Testing candidate genes that may affect susceptibility to leprosy.

Several statistical methods have been used to search familial data sets for marker alleles associated with the occurrence of a disease. In the present paper, a recently developed method is used to re-analyze published data on leprosy and candidate genes at the HLA loci. This new method of analysis, the randomization transmission disequilibrium test (TDT), confirmed previous conclusions that there was no significant evidence against random transmission at the HLA-A locus but significant positive association with the HLA-DR2 allele. The randomization TDT detected significant protective associations, that had not previously been found, with alleles HLA-B8 in Egyptian families and HLA-B21 (current nomenclature B x 4901, 5001-5002) in South Indian families, highlighting a major advantage of permutation tests in analyzing candidate gene loci with rare alleles. These findings provide evidence that HLA class I restricted T lymphocytes may be of protective importance in leprosy.