alnaqbi 1 2 , Guan Tay 2 3 4 , Habiba Alsafar 1 2
  1. Biomedical Engineering, Khalifa University, Abu Dhabi, United Arab Emirates
  2. Center for Biotechnology, Khalifa University, Abu Dhabi, United Arab Emirates
  3. Division of Psychiatry, UWA Medical School, The University of Western Australia, Perth, Australia
  4. School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia

Major histocompatibility Complex (MHC) class I and class II allele variants exist in specific combinations with other non-classical MHC genes in long stretches of conserved sequences known as Ancestral Haplotypes (AHs) (Degli-Esposti et al., 1992; Gaudieri et al., 1997) and/or Conserved Extended Haplotypes (CEHs) (Alper et al., 2017). Those conserved sequences are useful as markers to characterize human diversity, localize disease susceptibility genes, and for bone marrow transplant matching (Dawkins et al., 2019). MHC disease association studies have been dominated by analyses based on populations of European ancestries (Sirugo et al., 2019). Despite its unique population makeup and ethnic diversity, the Middle East remains underrepresented in the global genome catalogue (Al Naqbi et al., 2021). This scarcity of genomic information, including that of the MHC, poses a challenge to the healthcare system’s ability to translate genetic research into clinical practice. This is evident in critical clinical assays such as histocompatibility matching, where transplantation donors are often limited to nuclear family members. This study was conceived to address this gap in knowledge by characterising MHC CEHs/AHs in families from the United Arab Emirates (UAE) and investigating their association with autoimmune (Type 1 Diabetes) and communicable (COVID-19) diseases using family-phased high-resolution haplotypes. Several CEHs that were also observed in populations from South to East Asia were identified in this study, suggesting a great degree of gene flow with neighbouring ethnic groups in Asia (Witt et al., 2002), and to a less extent with Africa, in the contemporary UAE population. Some of those CEHs were also associated with autoimmune diseases (e.g., Type 1 Diabetes and Behçet’s disease) (Mehra et al., 2007). Other CEHs identified were UAE-specific, underscoring that appreciation for ethnic differences can provide insights into subpopulation-specific disease-related polymorphisms. By using CEHs, the findings presented in this study provided insights into the MHC genomic organization of an understudied admixed population and offers a foundation for improved disease association studies, and histocompatibility matching in organ transplantation that can be applied to other neighboring populations.

  1. Degli-Esposti, M. A. et al. Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM. Immunogenetics 36, 345–356. https://doi.org/10.1007/bf00218041 (1992).
  2. Gaudieri, S., Leelayuwat, C., Tay, G. K., Townend, D. C. & Dawkins, R. L. The major histocompatibility complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes. J Mol Evol 45, 17–23. https://doi.org/10.1007/pl00006194 (1997).
  3. Alper, C. A. & Larsen, C. E. Pedigree-defined haplotypes and their applications to genetic studies. Methods Mol. Biol. 1551, 113–127. https://doi.org/10.1007/978-1-4939-6750-6_6 (2017).
  4. Dawkins, R. L. & Lloyd, S. S. MHC Genomics and Disease: Looking Back to Go Forward. Cells 8, 944. https://doi.org/10.3390/cells8090944 (2019).
  5. Sirugo, G., Williams, S. M. & Tishkoff, S. A. The missing diversity in human genetic studies. Cell 177, 26–31. https://doi.org/10.1016/j.cell.2019.02.048 (2019).
  6. Al Naqbi, H., Mawart, A., Alshamsi, J., Al Safar, H. & Tay, G. K. Major histocompatibility complex (MHC) associations with diseases in ethnic groups of the Arabian Peninsula. Immunogenetics 73, 131–152. https://doi.org/10.1007/s00251-021-01204-x (2021).
  7. Witt, C. S. et al. Common HLA-B8-DR3 haplotype in Northern India is different from that found in Europe. Tissue Antigens 60, 474–480. https://doi.org/10.1034/j.1399-0039.2002.600602.x (2002).
  8. Mehra, N., Kumar, N., Kaur, G., Kanga, U. & Tandon, N. Biomarkers of susceptibility to type 1 diabetes with special reference to the Indian population. Indian J. Med. Res. 125, 321–344 (2007).