HLA-B*13:01 and the dapsone hypersensitivity syndrome.

BACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome. METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls. RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans. CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).

IL-10 promoter SNPs and susceptibility to leprosy in ethnic groups from southwest China.

The purpose of this study was to determine whether interleukin-10 (IL-10) promoter polymorphisms are associated with leprosy or their subtypes in ethnic groups from southwest China. Genotyping using TaqMan® SNP Genotyping Master Mix and ABI 7500 real-time PCR system was performed for IL-10 T3575A, G2849A, C2763A, A1082G, C819T, and C592A in 189 healthy controls (40 ± 18 years) and 193 patients (46 ± 18 years) with leprosy [multibacillary, N = 131; paucibacillary (PB), N = 62]. The allelic frequencies of -2763C (97.9 vs 94.0%, P = 0.0074) and -1082A (92.8 vs 88.6%, P = 0.0452) in leprosy patients were significantly higher than in control subjects. The genetic frequency of -2763CC and -1082AA was not only significantly higher among leprosy patients than among control subjects [odds ratio (OR) = 3.33, 95% confidence interval (95%CI) = 1.39-7.99, P = 0.0071 and OR = 1.76, 95%CI = 1.02-3.03, P = 0.0420, respectively] but also significantly higher among PB patients than among control subjects (OR = 2.46, 95%CI = 1.22-4.96, P = 0.0115 and OR = 5.58, 95%CI = 2.06-15.12, P = 0.0007, respectively). The frequency of IL-10 haplotype 3575A/2849G/2763A/1082G/819C/592C was significantly higher among leprosy patients (OR = 5.57, 95%CI = 1.13-27.52, P = 0.0351) and PB patients (OR = 10.5, 95%CI = 1.36- 81.05, P = 0.0241) than among control subjects. IL-10 promoter -2763C/CC,-1082A/AA and haplotype 3575A/2849G/2763A/1082 G/819C/592C are associated with susceptibility to leprosy and the PB subtype in southwest China.

An epidemiological analysis of leprosy from 1951-1996 in Sichuan.

Through the leprosy surveillance system established in 1990s the authors analysed the epidemiology of leprosy in Sichuan province from 1951 to 1996. By the end of 1996, the total number of registered cases was 32,772, the peak incidence rate (2.44/100,000) was in 1958. The annual average progressively decreasing speed (AAPDS) of the number of new cases, incidence rate, incidence rate among children, number of newly detected patients, detection rate, number of registered cases and registered prevalence rates were 4.7% (xg = 0.9534), 5.9% (xg = 0.9407), 7.4% (xg = 0.9263), 6.7% (xg = 0.9326), 8.1% (xg = 0.9195), 10.9% (xg = 0.8913) and 11.7% (xg = 0.8828) respectively. Among newly detected cases, the proportion of children gradually declined with an AAPDS of 2.9% (xg = 0.9712), but that of household contacts gradually increased, showing a gradual decline of source of infection. The multibacillary (MB) rate among new cases, newly registered cases and active cases also increased gradually. The MB rate among child cases was much lower than that among adults. The disability rates among newly registered cases tended to decline. The peak incidence was in the 20 to 35 years age group, the average age at onset being 31.92 years. Average age at onset gradually increased to 34.19 during 1991-1995. The average interval between onset of symptoms and diagnosis was 4.89 years and that had reduced gradually to 3.24 years during 1991-1995. The authors conclude that: (1) the epidemiological trend of leprosy in Sichuan province shows decline; (2) the case-finding activities have improved and intensified; but (3) the disability rate among newly detected cases is still high (> 20%) and the average delay in diagnosis is still too long, showing that early case finding is still not satisfactory.