Susceptibility to leprosy is associated with PARK2 and PACRG

Abstract

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.

HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients

“…9,[24][25][26][27] have been implicated in leprosy susceptibility, corroborated by result replication in more than one population. Thus, it is likely that genetic heterogeneity is a common feature of this disease, but other genes are also involved, as expected in any complex trait.…”

“…The phenotype characterization and the clinical classification of these patients have been described previously. 27 Ethical approval of the study was obtained from the Local Health Authorities in Ho Chi Min City, Vietnam and the Ethics Committee of the McGill University Health Centre, Montreal, Canada. All patients were diagnosed on the basis of clinical and bacteriological criteria and classified according to the Ridley and Jopling scale.…”

“…27 The DRB1 alleles were identified using sequence-specific primers (SSP) for PCR amplification as described previously. 28 …”

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

“…[7][8][9] Mutation in genes with ubiquitination functions have also been implicated as risks in both tuberculosis and leprosy. 10,11 On the basis of databases of genetic association study, nearly 100 genes had been studied for their association with tuberculosis. From these candidate gene association studies, apart from genes in IL12/23-IFNG axis, only SLC11A1 (formerly NRAMP1) had been consistently shown evidence of association with tuberculosis.…”

Identification d’un nouveau gène de susceptibilité à la lèpre par clonage positionnel

“…En effet, il est fréquent que la région chromosomique identifiée s'étende sur plusieurs dizaines de centimorgans. Ainsi, dans notre étude, l'intervalle de confiance à 90 % pour le positionnement du locus de susceptibilité à l'origine du signal de liaison était compris entre deux marqueurs distants de 6,4 mégabases (Mb, Figure 1A) et contenait 31 gènes ayant des fonctions connues ou prédites ( Figure 1B) Figure 1B) [7]. Parmi les six SNP significativement associés à la lèpre per se, quatre, dont les deux plus significatifs, étaient situés dans une région chevauchant le promoteur commun au gène PARK2, dont des mutations sont responsables de certaines formes juvé-niles de maladie de Parkinson, et au gène coréglé PACRG.…”