The Genetics of Susceptibility to Leprosy

Meisner, Sarah (1999). The Genetics of Susceptibility to Leprosy. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ff3c

Abstract

There is strong evidence that genetic factors play a role in susceptibility to leprosy. Although the major histocompatibility complex is known to play a part, it does not account for the whole picture. Recent advances in genetic technology have made it possible to identify loci involved in complex traits. In this thesis I discuss two contrasting approaches: a genome-wide search for the detection of major genes, and candidate gene association studies capable of detecting smaller genetic effects.

242 affected sibling pairs with leprosy were identified in Tamil Nadu in South India. DNA extracted from their blood was used to perform a two-stage genome wide search. Initially 92 families were screened using 293 polymorphic microsatellite markers. A further 96 families were then used to rescreen the markers that showed lod scores suggestive of linkage. Markers on chromosomes 2, 6, 10, 16 and 17 showed increased sharing which could be consistent with the presence of minor genes. These regions include some interesting candidate genes that warrant further investigation.

Association studies were performed on 5 candidate gaies using cases and controls from South India, Bengal, and Mali: Interleukins-4 and —10, tumour necrosis factor (INF), vitamin D receptor, and the natural resistance associated macrophage protein 1 (NRAMP1). An association was found between the NRAMP1 1729+55del4 polymorphism and leprosy type in a population from Mali, mutant homozygotes being susceptible to paucibacillary leprosy whilst heterozygotes were susceptible to multibacillary leprosy (x² =8.88, p=0.00288 OR=5.79{CI 1.46-24.61}). These findings persisted after logistic regression to allow for region and ethnicity. This association was not observed in the South Indian cases and controls. A borderline association was found between the TNF — 238 polymorphism and susceptibility to leprosy in a South Indian population, cases having an excess of the common allele compared to controls (2x2 x² = 4.12, p=0.042 OR=1.68{CI 0.98-2.87}).