Significant Increase Of DRB1 Research Articles

Susceptibility of Specific HLA DRB1*15 AlleleAmong Chronic Hepatitis B Infected Bangladeshi Patients

Background: The outcome of hepatitis B virus (HBV) infection may be influenced by host factors like Human Leukocyte Antigen (HLA).The expression of HLA genes in peripheral blood mononuclear cells (PBMCs) may reflect the molecular mechanism underlying different HBV infection outcomes.
 Objective: The purpose of the present study was to explore whether HLA DRB1*15 allele confer susceptibility to chronic hepatitis B infected Bangladeshi patients.
 Method: This cross sectional study was carried out in the Department of Virology, Bangabandhu Sheikh Mujib Medical University (BSMMU) during July 2012 to June 2013 for a period of one year.Evaluation of HLA DRB1*15 allele distribution among 30 chronic hepatitis B infected (HBV) Bangladeshi patients compared them with 30 healthy individuals.HLA DRB1*15 allele distribution was detected by conventional PCR followed by agarose gel electrophoresis, using commercial low-resolution DRB1*15 allele polymerase chain reaction sequence specific priming kit.
 Result: A total of 30 chronic hepatitis B infected (HBV) Bangladeshi patients were evaluated together with 30 healthy controls. The study revealed a significant increase of DRB1*15 allele (46.7% vs 20%; RR= 3.5; X2 = 7.2; P<0.05) compared to healthy controls. This is the first report on HLA DRB1*15 allele associations among chronic hepatitis B (HBV) infected Bangladeshi patients.
 Conclusion: The present study reveals that HLA DRB1*15 allele was more frequent in chronic hepatitis B infected Bangladeshi patients compared to healthy individuals. Thus, HLA DRB1*15 allele of HLA class II molecules significantly affect the outcome of hepatitis B infection.
 Bangladesh Journal of Medical Science Vol.18(4) 2019 p.783-788

Prevalence of Autoantibodies and HLA DR, DQ in Type 1 Diabetes Mellitus.

Type I diabetes Mellitus (T1DM) is caused by autoimmune destruction of β-cells of pancreas. Two forms of T1DM are known called as 1A (autoimmune) and 1B (idiopathic). Aim was to study the prevalence of Anti-TTG IgA, Anti-TPO, GADA, ZnT8 and IA-2 autoantibodies and HLA DR and DQ genes and its diagnostic value in T1DM. Thirty four T1DM patients, 59 type 2 diabetes mellitus (T2DM) patients and 28 healthy controls were included in study. Antibodies levels were estimated by ELISA and HLA typing was performed by SSP-PCR method. The prevalence of various autoantibodies in T1DM were Anti-TTG 14.7%, Anti-TPO 17.65%, GADA 38.23%, ZnT8 11.76% and IA-2 5.88%. Only GADA and ZnT8 were significantly positive in T1DM. GADA (66.67%) and ZnT8 (33.33%) positivity was more in patients below 15 years age while levels of other antibodies were higher after 15 years age. All autoantibodies were detected in higher frequency in T1DM than in T2DM and controls. HLA DR and DQ typing showed highly significant increase in DRB1*0301 (61.76%, p=0.00) and DQB1*0201 (64.71%, p=0.00) in T1DM. Subjects with HLA DRB1*0301 and DQB1*0201 had 80-100% positive prevalence of GADA, ZnT8, IA-2, Anti-TTG and Anti-TPO autoantibodies. Combination of GADA antibody with DRB1 and DQB1 estimation improved diagnosis of T1A than insulin antigen specific antibodies alone.

Inflammatory Bowel Disease: Susceptibility and Disease Heterogeneity Revealed by Human Leukocyte Antigen Genotyping

