Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family

An epidemic of tuberculosis occurred in a community of Aboriginal Canadians during the period 1987-89. Genetic and epidemiologic data were collected o n an extended family from this community, and the evidence for linkage to N RAMP1, a candidate gene for susceptibility to mycobacterial diseases, was a ssessed. Individuals were grouped into risk (liability) classes leased on v accination, age, previous disease, and tuberculin skin-test results. Under the assumption of a dominant mode of inheritance and a relative risk of 10, which is associated with the high-risk genotypes, a maximum LOD score of 3 .81 was observed for linkage between a tuberculosis-susceptibility locus an d D2S424, which is located just distal to NRAMP1, in chromosome region 2q35 . Significant linkage was also observed between a tuberculosis-susceptibili ty locus and a haplotype of 10 NRAMP1 intragenic variants. No linkage to th e major histocompatibility-complex region on chromosome 6p was observed, de spite distortion of transmission from one member of the oldest couple to th eir affected offspring. The ability to assign individuals to risk classes w as crucial to the success of this study.