Genetic susceptibility to leprosy

Leprosy (Hansen's disease) is a human infectious disease that can be effectively treated with 6-12 month administration of multi-drug therapy. In 2008, approximately 250,000 new cases were reported to the World Health Organization. The etiological agent, Mycobacterium leprae, was identified by G.H.A. Hansen in the nineteenth century. Subsequent to exposure, epidemiological studies maintain the importance of host genetics in leprosy susceptibility. A previous model-free genome-wide linkage scan in multi-case families from Vietnam detected linkage between chromosome region 6p21 (lod = 2.62) and leprosy per se and between 10p13 (lod = 1.98) and the paucibacillary sub-type. A ‘first-round' high-density association scan (307 SNPs) of a 10.4 Mb target interval on 6p21 (BAT1→CCND3) in 194 single-case families from Vietnam led to the identification of a SNP in lymphotoxin-alpha (LTA) – LTA+80 – as major risk factor for early-onset leprosy (P = 4.0×10-5). The association was replicated in 364 cases and 371 controls from North India (P = 0.006) and 104 single-case families from Vietnam (combined Vietnam P = 4.0×10-7). A ‘second-round' ultra-high-density association scan (682 SNPs) of a 1.9 Mb sub-interval on 6p21 (HCG27→HLA-DPA3) in 198 single-case families from Vietnam led to the identification of two intergenic SNPs in the HLA class I region – rs2394885 (P = 0.0063) and rs2922997 (P = 0.0094) – as risk factors for leprosy. The associations were replicated in 292 single-case leprosy families from Vietnam (P = 8.8×10-5 and P = 0.0037, respectively) and the population-based sample from North India (P = 3.0×10-8 and P = 2.0×10-5, respectively). Finally, mannose receptor, C type 1 (MRC1) was selected as a candidate paucibacillary gene in the 10p13 region. In 490 single-case and 90 multi-case families from Vietnam a non-synonymous SNP in exon 7 – rs1926736 (G396S) – was associated with leprosy (P = 0.035) but not the paucibacillary sub-type. The association was replicated in 384 cases and 399 controls from Rio de Janiero, Brazil (P = 0.016). The process of identifying the susceptibility variants provided valuable insight into the replication of genetic effects. As such, these studies served to improve our understanding of leprosy pathogenesis by implicating novel biological pathways while simultaneously providing a genetic model for common infectious diseases.