Association of an MHC Class II Haplotype with Increased Risk of Polymyositis in Hungarian Vizsla Dogs

A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 “graded” controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.     

DLA Class II Alleles and Haplotypes Are Associated with Risk for and Protection from Chronic Hepatitis in the English Springer Spaniel

Chronic hepatitis (CH) is common in dogs in the United Kingdom. An increased prevalence of the disease is seen in the English Springer spaniel (ESS), and this breed suffer from a severe form with young to middle aged female dogs being predisposed. The disease shares histological features with those of human viral hepatitis, although the specific aetiological agent has not yet been identified. The aim of the current study was to investigate whether dog leucocyte antigen (DLA) class II alleles and haplotypes are associated with susceptibility/resistance to CH in the ESS. Sequence-based genotyping of the polymorphic exon 2 from DLA-DRB1, -DQA1 and -DQB1 class II loci were performed in 66 ESSs with CH and 84 healthy controls. There was a significant difference in the distribution of the protective alleles DRB1*00501 (3.0% vs. 12.0%, odds ratio [OR] = 0.23, 95% confidence interval [CI] = 0.06–0.74) and DQB1*00501 (3.8% vs. 12.0%, OR = 0.29, 95% CI = 0.09–0.85) between cases and controls. The haplotype DLA-DRB1*00501/DQA1*00301/DQB1*00501 was present in 11.9% of controls and 3.0% of cases and was significantly associated with protection against disease development (OR = 0.26, 95% CI = 0.08–0.80). There was a significant difference in the distribution of the risk alleles DRB1*00601 (14.4% vs. 6.5%, OR = 2.40, 95% CI = 1.10–5.63) and DQB1*00701 (14.4% vs. 6.5%, OR = 2.40, 95% CI = 1.10–5.63) between cases and controls. A risk haplotype (DLA-DRB1*00601/DQA1*005011/DQB1*00701) was present in 14.4% of cases and 6.5% of controls and conferred an elevated risk of developing CH with an OR of 3.13 (95% CI = 1.20–8.26). These results demonstrate that DLA class II is significantly associated with risk and protection from developing CH in ESSs.     

High-Density SNP Screening of the Major Histocompatibility Complex in Systemic Lupus Erythematosus Demonstrates Strong Evidence for Independent Susceptibility Regions

A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10⁻¹⁶). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10⁻¹²), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10⁻¹³. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.     

Polymorphism Located between CPT1B and CHKB,and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

Background

SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy.

Principal Findings

EHS was significantly associated with SNP rs5770917 (P_allele = 3.6×10⁻³; OR = 1.56; 95% c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (P _positivity = 9.2×10⁻¹¹; OR = 3.97; 95% c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS.

Conclusion

CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy.     

MHC class II polymorphism is associated with a canine SLE-related disease complex

Nova Scotia duck tolling retrievers are predisposed to a SLE-related disease complex including immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis–arteritis (SRMA). IMRD involves symptoms that resemble those seen in systemic autoimmune rheumatic diseases, such as systemic lupus erythematosus, SLE, or SLE-related diseases, in humans. This disease complex involves persistent lameness, stiffness, mainly after resting, and palpable pain from several joints of extremities. The majority of affected dogs display antinuclear autoantibody (ANA)-reactivity. SRMA is manifested in young dogs with high fever and neck stiffness and can be treated with corticosteroids. We have investigated the possible role of MHC class II as a genetic risk factor in IMRD and SRMA etiology. We performed sequence-based typing of the DLA-DRB1, -DQA1, and -DQB1 class II loci in a total of 176 dogs including 51 IMRD (33 ANA-positive), 49 SRMA cases, and 78 healthy controls (two dogs were both IMRD- and SRMA-affected). Homozygosity for the risk haplotype DRB1*00601/DQA1*005011/DQB1*02001 increased the risk for IMRD (OR?=?4.9; ANA-positive IMRD: OR?=?7.2) compared with all other genotypes. There was a general heterozygote advantage, homozygotes had OR?=?4.4 (ANA-positive IMRD: OR?=?8.9) compared with all heterozygotes. The risk haplotype contains the five amino acid epitope RARAA, known as the shared epitope for rheumatoid arthritis. No association was observed for SRMA. We conclude that DLA class II is a highly significant genetic risk factor for ANA-positive IMRD. The results indicate narrow diversity of DLA II haplotypes and identify an IMRD-related risk haplotype, which becomes highly significant in homozygous dogs.     

HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia

Introduction

Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients'' genotypic risk of developing MS.

