Indonesians Human Leukocyte Antigen (HLA) Distributions and Correlations with Global Diseases.

In Human, Major Histocompatibility Complex known as Human Leukocyte Antigen (HLA). The HLA grouped into three subclasses regions: the class I region, the class II region, and the class III region. There are thousands of polymorphic HLAs, many of them are proven to have correlations with diseases. Indonesia consists of diverse ethnicity people and populations. It carries a unique genetic diversity between one and another geographical positions. This paper aims to extract Indonesians HLA allele data, mapping the data, and correlating them with global diseases. From the study, it is found that global diseases, like Crohn's disease, rheumatoid arthritis, Graves' disease, gelatin allergy, T1D, HIV, systemic lupus erythematosus, juvenile chronic arthritis, and Mycobacterial disease (tuberculosis and leprosy) suspected associated with the Indonesian HLA profiles.

Association of interleukin 1 receptor antagonist intron 2 variable number of tandem repeats polymorphism with vitiligo susceptibility in Gujarat population.

BACKGROUND: Vitiligo is a multifactorial, polygenic, autoimmune skin disorder caused by selective destruction of melanocytes. Interleukin 1 receptor antagonist intron 2 polymorphism was found to be associated with various autoimmune disorders. AIMS: We aimed to investigate the association of interleukin 1 receptor antagonist intron 2 variable number of tandem repeats polymorphism (rs2234663) with vitiligo to assess interleukin 1 receptor antagonist transcript levels and to perform possible genotype-phenotype correlation. METHODS: Three hundred and seven vitiligo patients and 316 controls were enrolled in the study, genotyping of interleukin 1 receptor antagonist rs2234663 was performed by polymerase chain reaction, and relative gene expression of interleukin 1 receptor antagonist was carried out in peripheral blood mononuclear cells from patients (n = 36) and controls (n = 36) by real-time-PCR. RESULTS: A significant difference was observed in the frequency of interleukin 1 receptor antagonist *A (1/2) genotype among patients with active and stable vitiligo (P = 0.0172). Interleukin 1 receptor antagonist*A (2/2) genotype and allele frequencies were significantly different between SV patients and controls (P = 0.0246 and P = 0.0046, respectively). Significant difference was also observed for interleukin 1 receptor antagonist*A2 (allele) in active and stable vitiligo patients (P = 0.0060). However, other comparisons did not show any significant difference in genotype and allele frequencies. Moreover, interleukin 1 receptor antagonist*A (3/2) genotype was observed only in patients whereas interleukin 1 receptor antagonist*A (5/2) was observed only in controls. Gene expression analysis showed no significant difference in interleukin 1 receptor antagonist transcript levels in patients compared to controls (P = 0.5962). Interestingly, genotype-phenotype correlation analysis revealed that individuals with IL1RN*A (2/2) exhibited higher interleukin 1 receptor antagonist expression compared to other major genotypes interleukin 1 receptor antagonist*A (1/2) (P = 0.01) and interleukin 1 receptor antagonist*A (1/1) (P = 0.03). LIMITATIONS: More case-control studies on interleukin 1 receptor antagonist rs2234663 polymorphism and gene expression from different ethnic populations are required to explore the impact of interleukin 1 receptor antagonist in vitiligo susceptibility. CONCLUSION: Interleukin 1 receptor antagonist*A2 might be a risk factor for progressive vitiligo.

Polymorphism of glutathione S-transferase M1 and T1 genes and susceptibility to psoriasis disease: A study from North India.

BACKGROUND: Increased oxidative stress and resulting inflammation has been emphasized as a factor in the pathogenesis of many diseases including psoriasis. Glutathione S-transferases (GSTs) protect against oxidative stress, inflammation, and genotoxicity. Polymorphisms in the GST genes may lead to an imbalance in pro- and antioxidant systems resulting in the increased production of reactive oxygen species that could influence the pathogenesis of psoriasis. AIM: The aim of this study was to investigate the association between GSTs (GSTM1 and GSTT1) gene polymorphism in patients with chronic plaque psoriasis as a factor in the susceptibility and development of psoriasis. MATERIALS AND METHODS: We assessed 128 patients with psoriasis and 250 age- and sex-matched healthy controls. Genomic DNA was extracted from peripheral blood by the phenol chloroform method. The null GSTT1 and GSTM1 genotypes were identified by multiplex polymerase chain reaction (PCR) method. RESULTS: The null genotype of GSTM1 and GSTT1 was seen in 45.3% and 40.6% in psoriasis patients whereas in the controls it was 34.4% and 20.0%, respectively. A significant association was seen between the null alleles of the GSTT1 (OR = 2.74) and GSTM1 (OR = 1.58) alone or in combination with tobacco use (P < 0.001) and psoriasis risk. The presence of both null genotypes of GSTM1 and GSTT1 further increased the risk of psoriasis (OR = 3.52) when compared with the positive genotypes of GSTM1 and GSTT1. LIMITATIONS: A major limitation of this study was the small sample size. A large epidemiological study is necessary to confirm these findings. CONCLUSIONS: The null genotype of GSTT1 is a strong predisposing factor for psoriasis in North India.

