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GWAS Exposes New Loci Linked to Leprosy Risk

NEW YORK (GenomeWeb News) – In a study in the early, online version of Nature Genetics yesterday, researchers from China and Singapore reported that they have tracked down two new loci that are associated with susceptibility to leprosy, an infection caused by the bacterial species Mycobacterium leprae.

The investigators did a genome-wide association study involving more than 700 individuals with leprosy and nearly 5,600 unaffected controls, followed by replication studies involving thousands more cases and controls from China. In the process, they confirmed some genetic associations found in the past, including ties between leprosy and variations in genes in an innate immune pathway containing NOD2. The search also led the team to previously undetected risk variants in and around the chromosome 6 gene RAB32 and the C1orf141-IL23R locus on chromosome 1.

The potential association between leprosy and the interleuken 23 cytokine receptor coding gene IL23R marks the first time that an innate immunity gene has been linked to infectious disease susceptibility, researchers noted. Alterations to IL23R have been implicated in past studies of conditions such as psoriasis, Crohn's disease, and ulcerative colitis. RAB32 associations, meanwhile, point to a possible role for autophagy during M. leprae infection.

"Whereas the identification of IL23R as a new susceptibility gene has firmly established the involvement of innate immunity in the pathogenesis of leprosy, the identification of RAB32 has provided new biological insight into the mechanism of leprosy development," senior author Xuejun Zhang, a dermatology researcher affiliated with Anhui Medical University in China and with the Ministry of National Science and Technology, and co-authors wrote.

"This finding highlights the potential involvement of autophagocytosis in host defense against M. leprae infection," they added, "which has parallels with Crohn's disease."

Genetic factors are increasingly being explored not only with respect to Mendelian and common disease risk, but also for their influence on infectious diseases, the study authors explained, since genetics can influence an individual's susceptibility to infection, disease progression, and severity. In the case of leprosy, they noted, past research suggests that the heritability of genetic features mediating disease susceptibility is as high as 57 percent.

Some of the genetic variants that contribute to leprosy risk were identified through a GWAS in China, reported by members of the same research group in the New England Journal of Medicine in 2009. That effort uncovered half a dozen leprosy-linked loci, including variants in genes contributing to NOD2-mediated innate immune function.

For the new study, they looked at the same 706 leprosy cases studied in that GWAS, but dramatically increased the number of controls assessed, from 1,225 individuals to nearly 5,600.

The additional control samples came from individuals of Han Chinese descent who had been genotyped on Illumina Human 610-Quad Bead chip arrays through other GWAS. Among them were individuals with atopic dermatitis, psoriasis, systemic lupus erythematosus, and vitilago.

In replication analyses of 3,301 more Chinese individuals with leprosy and 5,299 controls from three cohorts, the researchers tested two-dozen of the most promising candidate SNPs identified in the discovery phase of the study. Controls in these validation groups did not have leprosy, autoimmune disease, or systemic conditions.

After this validation step, researchers were left with new loci on chromosomes 1, 6, and 16, near the C1orf141-IL23R locus, RAB32 gene, and CYLD gene, respectively.

Follow-up experiments suggested that the variants near CYLD on chromosome 16 may not be independently associated with leprosy risk, researchers reported, explaining that additional research is needed to explore the nature of that potential interaction.

The team also saw interactions amongst different leprosy susceptibility loci, including variants in NOD2 and RIRK2, genes that form a complex that signals to the NF-kappaB signaling pathway.

Nevertheless, they were not able to replicate associations with TLR1, a leprosy susceptibility gene found through a gene-centric association study done by another research group in India.

"The clear disparity of the association at TLR1 between the Chinese and Indian populations suggests a possible population-specific effect of TLR1 variation and potential heterogeneity of leprosy susceptibility based on ancestry," Zhang and co-authors wrote.

"This heterogeneity may not be surprising, given the common belief that the human population has been subjected to strong selection by infection," they added, "and therefore susceptibility to pathogens is likely to vary across different human populations."