This study aimed to investigate the association between HLA DR/DQ and inflammatory bowel diseases (IBD) in Tunisian patients and to determine the relationship between HLA DR/DQ alleles with the clinical disease patterns. DNA typing of human leukocyte antigen (HLA) genes was performed in 70 ulcerative colitis (UC) patients, 40 Crohn's disease (CD) patients, and 123 healthy controls (HC) using a polymerase chain reaction sequence specific primer technique. Data were analyzed using Cochran-Mantel-Haenszel test and binary logistic regression. Compared with HC, IBD patients showed an increased frequency of the homozygous DRB1*07 genotype. This positive association was maintained when UC and CD were separately compared to HC. In UC patients, DQB1*03:02 was predictive of colonic extension whereas DRB1*13 and DQB1*03:01 were associated limited disease localization (left-sided colitis and proctitis). The DRB1*15 allele increased in patients with extraintestinal manifestations. In CD, female patients showed an increased frequency of DRB1*13, DRB1*15, and DQB1*06 alleles and DRB1*13-DQB1*06 haplotype, whereas a significant increase of DRB1*07, DQB1*02 alleles, and DRB1*07-DQB1*02 haplotype was noted in male patients. These results show a significant association of the homozygous HLA-DRB1*07 genotype with UC and CD and of several HLA DR/DQ alleles and haplotypes with the clinical phenotypes of these diseases in Tunisian patients. Because of limited statistical power, our study findings are subject to further investigation.

HLA-B, DR and DQ antigens polymorphism in Tunisian patients with ankylosing spondylitis (a case–control study)

The objective of the study is to assess the distribution of HLA-B genes, HLA-B27 subtypes, HLA-DRB1 and HLA-DQB1 alleles in patients with ankylosing spondylitis (AS) and in control subjects in the Tunisian population and to compare their distribution with that found in other countries. This is a case-control study that included 100 consecutive patients (85 males/15 females) with AS according to the modified New York criteria and 100 control individuals. HLA-B, B27 subtypes and class II (DR and DQ) typing of all subjects was performed by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP). HLA-B27 was found in 62% of patients against 3% in controls (P = 0.0000, OR = 52.6, 15.6 < CI < 166.7). On the other hand, B*07 and B*51 were significantly decreased in comparison with controls (P = 0.01, OR = 0.3, 0.1 < CI < 0.8 and P = 0.0000, OR = 0.2, 0.1 < CI < 0.4, respectively). Eight B*27 subtypes were identified in the AS group, but the most frequent ones were B*2702 (32%) and B*2705 (24%). Among HLA-DRB1 alleles, a significant increase in DRB1*11 was found in comparison with controls (P = 0.01, OR = 2.2, 1.2 < CI < 4.5). However, DRB1*13 had a negative association with AS (P = 0.01, OR = 0.4, 0.2 < CI < 0.8). For HLA-DQB1 alleles, a significant positive association with DQB1*03 was observed in AS group (P = 0.03, OR = 1.8, 1.0 < CI < 3.4). Multivariate analysis by logistic regression revealed that DRB1*11 and DQB1*03 had no direct links with the disease, but were dependent on the presence of HLA-B27. Moreover, B*07 and B*51 seemed to have independently a negative correlation with AS, but DRB1*13 seemed to depend on B*51. Haplotypes carrying B27 were significantly associated with AS and those carrying B*07 or B*51 were negatively correlated with the disease. In conclusion, our study confirms that B27 predisposes to AS while B*07 and B*51 are negatively correlated with the disease.

Human leukocyte antigen class II allele association to disease progression in Iranian patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in Western countries, but its incidence is low in Asian populations. In the present study we determined the frequency of DRB1 and DQB1 alleles in 87 Iranian CLL patients and 100 healthy controls using a polymerase chain reaction (PCR) technique. An increased frequency of DRB1*07 (p = 0.04), DQB1*06 (p = 0.01) alleles, and DRB1*13/DQB1*03 haplotype (p = 0.01) and decreased frequency of the DQB1*03 (p = 0.01) allele were observed in our patients compared with healthy controls. Comparison between patients with indolent (n = 42) and progressive (n = 38) disease revealed a significant increase in DRB1*04 and DRB5 alleles in progressive patients. Similarly, a higher frequency of DRB5 (p = 0.01) allele was observed in CD38(+) compared with CD38(-) patients. Classification of the patients into immunoglobulin variable region heavy-chain genes mutated and unmutated subtypes did not reveal significant differences for the expression of any of the HLA alleles or haplotypes between these two subtypes. Our findings observed in an Iranian population indicate that CLL could be associated with distinct HLA class II alleles and haplotypes of which the DQB1*06 allele and DRB1*13/DQB1*03 haplotype have not already been reported in CLL patients from other ethnic backgrounds. Some HLA class II alleles may contribute to disease progression in CLL.

HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women

We investigated HLA class II alleles in women with systemic sclerosis (SSc), a rare disease that preferentially affects women. Specific alleles of DRB1, DQA1 and DQB1 were determined by DNA-based HLA typing for women with SSc (n = 102) and healthy women (n = 533). All study subjects were Caucasian. DRB1, DQA1 and DQB1 allele frequencies of women with SSc were compared with those of healthy women. Among women with SSc, 29.4% (30/102) and among healthy women 10.7% (57/533) had DRB1*11. Allele frequencies were compared for women with SSc and healthy women (each woman has two alleles). The allele frequency of DRB1*11 was 15.7% (32/204 alleles) in SSc women and 5.8% (62/1066 alleles) in healthy women (P = 0.000002). The increase of DRB1*11 was found both in diffuse (P = 0.0001) and limited SSc (P = 0.002) (allele frequencies 15.0 and 17.2%, respectively). Among women with diffuse SSc, there was a disproportionate increase of the DRB1*1104 allele (P = 0.0004) with no increase of DRB1*1101 (P = 1.00). In contrast, in limited SSc the strongest association was with DRB1*1101 (P = 0.008), with a less significant increase of DRB1*1104 (P = 0.04). An increase of DRB1*11 in SSc is consistent with other reports. Although present in both diffuse and limited SSc disease subsets, the increase was predominantly due to over-representation of DRB1*1104 in women with diffuse SSc. Women with limited SSc had a preponderance of DRB1*1101, the most common allele in healthy women. DRB1*1104 and DRB1*1101 differ by a single amino acid at position 86, where the former has valine and the latter glycine.

Preeclampsia: a multifactorial disease resulting from the interaction of the feto-maternal HLA genotype and HCMV infection.

To clarify the possible influence of human leukocyte antigen (HLA) mother-child genotypes and human cytomegalo virus (HCMV) presence on the development of preeclampsia. One hundred and four DNA samples from mothers with preeclampsia, mothers with a normal history of pregnancies and their neonates were tested by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) for HLA-A, -G, -DRB1, -DQA1, -DQB1 alleles. The HCMV sequences were analyzed using a PCR-SSOP method and the four primers described by Chou (Chou S: J Clin Microb 1992; 30:2307-2310). Compared with their respective controls, a significant increase of DRB1*07 among neonates (P(c) = 0.05) and of DRB1*07 and/or DRB1*06 among pre-eclamptic mothers (P(c) = 0.003, RR = 8,5) was found. When HCMV sequences were detected in pre-eclamptic mothers carrying those phenotypes the RR increased up to 40. Furthermore, the fetal inheritance of a maternal HLA-G*0104 increased the risk for the appearance of the disease (RR = 30; P = 0.025). The results suggest that the presence of alleles HLA-G*0104, DRB1*07/06, HCMV sequences and the fetal inheritance of maternal G*0104, should be considered as conditioning factors for the development of preeclampsia.

Association of HLA with Vogt-Koyanagi-Harada syndrome in Koreans

PURPOSE: To study the distribution of human leukocyte antigen HLA-A/B antigens and HLA-DR/-DQ/-DP alleles and to investigate the immunogenetic background of Korean patients with Vogt-Koyanagi-Harada (VKH) syndrome and clinical course with different types of HLA. METHODS: Human leukocyte antigen typings were performed in 18 Korean patients with VKH syndrome and in 128 healthy control subjects. HLA-A/B loci serologic typing was performed according to the standard microlymphocytotoxicity technique. DNA was extracted through the salting out method, and HLA-DR phenotyping and HLA DR4, HLA-DQ, and HLA-DP subtyping were performed with the polymerase chain reaction- sequence specific oligonucleotide probe (PCR-SSOP) method. RESULTS: Among HLA-A/B antigens typed by the standard microlymphocytotoxicity method, the frequencies of HLA-A31 (RR = 6.1, P < 1 × 10 −2) and HLA-B55 (RR = 15.8, P < .05) were significantly increased in the patient group compared with the control group. Among HLA-DR/ -DQ/-DP alleles subtyped by DNA methods, the frequencies of HLA-DRB1∗04 (RR = 45.1, P < 1 × 10 −7) and HLA-DRB1∗07 (RR = 3.2, P < .05) were significantly increased. However, significant decreases in HLA-DRB1∗08 (RR = .1, P < .05), HLA-DRB1∗13 (RR = .1, P < .05), and HLA-DRB1∗14 (RR = .1, P < .05) frequencies were observed. The result of HLA-DR, HLA-DQ, and HLA-DP subtying showed the significant increase in DRB1∗0405 (RR = 45.1, P < 1 × 10 −7), DQA1∗0302 (RR = 12.0, P < 1 × 10 −4), DQB1∗0303 (RR = 5.0, P < 1 × 10 −2), DQB1∗0401 (RR = 18.9, P < 1 × 10 −6), and DPB1∗0501 (RR = 3.8, P < .05). However, significant decreases in DQA1∗0101 (RR = .1, P < .05), DQA1∗0102 (RR = .1, P < 1 × 10 −2), DQA1∗0103 (RR = .1, P < .05), DQA1∗0501 (RR = .1, P < 1 × 10 −2), DQB1∗0301 (RR = .1, P < .05), DQB1∗0601 (RR = .1, P < .05), DPB1∗0201 (RR = .3, P < .05), and DPB1∗0401 (RR = .1, P < .05) frequencies were also observed. In patients with DRB1∗0405 itself or HLA-DRB1∗0405-DQA1∗ 0302-DQB1∗0401 haplotype, a reduction in visual acuity and ocular complications was common. CONCLUSIONS: These results suggest that HLA-DRB1∗0405 itself or HLA-DRB1∗0405-DQA1∗ 0302-DQB1∗0401 haplotype is greatly increased and may play the most important role in the development and the clinical course of VKH syndrome in Korean patients.

