Human leukocyte antigen Class II alleles associated with acral lentiginous melanoma in Mexican Mestizo patients: A case-control study.

Background Melanoma is an aggressive cutaneous cancer. Acral lentiginous melanoma is a melanoma subtype arising on palms, soles, and nail-units. The incidence, prevalence and prognosis differ among populations. The link between expression of major histocompatibility complex Class II alleles and melanoma progression is known. However, available studies report variable results regarding the association of melanoma with specific HLA Class II loci. Aims The aim of the study was to determine HLA Class II allele frequencies in acral lentiginous melanoma patients and healthy Mexican Mestizo individuals. Methods Eighteen patients with acral lentiginous melanoma and 99 healthy controls were recruited. HLA Class II typing was performed based on the sequence-specific oligonucleotide method. Results Three alleles were associated with increased susceptibility to develop acral lentiginous melanoma, namely: HLA-DRB1*13:01; pC = 0.02, odds ratio = 6.1, IC95% = 1.4-25.5, HLA-DQA1*01:03; pC = 0.001, odds ratio = 9.3, IC95% = 2.7-31.3 and HLA-DQB1*02:02; pC = 0.01, odds ratio = 3.7, IC95% = 1.4-10.3. Limitations The small sample size was a major limitation, although it included all acral lentiginous melanoma patients seen at the dermatology department of Dr. Manuel Gea González General Hospital during the study period. Conclusion HLA-DRB1*13:01, HLA-DQB1*02:02 and HLA-DQA*01:03 alleles are associated with increased susceptibility to develop acral lentiginous melanoma in Mexican Mestizo patients.

Association between NDO-LID and PGL-1 for leprosy and class I and II human leukocyte antigen alleles in an indigenous community in Southwest Amazon

The frequencies of the Human leukocyte antigen (HLA) alleles in the Puyanawa indigenous reserve population and their association with the NDO-LID and ELISA PGL-1 rapid serological test was assessed. This was a cross-sectional study with an epidemiological clinical design conducted in two indigenous communities in the state of Acre, Brazil. Blood was collected in a tube with EDTA to identify HLA alleles and perform serological tests. DNA was obtained using the salting out procedure. The LabType™ technique (One-Lambda-USA) was used for HLA class I (loci A*, B* and C*) and II (loci DRB1*, DQA1* and DQB1*) typing. Allele frequency was obtained by direct count, and the chi-square test was used to assess the association with the NDO-LID and PGL-1 tests. The most frequent alleles in the two communities were: HLA-A*02:01, HLA-B*40:02, HLA-DRB1*16:02, HLA-DQA1*05:05 and HLA-DQB1*03:01. The allele HLA-C*04:01 was the most common in the Barão community, and the allele HLA-C*07:01 in Ipiranga. Among individuals who presented seropositivity to the NDO-LID test, the association with alleles HLA-A*02 (43.18% vs 24.8%, p = 0.03, OR = 2.35) and HLA-B*53 (6.83% vs 0.0%, p = 0.03, OR = 8.95) was observed in the Barão community. HLA-B*15 was associated with non-seroconversion to the NDO-LID test in Ipiranga. In both communities, HLA-B*40 and HLA-C*03 were associated with positive serological response to ELISA PGL-1. The HLA class I and II alleles most frequently found in this study have already been described among Terena indigenous groups, and HLA class I contributes to seroconversion to NDO-LID and PGL-1 tests in inhabitants of the Barão and Ipiranga communities(AU).

Association between NDO-LID and PGL-1 for leprosy and class I and II human leukocyte antigen alleles in an indigenous community in Southwest Amazon.