Study of the relation between two common cyclooxygenase 2 gene polymorphisms with risk of developing and subtypes of vitiligo in Egyptian patients.

BACKGROUND/PURPOSE: Genetic factors play an important role in the pathogenesis of vitiligo. Cyclooxygenase 2 (COX2) gene induced by ultraviolet radiation controls the synthesis of prostaglandins, which are are found to be beneficial in treating vitiligo. COX2 gene polymorphism has been previously evaluated in Chinese population. We aimed to study the relation between two common COX2 gene polymorphisms with vitiligo and its subtypes amongEgyptian patients. PATIENTS AND METHODS: This study included 200 participants (100 vitiligo patients and 100 healthy controls). COX2-765G/C and -1195A/G gene polymorphism was studied by restriction fragment length polymorphism polymerase chain reaction analysis and the results were compared between the two groups and among different subtypes of vitiligo. RESULTS: Frequency of COX2-1195 AA, AG, GG genotypes showed no significant association among patients with vitiligo (P = 0.626, 0.321, 0.08, respectively); those with generalized vitiligo (P = 0.739, 0.291, 0.101, respectively) and those with segmental vitiligo (P = 0.410, 1.00, 0.676, respectively) compared to the control group. Regarding COX2-765G/C genotypes, GG genotype was more frequent among patients with vitiligo [84 (84%)] compared to controls [63 (63%)] (P = 0.001). GC genotype was significantly less frequent [15 (15%)] among patients compared to controls [32 (32%)] (P = 0.005). Generalized and segmental types of vitiligo also showed no significant difference in the frequency of COX2-765G/C genotypes compared with controls. LIMITATIONS: Being a pilot study, a relatively small number of participants were included. CONCLUSION: COX2-1195A/G gene polymorphism is not associated with the risk of developing vitiligo or with vitiligo subtypes. COX2-765 GG genotype is associated with vitiligo, especially of the generalized type.

Association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism and susceptibility to vitiligo: Systematic review and meta-analysis.

BACKGROUND: Protein tyrosine phosphatase, non-receptor type 22 gene, which translates to lymphoid tyrosine phosphatase, is considered to be a susceptibility gene marker associated with several autoimmune diseases. Several studies have demonstrated the association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism with vitiligo. However, these studies showed conflicting results. Meta-analysis of the same was conducted earlier that included fewer number of publications in their study. AIM: We performed a meta-analysis of a total of seven studies consisting of 2094 cases and 3613 controls to evaluate the possible association of protein tyrosine phosphatase, non-receptor type 22 +1858C>T polymorphism with vitiligo susceptibility. METHODS: We conducted a literature search in PubMed, Google Scholar and Dogpile for all published paper on protein tyrosine phosphatase, non-receptor type 22 +1858C→T polymorphism and vitiligo risk till June 2016. Data analysis was performed by RevMan 5.3 and comprehensive meta-analysis v3.0 software. RESULTS: Meta-analysis showed an overall significant association of protein tyrosine phosphatase, non- receptor type 22 +1858C→T polymorphism with vitiligo in all models (allelic model [T vs. C]: odds ratio = 1.50, 95% confidence interval [1.32-1.71], P< 0.001; dominant model [TT + CT vs. CC]: odds ratio = 1.61, 95% confidence interval [1.16-2.24], P = 0.004; recessive model [TT vs. CT + CC]: odds ratio = 4.82, 95% confidence interval [1.11-20.92], P = 0.04; homozygous model [TT vs. CC]: odds ratio = 5.34, 95% confidence interval [1.23-23.24], P = 0.03; co-dominant model [CT vs. CC]: odds ratio = 1.52, 95% confidence interval [1.09-2.13], P = 0.01). No publication bias was detected in the funnel plot study. LIMITATIONS: Limited ethnic-based studies, unable to satisfy data by gender or vitiligo-type are some limitations of the present meta-analysis. CONCLUSION: Stratifying data by ethnicity showed an association of protein tyrosine phosphatase, non-receptor type 22 +1858C→T with vitiligo in European population (odds ratio = 1.53, 95% confidence interval [1.34-1.75], P< 0.001) but not in Asian population (odds ratio = 0.59, 95% confidence interval [0.26-1.32], P = 0.2). In conclusion, protein tyrosine phosphatase, non-receptor type 22 +1858 T allele predisposes European individuals to vitiligo.

