Leprosy, Susceptibility To, 6
See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity.
MappingZhang et al. (2009) performed a genomewide association study to identify leprosy susceptibility loci in 706 patients and 1,225 controls, all of whom were self-identified Han Chinese from eastern China. Diagnosis was made on the basis of the consensus of at least 2 dermatologists. Patients and controls reported an absence of M. tuberculosis and other chronic infections. Controls lacked a history of leprosy in themselves and their families, as well as autoimmune and systemic disorders. The initial genomewide association study revealed 93 SNPs that showed strongest association with leprosy. Genotyping of these 93 SNPs in 3 replication studies showed highly significant associations (P less than 1.00 x 10(-10) for all analyses combined) with SNPs in or near several genes, including 2 SNPs in the CCDC122 gene (613408), rs9533634 (P = 4.77 x 10(-12); OR = 0.76) and rs3088362 (P = 1.36 x 10(-31); OR = 1.52), and 2 SNPs in the C13ORF31 gene (LACC1; 613409), rs3764147 (P = 3.72 x 10(-54); OR = 1.68) and rs10507522 (P = 4.64 x 10(-24); OR = 0.68). These replication studies included 3,254 patients and 5,955 controls who were predominantly Han Chinese from eastern China, as well as some individuals from non-Han ethnic groups from southern China. The SNPs in CCDC122 and C13ORF31 were associated with both multibacillary and paucibacillary forms of leprosy. However, the associations with the 2 SNPs in C13ORF31 were stronger for multibacillary than paucibacillary leprosy. The CCDC122 and C13ORF31 genes both map to chromosome 13q14.
In an attempt to reproduce the findings of Zhang et al. (2009) and to extend these findings to other populations, Wong et al. (2010) genotyped SNPs implicated by Zhang et al. (2009) in 2 Indian case-control cohorts (492 patients in New Delhi and 382 in Kolkata) and in 273 patients and 221 controls from Mali, West Africa. They found associations between leprosy and SNPs in C13ORF31 (rs3764147; P = 6.1 x 10(-8)) and CCDC122 (rs9533634; P = 1.1 x 10(-5)). However, they found no associations between leprosy and SNPs in the other 4 non-major histocompatibility complex genes implicated by Zhang et al. (2009). Wong et al. (2010) proposed that association of the chromosome 13q14.11 locus containing C13ORF31 and CCDC122 with leprosy in these additional populations supports a molecular link between mycobacterial infection and Crohn disease (see 266600), since the same chromosome 13q14.11 locus had been associated with Crohn disease in a genomewide association study by Barrett et al. (2008). In a reply, Zhang et al. (2010) stated that confirmation by Wong et al. (2010) of associations between leprosy and SNPs in C13ORF31 and CCDC122 highlight the commonality of leprosy susceptibility loci across populations.
By genotyping 16 SNPs belonging to 6 loci found by Zhang et al. (2009) to be associated with leprosy in Chinese patients, Grant et al. (2012) replicated SNPs in HLA-DR (see 142860)-DQ (see 146880), RIPK2 (603455), CCDC122-LACC1, and NOD2 (605956) as leprosy susceptibility factors in 474 Vietnamese leprosy simplex families. As in the Chinese study, stronger genetic effects for these markers were detected in multibacillary patients compared with paucibacillary patients. Grant et al. (2012) noted that the associations were stronger in the Vietnamese and Chinese populations, which are genetically less distant, than in the Indian and Malian populations studied by Wong et al. (2010), suggesting that the populations may share a particular linkage disequilibrium with the causative genetic variant. Grant et al. (2012) noted that the G allele at rs3764147 in LACC1, which produces an ile-to-val change in the multicopper oxidoreductase domain of the LACC1 protein, was found to be associated with leprosy in all 4 populations and had previously been found to be associated with Crohn disease.