The frequencies of the Human leukocyte antigen (HLA) alleles in the Puyanawa indigenous reserve population and their association with the NDO-LID and ELISA PGL-1 rapid serological test was assessed. This was a cross-sectional study with an epidemiological clinical design conducted in two indigenous communities in the state of Acre, Brazil. Blood was collected in a tube with EDTA to identify HLA alleles and perform serological tests. DNA was obtained using the salting out procedure. The LabType™ technique (One-Lambda-USA) was used for HLA class I (loci A*, B* and C*) and II (loci DRB1*, DQA1* and DQB1*) typing. Allele frequency was obtained by direct count, and the chi-square test was used to assess the association with the NDO-LID and PGL-1 tests. The most frequent alleles in the two communities were: HLA-A*02:01, HLA-B*40:02, HLA-DRB1*16:02, HLA-DQA1*05:05 and HLA-DQB1*03:01. The allele HLA-C*04:01 was the most common in the Barão community, and the allele HLA-C*07:01 in Ipiranga. Among individuals who presented seropositivity to the NDO-LID test, the association with alleles HLA-A*02 (43.18% vs 24.8%, p=0.03, OR=2.35) and HLA-B*53 (6.83% vs 0.0%, p=0.03, OR=8.95) was observed in the Barão community. HLA-B*15 was associated with non-seroconversion to the NDO-LID test in Ipiranga. In both communities, HLA-B*40 and HLA-C*03 were associated with positive serological response to ELISA PGL-1. The HLA class I and II alleles most frequently found in this study have already been described among Terena indigenous groups, and HLA class I contributes to seroconversion to NDO-LID and PGL-1 tests in inhabitants of the Barão and Ipiranga communities.

Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans.

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today.

Association between human leukocyte antigen-DRB1 and human leukocyte antigen-DQB1 alleles and pemphigus vulgaris in Indian patients: A case-control study.

BACKGROUND: HLA-DRB1*04, -DRB1*08, -DRB1*14, -DQB1*03 and -DQB1*05 are reported to have significant association with pemphigus vulgaris; however, this is partially dependent on ethnicity. This study was done to determine the HLA-DR and -DQ types prevalent in Indian patients with pemphigus vulgaris. METHODS: A prospective case-control study was done for a period of 9 months in Christian Medical College Vellore, India. HLA typing was done by PCR-SSOP method in 50 cases and 50 healthy controls. Allele frequencies in cases and controls were compared and odds ratios with 95% confidence interval were calculated. RESULTS: The mean age of the patients (29 females, 21 males) and that of controls (36 males, 14 females) were 41.3 ± 13.65 and 35.42 ± 11.09 years, respectively. HLA-DRB1*14 was present in 47 patients and 18 controls (OR, 27.85; 95% CI, 7.57-102.42) and HLA-DQB1*05 was seen in 47 patients and 24 controls (OR, 16.97; 95% CI, 4.66-61.80). The haplotype DRB1*14, DQB1*05 was present in 44 patients and 14 controls (OR, 18.86; 95% CI, 6.58-54.05). DRB1*15 was present in 7 cases and 16 controls (OR, 0.35; 95% CI, 0.13-0.94) and DQB1*06 was present in 8 cases and 19 controls (OR, 0.31; 95% CI, 0.12-0.80). HLA-DQB1*03 was associated with significantly higher pemphigus disease area index scores. LIMITATIONS: The main limitations were that the numbers studied were small as the study was conducted at a single center, and the haplotype analysis was limited only to the proband. PDAI scores could have been influenced by prior treatment. CONCLUSION: There was a significant association between HLA-DRB1*14 and HLA-DQB1*05 and pemphigus vulgaris in our patients. A negative association was seen with DRB1*15 and DQB1*06.

Amino Acid Variants of HLA-DRB1 Confer Susceptibility to Dapsone Hypersensitivity Syndrome in Addition to HLA-B*13:01.

Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in multidrug therapy for leprosy. HLA-B*13:01 has been identified as a strong risk factor of dapsone hypersensitivity syndrome; however, its low positive predictive value indicated that additional genetic variants may be involved in the disease development. To discover contributing genetic variants within HLA loci in addition to HLA-B*13:01, we performed a high-coverage next-generation sequencing (NGS)-based HLA typing analysis in 103 dapsone-hypersensitive and 857 dapsone-tolerant HLA-B*13:01-positive leprosy patients in a Chinese population. Five amino acid variants in high linkage disequilibrium of HLA-DRB1 were significantly associated with dapsone hypersensitivity syndrome (positions 133, 142, -17, 11, and 13). DRB1*16:02 and DRB1*15:01 tagged by these risk-conferring amino acid residues were associated at a nominal significance level. This study identifies five amino acid variants within HLA-DRB1 that are in high linkage disequilibrium and significantly associated with dapsone hypersensitivity syndrome in a Chinese population.

