RESUMO
In recent years, genome wide association studies have discovered a large number of gene loci that play a functional role in innate and adaptive immune pathways associated with leprosy susceptibility. The immunological control of intracellular bacteria M. leprae is modulated by NOD2-mediated signaling of Th1 responses. In this study, we investigated 211 clinically classified leprosy patients and 230 ethnically matched controls in Indian population by genotyping four variants in NOD2 (rs9302752A/G), LRRK2 (rs1873613A/G), RIPK2 (rs40457A/G and rs42490G/A). The LRRK2 locus is associated with leprosy outcome. The LRRK2 rs1873613A minor allele and respective rs1873613AA genotypes were significantly associated with an increased risk whereas the LRRK2 rs1873613G major allele and rs1873613GG genotypes confer protection in paucibacillary and leprosy patients. The reconstructed GA haplotypes from RIPK2 rs40457A/G and rs42490G/A variants was observed to contribute towards increased risk whereas haplotypes AA was observed to confer protective role. Our results indicate that a possible shared mechanisms underlying the development of these two clinical forms of the disease as hypothesized. Our findings confirm and validates the role of gene variants involved in NOD2-mediated signalling pathways that play a role in immunological control of intracellular bacteria M. leprae.
Assuntos
Predisposição Genética para Doença , Hanseníase/genética , Mycobacterium leprae , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Serina-Treonina Quinases/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Transdução de Sinais/genética , Alelos , Feminino , Haplótipos/genética , Haplótipos/imunologia , Humanos , Índia/epidemiologia , Hanseníase/epidemiologia , Hanseníase/imunologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Proteína Adaptadora de Sinalização NOD2/imunologia , Polimorfismo Genético/genética , Polimorfismo Genético/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/imunologia , Transdução de Sinais/imunologia , Células Th1/imunologiaRESUMO
The heterodimeric transporter associated with antigen processing (TAP) gene loci is known to play a vital role in immune surveillance. We investigated a possible association of gene polymorphisms both in TAP1 and TAP2 in a cohort of clinically classified leprosy patients (n=222) and in ethnically matched controls (n=223). The TAP1 and TAP2 genes were genotyped for four single nucleotide polymorphisms TAP1 (rs1057141 Iso333Val and rs1135216 Asp637Gly) and TAP2 (rs2228396 Ala565Thr and rs241447 Ala665Thr) by direct sequencing and ARMS-PCR. The minor allele of TAP1 637G contributes to an increased risk to leprosy compared to controls (OR: 1.68, 95% CI 1.2-2.36, P=0.0057). An increased risk for the variant minor allele of the TAP1 637G to multibacillary (BL+LL) or paucibacillary (BT+TT) infections was also observed [multibacillary vs. controls (OR: 1.56, 95% CI 1.07-2.28, P=0.054); paucibacillary vs. controls (OR: 1.92, 95% CI 1.21-3.01, P=0.013)]. In the dominant model, the genotypes of the TAP1 rs1135216AG+GG additionally contributed to an increased risk. Overall our findings demonstrate that the TAP1 gene variant (rs1135216 Asp637Gly) influences the susceptibility to clinically classified leprosy patients in Indian population.