Association between genetic variants in NOD2, C13orf31, and CCDC122 genes and leprosy among the Chinese Yi population.

BACKGROUND: A significant association between single nucleotide polymorphisms in NOD2, C13orf31, and CCDC122 genes and leprosy has been reported in a previous genome-wide association study of leprosy in the Chinese Han population. However, it remains unknown whether this association exists among the Chinese Yi population. The aim of this study was to investigate whether single nucleotide polymorphisms in NOD2, C13orf31, and CCDC122 genes are associated with leprosy among the Chinese Yi population in China. METHODS: We genotyped rs9302752, rs7194886, rs8057341, and rs3135499 in the NOD2 gene; rs3764147 and rs10507522 in the C13orf31 gene; and rs3088362 and rs9533634 in the CCDC122 gene in a Chinese Yi cohort comprised of 319 patients with leprosy and 355 ethnic-matched controls. The differences between the patients and healthy controls were analyzed using chi-squared analysis. RESULTS: Significant differences of rs3135499 in NOD2, rs3764147 and rs10507522 in C13orf31, and rs3088362 and rs9533634 in CCDC122 were observed between the patients and the healthy control groups in the cohort. The allelic P values and odd ratios were as follows: rs3135499, 1.0 × 10(-8) and 2.55; rs3764147, 1.7 × 10(-7) and 1.88; rs10507522, 1.16 × 10(-5) and 1.95; rs3088362, 8.2 × 10(-4) and 1.51; rs9533634, 5.34 × 10(-5) and 1.73. No significant differences were found in the distributions of rs9302752, rs7194886, and rs8057341 between the patients and healthy controls. CONCLUSIONS: We demonstrated that genetic variants in the NOD2, C13orf31, and CCDC122 genes are closely associated with leprosy among the Chinese Yi population, which implicates the pathogenic role of NOD2, C13orf31, and CCDC122 genes in a different ethnicity.

Examining ERBB2 as a candidate gene for susceptibility to leprosy (Hansen’s disease) in Brazil

Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear.

Examining ERBB2 as a candidate gene for susceptibility to leprosy (Hansen's disease) in Brazil.

Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear.

Thrombophilia in venous leg ulcers: a comparative study in early and later onset.

BACKGROUND: Several studies found that the patients with chronic venous ulcers (CVU) have an increased prevalence of thrombophilia (44-75%), similar to that observed in deep vein thrombosis (DVT). The patients who develop CVU before their 50 th birthday appear to represent a distinct group in terms of etiology, natural history and prognosis. AIM: To analyze the nature and prevalence of thrombophilia in patients with early onset of CVU (before 50-years old) compared with a group of patients with later onset. METHODS: Twenty-seven consecutive patients of each group were studied. They underwent clinical assessment and blood testing for factor V Leiden, prothrombin G20210A, methyltetrahydrofolate reductase C677T, plasminogen activator inhibitor type 1 (PAI-1) mutations, antithrombin, proteins C and S levels, and also antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant), cryoglobulins and cryoagglutinins. RESULTS: All the patients had at least one thrombophilia. The prevalences of single, 2 and ≥3 thrombophilias were 29.6%, 40.7% and 29.6%, respectively, in the early onset group, compared with 33.3%, 59.2% and 7.4% in the later onset group. The PAI-1 4G/4G homozygous mutation was significantly more common in patients with early onset of ulcer. The prevalences of factor V Leiden, prothrombin G20210A, elevated titer of antiphospholipid antibodies and the presence of cryoglobulins were higher in the early onset group, although the differences were not statistically significant. CONCLUSION: Our study brings evidence of a higher thrombophilic risk among the patients with early onset of the CVU as they had significantly higher prevalence of multiple (≥3) thrombophilias (P=0.03), homozygous mutations (P=0.03) and family history of leg ulcer (P=0.02) when compared with patients with later onset. Thrombophilia screening is important in patients with CVU before the age of 50 in order to stratify the thrombotic risk and to allow an appropriate prophylactic and therapeutic management.