Association analysis of human leukocyte antigen class II (DRB1) alleles with leprosy in individuals from São Luís, state of Maranhão, Brazil

Epidemiological studies have demonstrated that the variability of the clinical response to infection caused by Mycobacterium leprae is associated with host genetic factors. The present study investigated the frequency of human leukocyte antigen (HLA) class II (DRB1) alleles in patients with leprosy from São Luís, Maranhão, Brazil. A case-control study was performed in 85 individuals with leprosy and 85 healthy subjects. All samples were analysed via polymerase chain reaction-sequence specific oligonucleotide probes. The HLA-DRB1*16 allele showed a higher frequency in the group with leprosy [(9.41% vs. 4.12%) odds ratio (OR) = 2.41 95% confidence interval (CI) (0.96-6.08) p = 0.05], whereas the HLA-DRB1*11 allele was less frequent in the group with leprosy [(6.47% vs. 11.76%) OR = 0.51 95% CI (0.23-1.12) p = 0.09]. The frequency of HLA-DRB1* alleles between the control group and leprosy patient subgroups presenting different forms of the disease showed that the HLA-DRB1*16 (16.13% vs. 8.24%, OR = 4.10, CI = 1.27-13.27, p = 0.010) and HLA-DRB1*14 (5% vs. 3.53%, OR = 4.63, CI = 1.00-21.08, p = 0.032) alleles were significantly more frequent in patients with different clinical subtypes of leprosy. The sample size was a limitation in this study. Nevertheless, the results demonstrated the existence of a genetic susceptibility associated with the clinical forms of leprosy. The low frequency of the HLA-DRB1*11 allele should be further studied to investigate the possible protective effect of this allele.

Association analysis of human leukocyte antigen class II (DRB1) alleles with leprosy in individuals from São Luís, state of Maranhão, Brazil.

Epidemiological studies have demonstrated that the variability of the clinical response to infection caused by Mycobacterium leprae is associated with host genetic factors. The present study investigated the frequency of human leukocyte antigen (HLA) class II (DRB1) alleles in patients with leprosy from São Luís, Maranhão, Brazil. A case-control study was performed in 85 individuals with leprosy and 85 healthy subjects. All samples were analysed via polymerase chain reaction-sequence specific oligonucleotide probes. The HLA-DRB1*16 allele showed a higher frequency in the group with leprosy [(9.41% vs. 4.12%) odds ratio (OR) = 2.41 95% confidence interval (CI) (0.96-6.08) p = 0.05], whereas the HLA-DRB1*11 allele was less frequent in the group with leprosy [(6.47% vs. 11.76%) OR = 0.51 95% CI (0.23-1.12) p = 0.09]. The frequency of HLA-DRB1* alleles between the control group and leprosy patient subgroups presenting different forms of the disease showed that the HLA-DRB1*16 (16.13% vs. 8.24%, OR = 4.10, CI = 1.27-13.27, p = 0.010) and HLA-DRB1*14 (5% vs. 3.53%, OR = 4.63, CI = 1.00-21.08, p = 0.032) alleles were significantly more frequent in patients with different clinical subtypes of leprosy. The sample size was a limitation in this study. Nevertheless, the results demonstrated the existence of a genetic susceptibility associated with the clinical forms of leprosy. The low frequency of the HLA-DRB1*11 allele should be further studied to investigate the possible protective effect of this allele.

Lsr2 peptides of Mycobacterium leprae show hierarchical responses in lymphoproliferative assays, with selective recognition by patients with anergic lepromatous leprosy.

Lsr2 protein of Mycobacterium leprae was shown earlier to elicit B and T cell responses in leprosy patients (20, 28). Lymphoproliferation to M. leprae and Lsr2 antigens was observed in >70% of tuberculoid (T) patients and in 16 and 34% of lepromatous (L) patients, respectively. We focused on the M. leprae nonresponders in the lepromatous group using 22 synthetic Lsr2 peptides (end-to-end peptides A to F and overlapping peptides p1 to p16) in in vitro T cell responses. A total of 125 leprosy and 13 tuberculosis patients and 19 healthy controls from the area of endemicity (here, healthy controls, or HC) were investigated. The highest responses were observed (67 to 100%) in HC for all peptides except p1 to p3, and the lowest was observed in tuberculosis patients. Significant differences in lymphoproliferation were observed in T, L, and HC groups (analysis of variance [ANOVA], P = 0.000 to 0.015) for all end-to-end peptides except B and for p5 and p7 to p10. Hierarchical recognition between lepromatous and tuberculoid leprosy was noted for p8 (P < 0.05) and between the HC and L groups for p7 to p10, p15, and p16 (P < 0.005 to P < 0.02). Significant lymphoproliferation was observed to peptides A to F and p1 to p9, p11, p12, p15, p16 (P = 0.000 to 0.001) with 40% responding to peptides C and p16 in L patients. Lepromatous patients also showed significantly higher levels of a gamma interferon (IFN-γ) response to peptide C than to other peptides (P < 0.05). Major histocompatibility complex (MHC) class II bias for peptide recognition was not observed. These studies indicate that Lsr2 has multiple T cell epitopes that induce in vitro T cell responses in the highly infective lepromatous leprosy patients.