HLA class II immunogenetics and incidence of insulin-dependent diabetes mellitus in the population of Cantabria (Northern Spain)

HLA class II genes were analyzed to study IDDM susceptibility in Cantabria (Northern Spain). Patients showed highly significant increases in DRB1∗0301 (RR = 4.581, p < 0.00005), DRB1∗0401 (RR = 2.6, p < 0.05), DRB1∗0402 (RR = 8.78, p < 0.05) and DRB1∗0405 (RR = 14.73, p < 0.005). Highly significant diferences were in the DQA1∗0301 (RR = 3.62, p < 0.000005) and DQA1∗0501 (RR = 2.13, p < 0.05) alleles. DQB1∗0201 (RR = 4.1, p < 0.00005) and DQB1∗0302 (RR = 5.42, p < 0.000005) alleles were also significantly increased. A significant increase in DRB1∗0402-DQA1∗0301-DQB1∗0302 (RR = 16.18, p < 0.05), DRB1∗0405-DQA1∗0301-DQB1∗0302 (RR = 16.12, p < 0.05), DRB1∗0301-DQA1∗0501-DQB1∗0201 (RR = 4.58, p < 0.00005) and DRB1∗0401-DQA1∗0301-DQB1∗0302 (RR = 4.36, p < 0.005) was apparent in the diabetic group, while the DRB1∗1501-DQA1∗0102-DQB1∗0602 and DRB1∗1401-DQA1 ∗0104-DQB1∗05031 protective haplotypes (RR = 0.17 and 0.09, p < 0.0005 and 0.05, respectively) were significantly lower in patients. The absence of Asp57 and the presence of Arg52 were associated with disease in a dose-dependent manner. Several genotypes encoding the identical DQα52/DQβ57 phenotype carried very different RRs. Finally, the Cantabrian population has the highest incidence of IDDM reported for Spain (15.2 of 100.000 in the 0–14 age group, Poisson’s 95% CI: 10.6–19.3).

HLA-DR and -DQ associations with melioidosis

Melioidosis is an important infectious disease of southeast Asia caused by an intracellular bacterium, Burkholderia pseudomallei. Cellular immunity is postulated to play important roles in immunity to melioidosis that may influence the severity and clinical outcome of the disease. The present study was undertaken to investigate possible associations of melioidosis with HLA class II alleles. HLA typing of HLA-DRB1, -DQA1, and -DQB1 was performed using polymerase chain reaction and sequence-specific oligonucleotide hybridization (PCR-SSO). Seventy-nine melioidosis patients and 105 healthy, ethnically and geographically matched controls were studied. Among 24 DRB1 alleles, 7 DQA1 alleles, and 13 DQB1 alleles identified in this population, an association with melioidosis was observed with DRB1∗1602 which was increased in melioidosis patients (10.1%) compared to normal controls (4.8%), p = 0.047 (odds ratio (OR) = 2.25). In addition, significant increase of DRB1∗1602 allele frequency and decrease of DQA1∗03 were also observed in septicemic melioidosis patients, the most severe form of the disease ( p = 0.01, OR = 3.10; and p = 0.047, respectively). Furthermore, a trend of association of DRB1∗0701, DQA1∗0201, and DQB1∗0201 with relapse cases of melioidosis was also noted. In contrast, no HLA association was observed in localized melioidosis or melioidosis with diabetes mellitus. These findings provide the suggestive evidence of an immunogenetic basis of certain aspects of melioidosis.

