Abstract
HLA (Human Leukocyte Antigen) molecules provide a framework for T-cell recognition of antigenic peptides and thus play an important role in the immune system and defence against pathogens. HLA molecules are encoded for by genes on the short arm of chromosome six in the human genome, a region of over 4000 kilo bases (kb) known as the human major histocompatibility complex (MHC) or HLA complex. According to structural and functional characteristics, the genes of this region have been classified into three families, namely classes ƒ¹, ƒ¹ƒ¹ and ƒ¹ƒ¹ƒ¹. The HLA genes are highly polymorphic and because of this characteristic, it increases the functional range of recognition of different antigens and contributes to immunological specificity.
Previous studies on population groups such as Indians and Cambodians, have identified an association between HLA polymorphisms and susceptibility to TB. A large number of different population groups with diverse gene pools reside in South Africa, of which the Cape Coloured population is one. This anthropologically distinct population group¡¦s diverse gene pool originated from founder individuals of the colonizing population, which came from various nations and cultural backgrounds, including Europe, Africa (such as Khoi, San Xhosa, Sotho and East African populations), Madagascar and the Far East. Unusual MHC allele frequencies and haplotypes have been identified in the Cape Coloured population. The Cape Coloureds are highly susceptible to TB and reside in the Western Cape, which has a TB incidence rate that is higher than that of any other province in South Africa. The recently admixed Coloured population is a valuable candidate population for the identification of genes/mutations underlying complex diseases. This study focussed on polymorphisms of class ƒ¹ƒ¹ genes, specifically HLA-DRB, and their possible contribution to disease susceptibility in populations of South Africa. Two questions have been formulated:
1) What knowledge can we gain from the current literature on HLA variants in the different population groups of South Africa and disease susceptibility?
2) Is there an association between alleles of the most polymorphic class ƒ¹ƒ¹ MHC gene, HLA-DRB, and susceptibility or resistance to TB in the Cape Coloured population?
These two primary questions have been addressed by:
1) Reviewing the literature concerning HLA alleles in diverse population groups in South Africa and their contribution to disease susceptibility. Chapter 2 addresses this objective and is written in the format of a review article to facilitate its future publication,
2) Conducting a TB case-control study, typing HLA-DRB in Cape Coloured individuals residing in the Western Cape to investigate the possible association between TB susceptibility or resistance and specific DRB alleles. The HLA-DRB1, DRB3 and DRB4 typing by means of PCR-SSP (polymerase chain reaction ¡V sequence specific primers) was done on DNA isolated from 106 TB patients and 107 controls from the Cape Coloured population. The results obtained for this experimental investigation is presented (also in publication format) in Chapter 3.
Summary of main findings:
1) The literature overview of publications describing HLA related disease association in the different population groups in South Africa (Chapter 2), revealed that unique alleles contributing to susceptibility of various diseases have been identified in some South African populations. The large number of ethnic groups in South Africa and unique populations such as the Cape Coloureds provide a genetic resource, which has the potential to be utilized for candidate gene hunting.
2) A weak association between susceptibility for TB and HLA-DRB1*0301-0302 (DR3) and HLA-DRB3*0101-0301 (DR52) exists in the Cape Coloured population (Chapter 3).
Since the South African population consists of a large number of different population groups with diverse gene pools, a unique opportunity to study disease predispositions among specific population groups with diverse genetic make-up is presented. With these different populations, often residing in a common environment, the interplay of environmental and genetic factors in disease development could be studied. For example, HLA typing of these populations could clarify the extent to which inter-population HLA variation contributes towards disease susceptibility. The identification of certain HLA-DRB alleles potentially contributing to TB susceptibility, could lead to an understanding of the differential factors involved in disease susceptibility and in turn lead to the understanding of the fundamental mechanisms involved. This could result in therapeutic approaches and treatments that will be advantageous to the population concerned.
Prof. L. Bornman