Distribution of the HLA class II frequency alleles in patients with leprosy from the mid-west of Brazil.

In an attempt to clarify the issue of genetic predisposition to leprosy, we examined the distribution of class II human leucocyte antigen variants (DR and DQ) in 70 patients from around the city of Goiânia, Brazil. Only two of the patients presented the tuberculoid form of the disease, whereas 17 fell into the lepromatous category; 51 were intermediate. The allele frequencies found were compared with those in a group of 77 healthy controls. We found an increased frequency of the HLA-DRB1*11 allele in patients with lepromatous leprosy compared with healthy controls (P=0.0132; RR=4.130, 95% Cl: 1.338 to 12.747). These results suggest that the DRB1*11 allele could be related with susceptibility to lepromatous leprosy in Brazil.

Leprosy and the adaptation of human toll-like receptor 1.

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.

Association of HLA-DRB1*0405 with resistance to multibacillary leprosy in Taiwanese.

Host factors play an important role in determining the immune response and development of leprosy. The human leukocyte antigen system (HLA) has repeatedly been found to be associated with the pathogenesis of leprosy. This study analyzes the polymorphism of the HLA class I and II antigens in multibacillary leprosy patients and a healthy control group to provide predictable prognostic indicators and/or a differential diagnostic for the disease. Sixty-5 multibacillary leprosy patients from Lo-Sheng Leprosarium and 190 healthy Taiwanese were used as cases and controls, respectively. A serologic method was initially used for HLA-A and HLA-B antigen determination, and sequence-based typing was later applied for HLA-DRB1 allele typing. Although no significant associations were found with HLA-A or HLA-B antigens, this study shows a strong HLA-DRB1*0405 association with resistance to multibacillary leprosy, supporting results previously reported in the literatures.

Mycobacterial ESAT-6 and katG are recognized by sarcoidosis CD4+ T cells when presented by the American sarcoidosis susceptibility allele, DRB1*1101.

INTRODUCTION: Genetic associations of American sarcoidosis susceptibility implicate MHC class II allele, DRB1*1101. We previously reported immune recognition of Mycobacterium peptides from peripheral cells of 26 sarcoidosis subjects, 24 PPD- healthy volunteers, and eight with latent tuberculosis infection. MATERIALS AND METHODS: In order to further link these genetic and immunologic pillars of sarcoidosis pathogenesis, we performed flow cytometry on these same subjects to identify the cells responsible for immune responses to ESAT-6 and katG peptides, followed by HLA typing to determine allelic associations with recognition. DISCUSSION AND CONCLUSION: Sarcoidosis CD4+ T cells were primarily responsible for the systemic responses. Recognition was inhibited by monoclonal antibody against HLA-DR and HLA-DQ, but not HLA-DP. Immune recognition of ESAT-6 peptide NNALQNLARTISEAG was associated with possession of DRB1*1101. ESAT-6 and katG presented by antigen-presenting cells expressing DRB1*1101-induced Th-1 responses from sarcoidosis T cells, thus providing a mechanistic insight for the association of HLA DRB1*1101 with sarcoidosis, and sarcoidosis T cell interaction with microbial antigens.

