A recessive major gene controls the mitsuda reaction in a region endemic for leprosy

Background. Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The Mitsuda reaction is a delayed granulomatous skin reaction elicited by intradermal injection of heat-killed M. leprae. Interestingly, results of the Mitsuda test are positive in the majority of individuals, even in areas not endemic for M. leprae. Like leprosy, the Mitsuda reaction is thought to be genetically controlled, but its mode of inheritance is unknown, although the role of the NRAMP1 gene has previously been reported. Methods. We conducted a segregation analysis of quantitative Mitsuda reactivity in 168 Vietnamese nuclear families ascertained through patients with leprosy. Results. We found strong evidence ( ) for a major gene controlling the Mitsuda reaction independently 9 P ! 10 of leprosy clinical status. Subsequent linkage analysis showed that this major gene was distinct from NRAMP1. Under the major-gene model, ∼12% of individuals are homozygous for the recessive predisposing allele and are predicted to display high levels of Mitsuda reactivity (mean, ∼10 mm, versus 5 mm in other individuals). Conclusion. We provide evidence that the Mitsuda reaction is controlled by a major gene. Our study paves the way for the identification of this gene and should provide novel insight into the mechanisms involved in granuloma formation, especially in M. leprae infection. Leprosy is a chronic infectious disease, caused by Mycobacterium leprae, that mainly affects skin and peripheral nerves [1]. Despite a dramatic decrease in prevalence during the past 15 years, partly due to the efficacy of multidrug therapy [2], the worldwide leprosy incidence is still approaching 500,000 novel cases/year. Whereas most infected individuals do not develop clinical disease, even after sustained exposure to M. leprae, others present a broad spectrum of clinical symptoms. Leprosy ranges from the tuberculoid form, characterized by mature, well-delineated, and well-differentiated