Comparative case control study of clinical features and human leukocyte antigen susceptibility between familial and nonfamilial vitiligo.

BACKGROUND: Various studies worldwide suggest that human leukocyte antigen (HLA) region may be involved in the genetic susceptibility of vitiligo but little information is available from India. AIM: To find the HLA associated susceptibility to develop vitiligo in Indian patients and to detect role of HLA in familial vitiligo. METHODS: This was a case controlled study which included all patients suffering from vitiligo over a period of one and half years. Clinical details were noted and sera collected from these patients were screened for the presence of HLA class I antibodies. The clinical features and HLA antigens were assessed and comparison was made between patients with familial and nonfamilial vitiligo. RESULTS: Out of 114 patients studied, 84 had family history and 30 had no family history. Patients with family history of vitiligo have higher chances of acquiring vitiligo if first degree relatives are affected compared to if second degree relatives are affected. Family history of vitiligo is associated with an early onset of vitiligo (< 20 years). There was no statistically significant difference in the type, stability, and severity of vitiligo in both the groups. HLA results in both the groups revealed increase in HLA A2, A11, A31, A33, B17, B35, B40, and B44 alleles while HLA A9, B13, and B53 alleles were decreased. Family history was associated with HLA A2, A28, A31, and B44 alleles. Early onset of vitiligo (< 20 years) was significantly associated with HLA A2, A11, B17, B35, and B44 alleles. The patients with severe affection (> 10% area) showed in significant association with HLA A10 and B8. CONCLUSION: Family history of vitiligo is associated with an early onset of vitiligo. There is no correlation of family history with the type of vitiligo, stability of lesions, and areas involved. Severity is not associated with family history. Apart from other alleles, alleles A2, and B44 play a significant role in vitiligo in the Indian patients.

Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for -819C/T in leprosy susceptibility.

Leprosy is a complex infectious disease influenced by genetic and environmental factors. The genetic contributing factors are considered heterogeneous and several genes have been consistently associated with susceptibility like PARK2, tumor necrosis factor (TNF), lymphotoxin-alpha (LTA) and vitamin-D receptor (VDR). Here, we combined a case-control study (374 patients and 380 controls), with meta-analysis (5 studies; 2702 individuals) and biological study to test the epidemiological and physiological relevance of the interleukin-10 (IL-10) genetic markers in leprosy. We observed that the -819T allele is associated with leprosy susceptibility either in the case-control or in the meta-analysis studies. Haplotypes combining promoter single-nucleotide polymorphisms also implicated a haplotype carrying the -819T allele in leprosy susceptibility (odds ratio (OR)=1.40; P=0.01). Finally, we tested IL-10 production in peripheral blood mononuclear cells stimulated with Mycobacterium leprae antigens and found that -819T carriers produced lower levels of IL-10 when compared with non-carriers. Taken together, these data suggest that low levels of IL-10 during the disease outcome can drive patients to a chronic and unprotective response that culminates with leprosy.

TLR2 Arg677rp polymorphism in leprosy: revisited

We investigated the Toll-like receptor 2 (TLR2) Arg677Trp polymorphism, associated with lepromatous leprosy in the Korean population and shown to abrogaet TLR2-mediated signalling in response to mycobacterial ligands, in 286 Indian leprosy patients and 183 ethnically matched controls. The case-control comparison also involved investigation of possible variation(s) in the promoter region of the TLR2 gene. Genotyping results after direct PCR sequencing showed that the TLR2 Arg677Trp polymorphism associated with lepromatous leprosy in the Korean population is not a true polymorphism of the TLR2 gene and has resulted from the variation present in the 93% homologous duplicated region of TLR2 exon 3 present approximately 23 kb upstream

Human genetics of common mycobacterial infections.

There is increasing interest in and understanding of the role of human genetic factors controlling susceptibility/resistance to infectious diseases. This is of particular importance for the two most common mycobacterial infections, tuberculosis and leprosy, because this will allow a genetic dissection of antimycobacterial immunity and should open new fields of preventive and therapeutic measures. In this review we will initially discuss various methods of genetic epidemiology that have been and are being developed to identify human genes controlling infectious diseases, and then illustrate the findings obtained in the numerous studies performed in tuberculosis and leprosy. Although the most convincing results were observed for HLA-DR2 and NRAMP1 (or a closely linked gene) in pulmonary tuberculosis and leprosy subtypes and for a 10p13 locus in paucibacillary leprosy, the molecular basis of their effects remains to be established.