A study to determine genetic susceptibility to tuberculosis / Kathleen Anne Meehan.

Abstract

Studies that document the higher incidence of tuberculosis as well as the variable efficacy of the BCG vaccine in Black, compared to White, populations have alluded to resistance or susceptibility to tuberculosis being genetically controlled.The HIA system has been associated with many diseases involving an immune aetiology. It has been shown that T cell receptor genes have limited restriction fragment length polymorphisrns, serving to create a variation in the repertoire of expressed T cell receptor genes. These repertoire differences may play a fundamental role in disease susceptibility.A study was therefore undertaken to establish whether linkage exists between the HIA system or the T cell receptor genes and a putative susceptibility gene for tuberculosis.Polymorphisrns of these genetic markers were examined in three Cape Coloured multiplex families, affected individuals having culture-positive pulmonary tuberculosis.HLA haplotypes were derived from serological typing of peripheral leucocytes from each individual. B-Iymphoblastoid cell lines were established from each family member. DNA was then extracted and digested with a variety of restriction endonucleases. After gel electrophoresis and Southern blotting, the DNA fragments were probed with a panel of T cell receptor cDNA probes, revealing the allelic polymorphisms.Linkage analysis was done using the Liped computer programme and Lad scores were determined for each marker locus using various genetic models. Haplotypes were also established for the T cell receptor genes and used in the linkage analysis.Although most of the Lad scores fell within the indeterminate range, a cumulative Lod score of 1.79 was obtained from the allele generated by the EcoRV/a2 enzyme/probe combination under a recessive model with 50% penetrance. This represents odds of about 52: 1 in favour of linkage between the T cell receptor a gene and a putative susceptibility gene to tuberculosis.