A gene dosage effect of the DQA1∗0501/DQB1∗0201 allelic combination influences the clinical heterogeneity of celiac disease

This study reports the HLA-DR and DQ molecular characterization of 62 CD patients of Sardinian descent. Patients were divided in two groups (36 in group I and 26 in group II) according to the clinical features at the disease onset. Among the patients of group I, having the fully expressed form of CD and a mean age of 3 years at disease onset, a significant increase of DRB1∗0301, DQA1∗0501, DQB1∗0201 homozygotes, encoding in cis two DQ (α1∗0501, β1∗0201) susceptibility heterodimers, was observed when compared either with the patients of group II (pIII < 0.012) or with healthy individuals (pI < 10 −6). On the other hand, in the patients of group II, presenting oligosymptomatic forms and a mean age of 5.7 years at the disease onset, the haplotype combinations encoding in cis or in trans only one DQ (α1∗0501, β1∗0201) heterodimer were significantly increased in comparison either with the patients of group I (pIII < 0.026) or with controls (pII < 10 −6). These findings suggest that a double dose of DQA1∗0501, DQB1∗0201 genes may predispose a person to an earlier onset and to more severe disease manifestations. Genotype analysis showed that only three patients (all in group I) failed to form in trans or in cis the DQ (α1∗0501, β1∗0201) heterodimer and carried the DQA1∗0101, DQB1∗0501 haplotype, suggesting its possible role in CD susceptibility. In addition, a significant increment of DQB1∗0501 gene ( p c < 0.0065) was found comparing the frequency of DQB1 alleles in CD patients and healthy controls, after exclusion of DQB1∗0201 chromosomes. In conclusion, this study suggests that the clinical picture of CD may be influenced by the DQA1∗0501/DQB1∗0201 susceptibility genes with a gene dosage effect and that Sardinian patients who are DQ (α1∗0501, β1∗0201) negative may carry another DQ heterodimer (i.e., DQ {α1∗0101, β1∗0501}) able to confer CD susceptibility in addition to the primary DQA1∗0501/DQB1∗0201 gene associations.

A shared HLA-DRB1 sequence confers RA susceptibility in Greeks.

Previous serological studies of Greek rheumatoid arthritis (RA) patients have failed to demonstrate an association with DR4. Using sequence specific oligonucleotide typing we have identified the DRB1 alleles in panels of Greek RA patients and controls. When patient and control HLA-DRB1 frequencies were compared, significantly higher frequencies of DRB1*0101 (23.3% vs. 7.0%, odds ratio [OR] 4.0, 95% confidence intervals [CI] 1.4-12.0) and DRB1*1001 (20.9% vs. 5.8%, OR 4.3, 95% CI 1.3-13.7) were found in RA patients compared with controls. No association of DRB1*04 with RA was observed (20.9% vs. 14.0% in controls) confirming earlier reports. However DRB1*04 subtyping demonstrated a small but significant increase of DRB1*0405 in patients (14.0% vs. 3.5%, OR 4.5, 95% CI 1.1-18.9). When the frequency of individuals carrying the shared RA susceptibility epitope was compared between patients and controls it was found to be significantly higher in RA patients (60.5% vs. 22.1%, OR 5.4, 95% CI 2.4-12.0). We conclude that the shared epitope is significantly associated with RA in this population, but that it is predominantly accounted for by DRB1*0101 and DRB1*1001. Previous studies of UK RA patients have demonstrated a negative association of DR2 with disease and articular erosions. HLA-DR2 variants, DRB1*1501 and *1502 are not at reduced frequency in Greek RA patients (DRB1*1501, 14.0% in patients vs. 7.0% in controls; DRB1*1502, 7.0% in patients vs. 7.0% in controls). Genes conferring RA resistance may be in linkage disequilibrium with DR2 in UK patients. This does not appear to be the case in Greek RA patients. No association was seen between RA and HLA-DPB1 type.