Differential HLA class I and class II associations in pemphigus foliaceus and pemphigus vulgaris patients from a prevalent Southeastern Brazilian region.

Genetic factors, particularly those concerning HLA class II, have been associated with the pathogenesis of pemphigus. Taking advantage of an area where pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are prevalent in the northeastern region of the state of São Paulo, Southeastern Brazil, we have studied the HLA class I (A, B and C) and class II (DRB1 and DQA1/DQB1) profiles in 86 and 83 patients with PF and PV, respectively, as compared with 1592 controls from the same region. Among all the HLA alleles described herein, the more prevalent susceptibility alleles for PF were HLA-A*11, 33, -B*14; -DRB1*01:01, *01:02; -DQA1*01:02; and -DQB1*05:01. In PV patients, the HLA-B*38; -C*12; -DRB1*04:02, *08:04, *14:01, *14:04; -DQA1*03:01; and -DQB1*03:02 and *05:03 alleles were associated with susceptibility. The HLA-DRB1*01:02 allele and the HLA-DRB1*01-DQA1*01-DQB1*05 haplotype in PF patients and the HLA-DRB1*04:02 and *14:01 alleles and the HLA-DRB1*14-DQA1*01-DQB1*05 haplotype in PV patients were related with the highest etiologic fraction values. Distinct genetic patterns and not yet described HLA susceptibility/protection alleles/haplotypes profiles have been observed in this series. Our findings corroborate the differential genetic markers in PF and PV in an area where pemphigus is prevalent but not yet reported.

Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample.

Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles.

INTRODUCTION: Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS: Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS: Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS: Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Family study of monozygotic twins affected by pemphigus vulgaris.

Rare are the family studies that include siblings affected by pemphigus vulgaris (PV) and in whom HLA class II alleles are related. HLA-DR and -DQ genotyping and profiling of antibodies against desmogleins (Dsg) 1 and Dsg3 were performed in ten members of a family including monozygotic twins affected by PV. The twin sisters were heterozygotes; they presented the haplotypes most commonly associated with increased susceptibility to PV (DRB1∗04:02-DQA1∗03:01-DQB1∗03:02 and DRB1∗14:04-DQA1∗01:01-DQB1∗05:03). Their parents and five siblings had only one or none of these two haplotypes in combination with the alleles or haplotypes associated with resistance to PV (DRB1∗07:01-DQA1∗02:01-DQB1∗02:02 and DRB1∗13:01-DQA1∗01:03-DQB1∗06:03). Only the monozygotic twins presented IgG antibodies against both Dsg1 and Dsg3. According to our knowledge based on a review of published literature on the topic, this is the first report of PV affecting monozygotic twins.

UCP1 -3826 A>G polymorphism affects weight, fat mass, and risk of type 2 diabetes mellitus in grade III obese patients.

OBJECTIVE: We investigated whether or not the UCP1 -3826 A>G polymorphism is associated with obesity and related metabolic disorders in grade III obese patients. METHODS: 150 obese patients (body mass index ≥35 kg/m(2)) who were candidates for bariatric surgery were studied. Weight (kg), body mass index (kg/m(2)); fat free mass (kg), fat mass (kg), energy intake (kcal), level of physical activity, plasma levels of glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein (HDL), triacylglycerols, and the prevalence of comorbidities associated with obesity were collected from medical records. Polymorphism rs1800592 genotyping was performed through allelic discrimination method in real time polymerase chain reaction using the TaqMan predesigned SNP Genotyping Assays kits. The t test was done to determine if genotypes of each polymorphism are associated with anthropometric and body composition variables. Linear regression models were used for age, sex, height, physical activity, and energy intake in weight and body composition variations (P < 0.05). RESULTS: Among these 150 individuals (47.2 ± 10.5 y, 80% women) the distribution of AA, AG, and GG was 41.3%, 45.3%, and 13.4%, respectively. Weight and body fat were lower in individuals who were carriers of a mutated allele G. It was observed that mutated homozygotes (GG) had a lower frequency of type 2 diabetes mellitus compared with those of wild allele (AA+AG). CONCLUSIONS: UCP1 -3826 A>G polymorphism is associated with weight, body fat mass, and risk of type 2 diabetes mellitus in obese individuals candidates for bariatric surgery.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles

Abstract INTRODUCTION Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD. METHODS: One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP. CONCLUSIONS: We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the progression of NAFLD.

Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

Correlation between beta-2-glycoprotein I gene polymorphism and anti-beta-2 glycoprotein I antibodies in patients with multibacillary leprosy.

Antiphospholipid antibodies, such as anti-beta2-glycoprotein I (beta2GPI), are present in multibacillary leprosy (MB) patients; however, MB patients do not usually present with antiphospholipid antibody syndrome (APS), which is characterized by thromboembolic phenomena (TEP). Rare cases of TEP occur in leprosy patients, but the physiopathology of this condition remains unclear. In this case-control study, we examined whether single-nucleotide polymorphisms (SNPs) of the beta2GPI gene contributed to the risk of leprosy and APS co-morbidity. SNPs Ser88Asn, Leu247Val, Cys306Gly and Trp316Ser were identified in 113 Brazilian leprosy patients. Additionally, anti-beta2GPI antibodies and plasma concentrations of beta2GPI were quantified. The Ser88Asn, Cys306Gly and Trp316Ser SNPs were not risk factors for APS in leprosy. A higher frequency of Val/Val homozygosity was observed in leprosy patients compared to controls (36 vs. 5%; P < 0.001). Forty-two percent of MB and 17% of paucibacillary leprosy patients were positive for anti-beta2GPI IgM (P = 0.014). There was no correlation between SNP Ser88Asn or Cys306Gly and anti-beta2GPI antibody levels. In MB patients with positive anti-beta2GPI IgM, the frequency of Val/Val homozygosity was higher than in controls (32 vs. 15%; P = 0.042). The frequency of the mutant allele Ser316 was higher in MB patients with positive rather than negative anti-beta2GPI IgM levels (6 vs. 0%; P = 0.040) and was greater than in the control group (6 vs. 1%; P = 0.034). The studied polymorphisms did not influence the plasma concentrations of beta2GPI. These results suggest that Leu247Val and Trp316Ser SNPs may represent genetic risk factors for anti-beta2GPI antibody production in MB patients.

[Val247Leu polymorphism of beta2 glycoprotein 1 gene may justify the genesis of anti beta2GP1 antibodies and antiphospholipid syndrome in multibacillary leprosy]. / Polimorfismo Val247Leu do gene beta2-glicoproteína 1 pode justificar a gênese de anticorpos antibeta2GP1 e síndrome do anticorpo antifosfolípide na hanseníase multibacilar.

UNLABELLED: BACKGROUND - Multibacillary (MB) leprosy may be manifested with antiphospholipid antibodies (aPL), among which anti-beta2GP1 (beta2-glycoprotein 1). High titers of aPL are associated with APS (Antiphospholipid Syndrome), characterized by thrombosis. The mutation Val247Leu in the domain V of beta2GP1 exposes hidden epitopes with consequent development of anti-beta2GP1 antibodies. OBJECTIVE: To evaluate the Val247Leu polymorphism of beta2GP1 gene and its correlation with anti-beta2GP1 antibodies in leprosy patients. METHODS: The Val247Leu polymorphism was performed by PCR-RFLP and anti-beta2GP1 antibodies were measured by ELISA. RESULTS: The genotypic Val/Val was more prevalent in the leprosy group, compared to controls. Regarding the 7 MB patients with APS, four presented heterozygosis and three, Val/Val homozygosis. Although higher titrations of anti-beta2GP1 IgM antibodies were seen in MB leprosy group with Val/Leu and Val/Val genotypes, there was no statistical difference when compared to Leu/Leu genotype. CONCLUSION: The prevalence of Val/Val homozygosis in leprosy group can partially justify the presence of anti-beta2GP1 IgM antibodies in MB leprosy. The description of heterozygosis and Val/Val homozygosis in 7 patients with MB leprosy and thrombosis corroborates the implication of anomalous phenotype expression of beta2GP1 and development of anti-beta2GP1 antibodies, with consequent thrombosis and APS.

