Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population

Single nucleotide polymorphisms (SNPs) in the regulatory region shared by PARK2 and PACRG have been identified as major risk factors for leprosy susceptibility in two ethnically distinct

populations. We investigated the association of six SNPs present in this regulatory region with leprosy susceptibility in an Indian population. Genotyping was performed by direct PCR

sequencing in 286 leprosy patients and 350 healthy controls. Our results showed that T allele of SNPs PARK2_e01 (−2599) and 28 kb target_2_1 was significantly associated with susceptibility

to leprosy per se (P=0.03 and 0.03, respectively). The T allele of SNPs PARK2_e01 (−2599) showed a significant recessive effect (P=0.04) in susceptibility to leprosy in Indian population as

against the dominant effect of haplotype T-C of the major risk SNPs PARK2_e01 (−2599) and rs1040079 in Brazilian and Vietnamese population. However, after bonferroni corrections, these

significant differences disappeared. Haplotype analysis also showed a lack of significant association of any haplotype with cases or controls. The noninvolvement of major risk SNPs in the

regulatory region of PARK2 and PACRG locus with leprosy susceptibility in Indian population highlights the differential effect of these SNPs in regulating genetic susceptibility to leprosy

in different populations.

Leprosy or Hansen's disease is a chronic and debilitating disease that affects an estimated 700 000 people each year.1 Leprosy is characterized by a wide spectrum of clinical manifestations

that depends upon the host cell mediated immune response against the pathogen.2 At one pole, tuberculoid leprosy patients manifest a strong cellular immune response that results in a few

localized, often self healing paucibacillary lesions. At the other end, lepromatous leprosy patients exhibit poor cell mediated immunity against Mycobacterium leprae antigens leading to a

disseminated disease involving extended multibacillary lesions of skin and nerves. Evidence from segregation and twin studies suggest the existence of a strong genetic component for

susceptibility to leprosy in human populations.3, 4 Numerous case control studies have identified variants in VDR, HLADR2 specificities, TAP1 and TAP2, CTLA4, COL3A, SLC11A1 (also called

NRAMP1) and TNF-α to be associated with leprosy or its subtypes.5 These associations reflect differential susceptibility to this polygenic disease in different populations. Genome wide

linkage scans so far have led to the identification of a chromosomal region 10p13, for loci controlling susceptibility to the PB form of leprosy6 and a chromosomal region 6q25–26 harboring

variants in the common regulatory region of PARK2 and PACRG genes as risk factors for susceptibility to leprosy per se.7 PARK2, a ubiquitination E3 ligase involved in delivery of

polyubiquitinated proteins to the proteasomal complex, as yet has an undefined role in leprosy pathogenesis. The function of PACRG in leprosy pathogenesis is unknown but also has been linked

to the ubiquitin–proteasome system.8, 9

India carries the majority of the global burden of leprosy. It was, therefore, pertinent to investigate whether the SNPs, implicated previously as major risk alleles, were also associated

with susceptibility to leprosy in an Indian population group.

In order to identify the possible association of PARK2 and PACRG regulatory region SNPs with susceptibility to leprosy per se, or with different clinical forms of the disease, we compared

leprosy patients to controls, and also compared PB and MB leprosy patients with controls. Power calculations carried out using PS software (www.biostat.mc.vanderbilit.edu/twiki/bin/view)

showed that our sample size of 286 patients and 350 controls had more than 75% (P0.10. Table 1 depicts the genotype distribution and allele frequency observed for the SNPs studied. Since the

minor allele frequency of the SNP rs1893450 was