ORPHA: 548; DO: 1024;
Cytogenetic location: 6q25 Genomic coordinates (GRCh38): 6:148,500,001-160,600,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q25 | {Leprosy, susceptibility to, 2} | 607572 | 2 |
See 609888 for a discussion of leprosy susceptibility in general and information on genetic heterogeneity.
In a study in a Vietnamese population, Mira et al. (2003) found significant evidence for a susceptibility gene for leprosy on chromosome region 6q25; maximum likelihood binomial (MLB) lod score was 4.31. They confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families (i.e., families with 2 unaffected parents and 1 affected child). Mira et al. (2003) confirmed the linkage of paucibacillary leprosy to 10p13 (LPRS1; 609888), as reported by Siddiqui et al. (2001). Their evidence suggested that the 6q25 locus is involved in leprosy of both the paucibacillary and multibacillary types.
Using a positional cloning strategy in 197 Vietnamese leprosy simplex families, Mira et al. (2004) found significant associations between leprosy and 17 markers in the 5-prime regulatory region shared by PARK2 (602544) and PACRG (608427). Possession of 2 or more of the 17 risk alleles was highly predictive of leprosy, particularly the SNP markers denoted PARK2_e01(-2599) and rs1040079, with P values calculated using genomic controls (Devlin and Roeder, 1999). Mira et al. (2004) confirmed these results in 587 Brazilian leprosy cases and 388 unaffected controls. RT-PCR analysis detected wide expression of both PARK2 and PACRG in tissues, including immune tissues, and suggested that, in addition to the common bidirectional promoter, gene-specific transcriptional activators may be involved in regulating cell- and tissue-specific gene expression. In addition, PARK2, and to a lesser extent, PACRG, were found to be expressed in Schwann cells and macrophages, the primary host cells of Mycobacterium leprae, the causative agent of leprosy. Mira et al. (2004) noted that both genes are linked to the ubiquitin-mediated proteolysis system, which heretofore has received little attention in the study of leprosy pathogenesis and the control of M. leprae in the human host.
Malhotra et al. (2006) studied an ethnically homogeneous population of Indian leprosy patients and controls for associations with SNPs in the common regulatory region of PARK2 and PACRG. After Bonferroni corrections, they found no significant associations, in contrast with the findings in Vietnamese and Brazilian populations reported by Mira et al. (2004). Malhotra et al. (2006) concluded that risks associated with these SNPs vary in different populations.
Using multivariate analysis, Alter et al. (2013) replicated the findings of Mira et al. (2004) showing a susceptibility locus in the shared PARK2 and PACRG promoter region in a Vietnamese population. They also found that 2 of the SNPs, rs1333955 and rs2023004, were associated with susceptibility to leprosy in a northern Indian population. The populations varied in terms of linkage disequilibrium, possibly explaining differences in univariate analysis between the 2 populations. There was also a stronger association in younger patients in the 2 populations.
Alter, A., Fava, V. M., Huong, N. T., Singh, M., Orlova, M., Thuc, N. V., Katoch, K., Thai, V. H., Ba, N. N., Abel, L., Mehra, N. Alcais, A., Schurr, E. Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy. Hum. Genet. 132: 107-116, 2013. [PubMed: 23052943] [Full Text: https://doi.org/10.1007/s00439-012-1227-6]
Devlin, B., Roeder, K. Genomic control for association studies. Biometrics 55: 997-1004, 1999. [PubMed: 11315092] [Full Text: https://doi.org/10.1111/j.0006-341x.1999.00997.x]
Malhotra, D., Darvishi, K., Lohra, M., Kumar, H., Grover, C., Sood, S., Reddy, B. S. N., Bamezai, R. N. K. Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Europ. J. Hum. Genet. 14: 438-442, 2006. [PubMed: 16391553] [Full Text: https://doi.org/10.1038/sj.ejhg.5201563]
Mira, M. T., Alcais, A., Thuc, N. V., Moraes, M. O., Di Flumeri, C., Thai, V. H., Phuong, M. C., Huong, N. T., Ba, N. N., Khoa, P. X., Sarno, E. N., Alter, A., and 11 others. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427: 636-640, 2004. [PubMed: 14737177] [Full Text: https://doi.org/10.1038/nature02326]
Mira, M. T., Alcais, A., Van Thuc, N., Thai, V. H., Huong, N. T., Ba, N. N., Verner, A., Hudson, T. J., Abel, L., Schurr, E. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nature Genet. 33: 412-415, 2003. [PubMed: 12577057] [Full Text: https://doi.org/10.1038/ng1096]
Siddiqui, M. R., Meisner, S., Tosh, K., Balakrishnan, K., Ghei, S., Fisher, S. E., Golding, M., Narayan, N. P. S., Sitaraman, T., Sengupta, U., Pitchappan, R., Hill, A. V. S. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nature Genet. 27: 439-441, 2001. [PubMed: 11279529] [Full Text: https://doi.org/10.1038/86958]