Alelos HLA-DRB1 en pacientes infectados con patógenos intracelulares en Rosario, Santa Fe / HLA-DRB1 alleles in patients infected with intracellular pathogens in Rosario, Santa Fe

En el desarrollo de la respuesta inmune a patógenos intracelulares participa el elevado polimorfismo de las moléculas HLA de clase II. El objetivo de este trabajo fue establecer la participación de los alelos HLA-DRB1 en personas con infección con Trypanosoma cruzi (T. cruzi) o con Mycobacterium leprae (M. leprae). Se estudiaron 252 individuos de la ciudad de Rosario, divididos en: 86 personas seropositivas para T cruzi (sin compromiso cardiológico de relevancia), 85 pacientes con diagnóstico de Lepra y 81 individuos controles, sin evidencia de patologías. El ADN genómico fue extraído de sangre periférica utilizando el método de salting out y empleado como templado para amplificar por PCR el segundo exón polimórfico de HLA-DRB1. Los alelos fueron tipificados mediante la técnica de PCR­-SSOP. La comparación de frecuencias mostró prevalencia de los alelos DRB1 *0409 y DRB1 *1503 en los individuos seropositivos para T. cruzi con respecto al grupo control. Por otra parte, el análisis estadístico indicó una disminución significativa del alelo DRB1 *1103 en pacientes con esta tripanosomiasis. Al examinar las frecuencias observamos en el grupo de pacientes con Lepra un aumento significativo de los alelos DRB1 *1401 y DRB1 *1406. Además observamos que las proporciones de los alelos DRB1 *0808 y DRB1 *1103 en los enfermos son significativamente inferiores con respecto al grupo control. Los alelos HLA DRB1 podrían actuar solos o en combinación con otros genes para conferir susceptibilidad o resistencia a estas infecciones en la población de Rosario, Argentina.

In the development of the immune response to intracellular pathogens implicated the high polymorphism of HLA class II molecules. The aim of this study was to establish the involvement of the HLA-DRB1 alleles in infected subjects with T. cruzi or leprosy patients in Rosario, Argentina. We studied 252 individuals who divided into: 86 positive people for T. cruzi without cardiac damage, 85 patients diagnosed with leprosy and controls 81 individuals without evidence of disease. Genomic DNA was extracted from peripheral blood using the standard salting out method and used as a template to amplify by the PCR the polymorphic second exon of the HLA­-DRB1. PCR products were hybridized separately with sequence-specifics oligonucleotides (SSOP). Statistical analysis indicated that of increased frequencies of DRB1 *0409, and DRB1 *1503 in individuals with Chagas' disease. DRB1 *1103 allele was prevalence in the group control and could be associated with resistance to the presence of trypanosomiasis. DRB1 *1401 and DRB1 *1406 alleles were significantly more prevalent in leprosy patients, whereas a decreased frequency of DRB1 *0808 and DRB1 *1103 alleles was found, by comparison with the group control. The HLA-DRB1 alleles could act alone or in combination with other genes to confer differential susceptibility and also protection to these diseases in Rosario, Argentina.

Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population.

BACKGROUND: Human leukocyte antigens (HLAs) have been proposed to modulate the immune response to Mycobacterium leprae. The association of HLA-DRB1 with leprosy has been reported in several populations, but not in a Chinese population. METHODS: The polymerase chain reaction-sequence-specific oligonucleotide probe with Luminex100 (PCR-SSOP-Luminex) method was used to genotype HLA-DRB1 alleles in 305 leprosy patients and 527 healthy control individuals. RESULTS: The HLA-DRB1*15 allele was significantly more prevalent among leprosy patients than healthy controls, whereas the frequency of the HLA-DRB1*09 allele was lower among leprosy patients, especially those with early-onset disease. CONCLUSION: HLA-DRB1 alleles are associated with leprosy susceptibility in a Chinese population. The HLA-DRB1*09 allele was found to be protective exclusively in a subset of early-onset leprosy patients.

HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance.

