An autosomal dominant major gene confers predisposition to pulmonary tuberculosis in adults

Abstract

The molecular basis of genetic predisposition to pulmonary tuberculosis in adults remains largely elusive. Few candidate genes have consistently been implicated in tuberculosis susceptibility, and no conclusive linkage was found in two previous genome-wide screens. We report here a genome-wide linkage study in a total sample of 96 Moroccan multiplex families, including 227 siblings with microbiologically and radiologically proven pulmonary tuberculosis. A genome-wide scan conducted in half the sample (48 families) identified five regions providing suggestive evidence (logarithm of the odds [LOD] score >1.17; P < 0.01) for linkage. These regions were then fine-mapped in the total sample of 96 families. A single region of chromosome 8q12-q13 was significantly linked to tuberculosis (LOD score = 3.49; P = 3 × 10−5), indicating the presence of a major tuberculosis susceptibility gene. Linkage was stronger (LOD score = 3.94; P = 10−5) in the subsample of 39 families in which one parent was also affected by tuberculosis, whereas it was much lower (LOD score = 0.79) in the 57 remaining families without affected parents, supporting a dominant mode of inheritance of the major susceptibility locus. These results provide direct molecular evidence that human pulmonary tuberculosis has a strong genetic basis, and indicate that the genetic component involves at least one major locus with a dominant susceptibility allele.

Mycobacteriosis in naturally infected ring-neck doves (Streptopelia risoria): investigation of the association between feather colour and susceptibility to infection, disease and lesions type

“…Their deficiency, functional defect or genetic polymorphism has been associated with altered susceptibility to mycobacteriosis (Taffik, 2001;Casanova & Abel, 2002;Phillips et al, 2002;Acevedo-Whitehouse et al, 2005;Bellamy, 2005;Okada & Shirakawa, 2005;Hill, 2006;Naik, 2006). The chromosome location of some of these genes has been elucidated (Cervino et al, 2002;Bellamy, 2005;Baghdadi et al, 2006).…”

Human genetic basis of interindividual variability in the course of infection

“…It taught us more about the impact of infections on the genome of human populations than about the genetic determinism of infectious diseases. In this regard, the work of my colleague Laurent Abel and his collaborators, first detecting major genes by segregation studies (142)(143)(144)(145)(146) and then mapping these genes for conditions such as schistosomiasis, leishmaniasis, leprosy, and tuberculosis, has bridged the gap between population-based and patient-based studies of infectious diseases (147)(148)(149)(150)(151)(152)(153)(154). Interestingly, the effect of most major genes decreases with age.…”

Tuberculosis infection: Insight from immunogenomics

“…Second, several primary immunodeficiency disorders are associated with susceptibility to mycobacteria in a Mendelian fashion attributable to rare single gene mutations with high penetrance [5]. Third, several genome-wide studies of susceptibility to TB have been performed with family-based linkage studies and have identified several promising chromosomal loci [16][17][18][19]. Fourth, candidate gene association studies, which evaluate whether common polymorphisms in candidate genes are associated with susceptibility to disease, suggest several loci that are associated with Tb susceptibility.…”