Polimorfismo Val247Leu do gene β2-glicoproteína 1 pode justificar a gênese de anticorpos antiβ2GP1 e síndrome do anticorpo antifosfolípide na hanseníase multibacilar / Val247Leu polymorphism of β2 glycoprotein 1 gene may justify the genesis of anti β2GP1 antibodies and Antiphospholipid Syndrome in Multibacillary Leprosy

FUNDAMENTOS - Anticorpos antifosfolípides (AAF), como antiβ2GP1 (β2-glicoproteína 1), são descritos na hanseníase multibacilar (MB) sem, contudo, caracterizar a síndrome do anticorpo antifosfolípide (SAF), constituída por fenômenos tromboembólicos (FTE). A mutação Val247Leu no V domínio da β2GP1 - substituição da leucina por valina - expõe epítopos crípticos com consequente formação de anticorpos antiβ2GP1. OBJETIVO: Avaliar a associação do polimorfismo Val247Leu do gene β2GP1 com títulos de anticorpos antiβ2GP1 na hanseníase. MÉTODO: O polimorfismo Val247Leu foi detectado por PCR-RFLP, e os títulos de anticorpos antiβ2GP1, por Elisa. RESULTADOS: O genótipo Val/Val estatisticamente predominou no grupo de hansênicos, em relação ao controle. Embora maiores títulos de anticorpos antiβ2GP1 IgM estivessem alocados no grupo MB com genótipos Val/Val e Val/Leu, não houve diferença estatística em relação ao genótipo Leu/Leu. Dos sete pacientes MB com FTE, quatro apresentaram heterozigose, e três Val/Val homozigose. CONCLUSÃO: A prevalência do genótipo Val/Val no grupo de hansênicos pode justificar parcialmente a presença de anticorpos antiβ2GP1 na forma MB. A heterozigose ou homozigose Val/Val nos sete pacientes com hanseníase MB e FTE corroboram a implicação de expressão fenotípica anômala da β2GPl e formação de anticorpos antiβ2GPl, com consequente FTE e SAF.

BACKGROUND - Multibacillary (MB) leprosy may be manifested with antiphospholipid antibodies (aPL), among which anti-β2GP1 (β2-glycoprotein 1). High titers of aPL are associated with APS (Antiphospholipid Syndrome), characterized by thrombosis. The mutation Val247Leu in the domain V of β2GP1 exposes hidden epitopes with consequent development of anti-β2GP1 antibodies. OBJECTIVE: To evaluate the Val247Leu polymorphism of β2GP1 gene and its correlation with anti-β2GP1 antibodies in leprosy patients. METHODS: The Val247Leu polymorphism was performed by PCR-RFLP and anti-β2GP1 antibodies were measured by ELISA. RESULTS: The genotypic Val/Val was more prevalent in the leprosy group, compared to controls. Regarding the 7 MB patients with APS, four presented heterozygosis and three, Val/Val homozygosis. Although higher titrations of anti-β2GP1 IgM antibodies were seen in MB leprosy group with Val/Leu and Val/Val genotypes, there was no statistical difference when compared to Leu/Leu genotype. CONCLUSION: The prevalence of Val/Val homozygosis in leprosy group can partially justify the presence of anti-β2GP1 IgM antibodies in MB leprosy. The description of heterozygosis and Val/Val homozygosis in 7 patients with MB leprosy and thrombosis corroborates the implication of anomalous phenotype expression of β2GP1 and development of anti-β2GP1 antibodies, with consequent thrombosis and APS.