Leprosy is a chronic infectious disease caused by Mycobacterium leprae, affecting both the skin and peripheral nerves. It has long been thought that the host genetics has an important role in the development of leprosy.1 Markers in several genes and genomic regions have been reported to be associated with or linked to susceptibility to leprosy, in which the 80-kb block region of PARK2 and PACRG was reported to be as a major risk locus for leprosy susceptibility in Vietnamese and Brazil.2 Although there is lack of association between polymorphisms of the PARK2 and PACRG genes and leprosy susceptibility in Indian population,3 which showed the differential effect of these SNPs in regulating genetic susceptibility to leprosy in different populations.
In 2009, we performed the first Genome-Wide Association Study of leprosy using Illumina Human610-Quad BeadChip (San Diego, CA, USA) and identified six host genetic risk factors with genome-wide significant evidence and an additional risk factor with suggestive evidence.4 And no promising SNPs were observed in the 80-kb shared locus of PARK2 and PACRG. But the pathway analysis showed variants of PARK2 and LRRK2 (a suggestive susceptibility locus of leprosy) interact directly, which suggest there may be a suggestive association of PARK2 with leprosy in Chinese population.
Owing to inadequate coverage of Human610-Quad BeadChip, we selected 13 SNPs associated with Vietnamese and Brazil population,2 and additional 2 SNPs according to allele frequency in Chinese population in the 80-kb block region of PARK2 and PARCG (all the 15 SNPs selected for replication, only 13 SNPs were designed in one panel). All samples were Chinese Han recruited from northern China (Shandong province) and matched regarding to age, gender and ethnicity. After informed consent, genotyping analyses of the 742 leprosy cases and 734 controls samples were conducted by using the Sequenom MassArray system (San Diego, CA, USA). In each replication sample, we excluded SNPs with a call rate <95%, low minor allele frequency (P<0.01) or deviation from Hardy–Weinberg equilibrium proportions (P<0.01) in the controls. Cochran–Armitage trend test was used to test the genotype–phenotype association in the validation study using Plink v 1.07 software. Power calculations, carried out using CaTS software (http://www.sph.umich.edu/csg/abecasis/CaTS/), showed that our sample size of 742 patients and 734 controls had >81% power to detect an odds ratio of 1.61 at a significance level of 0.1%, when the frequency of the allele of interest was >0.10.
Eleven previously indicated risk variants and other two SNPs (rs13195186 and rs1801474, MAF/Minor Allele count in Homo sapiens: G=0.447/538; T=0.1407/175, separately), which are all located in the region of PARK2 and PACRG, show no significant association with susceptibility to leprosy per se in the Chinese Population (Table 1).
Table 1. Association results between leprosy and the SNPs of the PARK2/PACRG region.
| SNP | Chromosome | Position | A1 | F-A | F-U | A2 | CHISQa | P | OR |
|---|---|---|---|---|---|---|---|---|---|
| rs10945859 | 6 | 163142602 | T | 0.37 | 0.35 | C | 1.89 | 0.17 | 1.11 |
| rs13195186 | 6 | 163159187 | G | 0.21 | 0.19 | A | 1.39 | 0.24 | 1.12 |
| rs2276201 | 6 | 163149497 | G | 0.19 | 0.17 | A | 1.37 | 0.24 | 1.12 |
| rs1801474 | 6 | 162622197 | A | 0.48 | 0.46 | G | 0.60 | 0.44 | 1.06 |
| rs9347684 | 6 | 163151824 | C | 0.49 | 0.50 | T | 0.35 | 0.55 | 0.96 |
| rs1040079 | 6 | 163214027 | C | 0.16 | 0.15 | T | 0.25 | 0.61 | 1.05 |
| rs4495257 | 6 | 163214110 | A | 0.16 | 0.15 | C | 0.23 | 0.63 | 1.05 |
| rs1514343 | 6 | 163213083 | T | 0.16 | 0.15 | C | 0.18 | 0.67 | 1.04 |
| rs2803104 | 6 | 163139180 | C | 0.31 | 0.31 | A | 0.04 | 0.84 | 0.98 |
| rs9356058 | 6 | 163151399 | C | 0.31 | 0.31 | T | 0.03 | 0.86 | 0.99 |
| rs6915128 | 6 | 163211789 | C | 0.33 | 0.34 | T | 0.02 | 0.88 | 0.99 |
| rs1333955 | 6 | 163213454 | A | 0.33 | 0.33 | G | 0.02 | 0.90 | 0.99 |
| rs6939278 | 6 | 163152600 | A | 0.31 | 0.31 | C | 0.01 | 0.95 | 1.00 |
Abbreviations: OR, odds ratio; SNP, single-nucleotide polymorphism.
χ2-test.
In summary, we confirmed that Chinese population as well as Indian population3 show no remarkable association with the risk SNPs within the region of PARK2 and PACRG with leprosy per se, which gave the general consideration that there may be a suggestive association of these SNPs with the ethnic heterogeneity of leprosy susceptibility. Furthermore, it was valuable to research more ethnic lines to conform the consideration in future.
Acknowledgments
We thank all the individuals who participated in this project. This work was funded by grants from the National Natural Science Foundation of China (81071288, 81072391) and Project of Taishan scholar (2008–), Project of Medical leading scholar of Shandong Province (2010–). Project of Research Foundation of Shandong Provincial Institute of Dermatology and Venereology (2008–2007), and the Shandong Provincial Leprosy Control Special Financial Support (2007).
The authors declare no conflict of interest.
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