A pleiotropic effect of the APOE gene: association of APOE polymorphisms with multibacillary leprosy in Han Chinese from Southwest China.

BACKGROUND: Patients with leprosy have a very low risk of Alzheimer disease (AD) and ß-amyloid (Aß) deposition is significantly lower in the brain tissue of elderly patients with leprosy compared with age-matched controls. Apolipoprotein E (ApoE) plays a critical role in lipid metabolic pathways and in the brain, facilitating the proteolytic clearance of Aß. We hypothesized that APOE confers risk of leprosy as lipid metabolism is involved in Mycobacterium leprae infection. OBJECTIVES: To investigate the potential genetic associations between APOE and leprosy in two independent Chinese case-control cohorts from the Yuxi and Wenshan prefectures, Yunnan Province of Southwest China. METHODS: Five APOE single-nucleotide polymorphisms (SNPs) were analysed in 1110 individuals (527 patients and 583 controls) from the Yuxi prefecture using a SNaPshot assay. Genetic variations in the entire APOE exons were screened in 1788 individuals (798 patients and 990 controls) from the Wenshan prefecture using next-generation sequencing technology. RESULTS: The AD-associated SNPs rs405509 and rs439401 increased the risk of leprosy per se and multibacillary leprosy (P < 0·005), but the APOE-ε4 allele did not. The SNPs rs405509 and rs439401 were cis expression quantitative trait loci (eQTL) for APOE expression in human skin. Differential APOE mRNA expression was observed in skin lesions of patients with type I reaction leprosy and those with multibacillary leprosy. APOE and related lipid genes are involved in an interaction network with leprosy susceptibility genes. CONCLUSIONS: The APOE gene is associated with leprosy, most likely by regulating lipid-metabolism-related genes.

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.).

Skin test responsiveness to a series of new tuberculins of children living in three Vietnamese cities.

A skin test survey was conducted among 1035 children aged 7-19 years living in three cities in Vietnam. Fifteen new tuberculins, including leprosin-A, were applied; an induration of 2 mm diameter or more was considered positive. Compared to some other tropical countries, low levels of sensitisation were recorded and remarkable regional differences were found. Positivity to any tuberculins (pooled data) among non-BCG-vaccinated children was significantly lower in Hanoi (13.1%) and HoChiMinh-City [HCMC] (15.5%) than in Nha Trang (25.7%) [p = 0.001 and p = 0.012, respectively]. The proportion of non-vaccinated children responding to Tuberculin ranged from 18.4% in Hanoi to 54.5% in Nha Trang. Leprosin-A elicited a response in 14.9% of the children in Nha Trang, but in very few of those in Hanoi (4.3%) or HCMC (3.0%). Thus, of the three cities studied, significant sensitisation to both M. tuberculosis and M. leprae was demonstrable only in Nha Trang. In Hanoi most of the response was to fast-growing species whilst in HCMC and Nha Trang it was mainly to slow-growing species. These results may account in part for the observed differences in the prevalence of tuberculosis and leprosy between the north and the south of Vietnam.

Responses to Mycobacterium leprae by lymphocytes from new and old leprosy patients: role of exogenous lymphokines.

Lepromatous leprosy patients generally have reduced response to Mycobacterium leprae antigens in an in vitro lymphocyte transformation test, which could be due to insufficient generation of reactions or to active suppression of any reaction generated. We could detect 3 types of lack of reactivity: one which could be restored by the addition of supernatants from healthy, PHA-stimulated lymphocyte cultures, one which could not thus be restored and one in which the culture supernatant contained factors able to suppress mitogen responses of healthy cells. We compared responses of cells from untreated patients, patients treated for 12-20 months with multiple drug therapy and patients with up to 20 years of dapsone treatment; all types of the disease were represented. Untreated patients of all types had low responses which were not always reconstituted by lymphokine-rich supernatants, but they did not produce the non-specific soluble suppressive factors. In most cases, including BL/LL types, after the initial months of treatment, antigen response improved and was further increased by the addition of supernatants containing lymphokines. Most of the long-term-treated, stable patients had a lymphokine-reconstitutable antigen response, and in most cases also produced non-specific suppressive factor(s). The question as to why leprosy patients do not respond to M. leprae antigen is a complex one; our results suggest that it is related to the activity of the infection in each group of patients.