BACKGROUND: Many epidemiological studies have shown that the genetic factors of the host play a role in the variability of clinical response to infection caused by M. leprae. With the purpose of identifying genes of susceptibility, the present study investigated the possible role of HLA-DRB1 and DQA1/DQB1 alleles in susceptibility to leprosy, and whether they account for the heterogeneity in immune responses observed following infection in a Southern Brazilian population. METHODS: One hundred and sixty-nine leprosy patients and 217 healthy controls were analyzed by polymerase chain reaction amplification and reverse hybridization with sequence-specific oligonucleotide probes and sequence-specific primers (One Lambda, CA, USA). RESULTS: There was a positive association of HLA-DRB1*16 (*1601 and *1602) with leprosy per se (7.3% vs. 3.2%, P = 0.01, OR = 2.52, CI = 1.26-5.01), in accord with previous serological studies, which showed DR2 as a marker of leprosy. Although, HLA-DQA1*05 frequency (29.8% vs. 20.9%, P = 0.0424, OR = 1.61, CI = 1.09-2.39) was higher in patients, and HLA-DQA1*02 (3.0% vs. 7.5%, P = 0.0392, OR = 0.39, CI = 0.16 - 0.95) and HLA-DQA1*04 (4.0% vs. 9.1%, P = 0.0314, OR = 0.42, CI = 0.19 - 0.93) frequencies lower, P-values were not significant after the Bonferroni's correction. Furthermore, HLA-DRB1*1601 (9.0% vs. 1.8%; P = 0.0016; OR = 5.81; CI = 2.05-16.46) was associated with susceptibility to borderline leprosy compared to control group, and while HLA-DRB1*08 (11.2% vs. 1.2%; P = 0.0037; OR = 12.00; CI = 1.51 - 95.12) was associated with susceptibility to lepromatous leprosy, when compared to tuberculoid leprosy, DRB1*04 was associated to protection. CONCLUSION: These data confirm the positive association of HLA-DR2 (DRB1*16) with leprosy per se, and the protector effect of DRB1*04 against lepromatous leprosy in Brazilian patients.

[Leprosy: a paradigm for the study of human genetic susceptibility to infectious diseases]. / La lèpre: un paradigme pour l'étude de la prédisposition génétique aux maladies infectieuses.

Fifty years ago, the first identification of a non Mendelian genetic contribution to the development of a common infectious disease, i.e. the association between malaria and sickle-cell trait, was shown using a supervised approach which tests a limited number of candidate genes selected by hypothesis. Since then, the few genes that were convincingly associated with susceptibility to human infectious diseases were identified following the same strategy. The study of leprosy has contributed to modifying this way of thinking. In the absence of a satisfying experimental model and because of the impossibility to grow the causative agent in vitro, the candidate gene approach has turned out to be of limited interest. Conversely, positional cloning led to the identification of two major genes involved in the control of the disease, establishing for the first time the oligogenic nature of a human genetic contribution to an infectious disease. It is likely that these major results obtained in leprosy and the recent burst of genomic tools will make the genome-wide screening (functional or positional) the main strategy of dissection of the genetic susceptibility to many common infectious diseases.

Association of leprosy with HLA-DRB1 in an Argentinean population.

BACKGROUND: Previous studies have suggested an influence of HLA molecules on the regulation of the anti Mycobacterium leprae immune response. METHODS: DNA typing of HLA-DRB1 alleles in 71 leprosy patients and 81 healthy controls was performed. Genomic DNA was extracted from peripheral blood and used as a template to amplify the polymorphic second exon of the HLA-DRB1 by the polymerase chain reaction (PCR). PCR products were hybridized separately with sequence-specific oligonucleotides. RESULTS: DRB1*1401 and DRB1*1406 alleles were significantly more prevalent in leprosy patients, whereas a decreased frequency of DRB1*0808 and DRB1*1103 alleles was found, by comparison with the group control. CONCLUSIONS: The HLA-DRB1 alleles could act alone or in combination with other genes to confer differential susceptibility and also protection to leprosy disease in endemic areas of the American continent.

HLA-DRB1*04 and DRB1*10 are associated with resistance and susceptibility, respectively, in Brazilian and Vietnamese leprosy patients.

The host genetic background has been considered one of the factors that influence leprosy outcome, a chronic infectious disease caused by Mycobacterium leprae. Genome scans demonstrated that the 6p21 region is associated with leprosy and a substantial number of population-based studies analyzing human leukocyte antigen (HLA) class II loci suggested association of HLA-DR with leprosy. However, some studies lacked robustness as they had limited power. Indeed, experimental designs require increased sample size to achieve adequate power, as well as replication studies with independent samples for confirmation of previous findings. In this work, we analyzed the influence of the HLA-DRB1 locus on leprosy susceptibility per se and disease type using a case-control design carried out in Brazilians (578 cases and 691 controls) and a replication study based on a family design in a Vietnamese population (n=194 families). The results showed that HLA-DRB1*10 is associated with susceptibility to leprosy and HLA-DRB1*04 is associated with resistance, both in the Brazilian and Vietnamese populations suggesting that these alleles play an important role in the activation of cellular immune responses against M. leprae.