Methods and Results

A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10⁻³), *04:05-*03:01 (OR = 2.4, P = 4.4×10⁻⁶) and *03:01-*02:01 (OR = 2.1, P = 1.0×10⁻¹⁵) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10⁻¹¹) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10⁻³) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient''s risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05:02, *06:01 alleles.

Conclusions

These findings show that the association of specific, independent DRB1*-DQB1* haplotypes confers susceptibility or resistance to MS in the MS-prone Sardinian population. The data also supports a functional role for specific residues of the DRB1 and DQB1 proteins in predisposing patients to MS.     

Injection Drug Use Is a Risk Factor for HCV Infection in Urban Egypt

Objective

To identify current risk factors for hepatitis C virus (HCV) transmission in Greater Cairo.

Design and Setting

A 1∶1 matched case-control study was conducted comparing incident acute symptomatic hepatitis C patients in two “fever” hospitals of Greater Cairo with two control groups: household members of the cases and acute hepatitis A patients diagnosed at the same hospitals. Controls were matched on the same age and sex to cases and were all anti-HCV antibody negative. Iatrogenic, community and household exposures to HCV in the one to six months before symptoms onset for cases, and date of interview for controls, were exhaustively assessed.

Results

From 2002 to 2007, 94 definite acute symptomatic HCV cases and 188 controls were enrolled in the study. In multivariate analysis, intravenous injections (OR = 5.0; 95% CI = 1.2–20.2), medical stitches (OR = 4.2; 95% CI = 1.6–11.3), injection drug use (IDU) (OR = 7.9; 95% CI = 1.4–43.5), recent marriage (OR = 3.3; 95% CI = 1.1–9.9) and illiteracy (OR = 3.9; 95% CI = 1.8–8.5) were independently associated with an increased HCV risk.

Conclusion

In urban Cairo, invasive health care procedures remain a source of HCV transmission and IDU is an emerging risk factor. Strict application of standard precautions during health care is a priority. Implementation of comprehensive infection prevention programs for IDU should be considered.     

HLA class II DR-DQ amino acids and insulin-dependent diabetes mellitus: application of the haplotype method.

Insulin-dependent diabetes mellitus (IDDM) HLA class II DRB1-DQA1-DQB1 data from four populations (Norwegian, Sardinian, Mexican American, and Taiwanese) have been analyzed to detect the amino acids involved in the disease process. The combination of sites DRB1#67 and 86; DQA1#47; and DQB1#9, 26, 57, and 70 predicts the IDDM component in these four populations, when the results and criteria of the haplotype method for amino acids, developed in the companion paper in this issue of the Journal, are used. The following sites, either individually, or in various combinations, previously have been suggested as IDDM components: DRB1#57, 70, 71, and 86; DQA1#52; and DQB1#13, 45, and 57 (DQB1#13 and 45 correlates 100% with DQB1#9 and 26). We propose that DQA1#47 is a better predictor of IDDM than is the previously suggested DQA1#52, and we add DRB1#67 and DQB1#70 to the HLA DR-DQ IDDM amino acids. We do not claim to have identified all HLA DR-DQ amino acids-or highly correlated sites-involved in IDDM. The frequencies and predisposing/protective effects of the haplotypes defined by these seven sites have been compared, and the effects on IDDM are consistent across the populations. The strongest susceptible effects came from haplotypes DRB1 *0301/DQA1 *0501/ DQB1*0201 and DRB1*0401-5-7-8/DQA1*0301/ DQB1*0302. The number of strong protective haplotypes observed was larger than the number of susceptible ones; some of the predisposing haplotypes were present in only one or two populations. Although the sites under consideration do not necessarily have a functional involvement in IDDM, they should be highly associated with such sites and should prove to be useful in risk assessment.     

The Interaction between Coagulation Factor 2 Receptor and Interleukin 6 Haplotypes Increases the Risk of Myocardial Infarction in Men

The aim of the study was to investigate if the interaction between the coagulation factor 2 receptor (F2R) and the interleukin 6 (IL6) haplotypes modulates the risk of myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP). Seven SNPs at the F2R locus and three SNPs at the IL6 locus were genotyped. Haplotypes and haplotype pairs (IL6*F2R) were generated. A logistic regression analysis was performed to analyze the association of the haplotypes and haplotype pairs with the MI risk. Presence of an interaction between the two haplotypes in each haplotype pair was calculated using two different methods: the statistical, on a multiplicative scale, which includes the cross product of the two factors into the logistic regression model; the biological, on an additive scale, which evaluates the relative risk associated with the joint presence of both factors. The ratio between the observed and the predicted effect of the joint exposure, the synergy index (S), indicates the presence of a synergy (S>1) or of an antagonism (S<1). None of the haplotypes within the two loci was associated with the risk of MI. Out of 22 different haplotype pairs, the haplotype pair 17 GGG*ADGTCCT was associated with an increased risk of MI with an OR (95%CI) of 1.58 (1.05–2.41) (p = 0.02) in the crude and an OR of 1.72 (1.11–2.67) (p = 0.01) in the adjusted analysis. We observed the presence of an interaction on a multiplicative scale with an OR (95%CI) of 2.24 (1.27–3.95) (p = 0.005) and a slight interactive effect between the two haplotypes on an additive scale with an OR (95%CI) of 1.56 (1.02–2.37) (p = 0.03) and S of 1.66 (0.89–31). In conclusion, our results support the hypothesis that the interaction between these two functionally related genes may influence the risk of MI and suggest new mechanisms involved in the genetic susceptibility to MI.     

Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study

Background

Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.

Methodology/Principal Findings

The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).

Conclusions/Significance

These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.     

HLA and Celiac Disease Susceptibility: New Genetic Factors Bring Open Questions about the HLA Influence and Gene-Dosage Effects

Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.     

Interaction between HLA-DRB1-DQB1 Haplotypes in Sardinian Multiple Sclerosis Population

We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10⁻⁵, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10⁻⁸, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10⁻³, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10⁻²²) and protection (*11, OR = 0.8, Pc = 2.7×10⁻², *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10⁻¹⁶, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10⁻⁴ and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10⁻⁴). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.     

A genome‐wide association study identifies a region strongly associated with symmetrical onychomadesis on chromosome 12 in dogs

Symmetrical onychomadesis causes periodic loss of claws in otherwise healthy dogs. Genome‐wide association analysis in 225 Gordon Setters identified a single region associated with symmetrical onychomadesis on chromosome 12 (spanning about 3.3 mb). A meta‐analysis including also English Setters indicated that this genomic region predisposes for symmetrical onychomadesis in English Setters as well. The associated region spans most of the major histocompatibility complex and nearly 1 Mb downstream. Like many other autoimmune diseases, associations of symmetrical onychomadesis with DLA class II alleles have been reported. In this study, no associated markers were revealed within any of the DLA‐DRB1, ‐DQA1 or ‐DQB1 genes, and the odds for symmetrical onychomadesis in the Gordon Setters were much higher, carrying significant single nucleotide polymorphisms compared to the odds of any of the recorded DLA‐DRB1/DQA1/DQB1 haplotypes. We noticed that some of the associated DLA haplotypes were different between the English Setters and the Gordon Setters. Interestingly, associated SNP chip markers showed a more consistent pattern of allelic variants related to cases or controls regardless of breed. In conclusion, the associated genetic markers identified in this study hold the potential to aid in selection of breeding animals to reduce the frequency of symmetrical onychomadesis in the dog.     

Analysis of SNPs and Haplotypes in Vitamin D Pathway Genes and Renal Cancer Risk

In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR), most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. RCC cases (N = 777) and controls (N = 1,035) were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P) tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP) sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02) and retinoid-X-receptor-alpha (RXRA) (p-value = 0.10) were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991) across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09–1.57) haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3′ of the coding sequence (rs748964, rs3118523), increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings.     

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

Background and Aim

The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.

Methods

High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.

Results

The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).

Conclusions

HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.     

HLA-DRB1 Shared Epitope-Dependent DR-DQ Haplotypes Are Associated with Both Anti-CCP–Positive and –Negative Rheumatoid Arthritis in Chinese Han

The association between Human Leukocyte Antigen (HLA) class II and rheumatoid arthritis (RA) has been extensively studied, but few reported DR-DQ haplotype. Here we investigated the association of HLA-DRB1, DQA1, DQB1, and DR-DQ haplotypes with RA susceptibility and with anti-CCP antibodies in 281 RA patients and 297 control in Han population. High-resolution genotyping were performed. The HLA-DRB1 shared epitope (SE)-encoding allele *0405 displayed the most significant RA association (P = 1.35×10⁻⁶). The grouped DRB1 SE alleles showed great association with RA (P = 3.88×10⁻¹³). The DRB1 DRRAA alleles displayed significant protective effects (P = 0.021). The SE-dependent DR-DQ haplotype SE-DQ3/4/5 remained strong association with both anti-CCP -positive (P = 3.71×10⁻¹³) and -negative RA (P = 3.89×10⁻⁵). Our study revealed that SE alleles and its haplotypes SE-DQ3/4/5 were highly associated with RA susceptibility in Han population. The SE-DQ3/4/5 haplotypes were associated with both anti-CCP positive RA and -negative RA.     

HLA class II DR and DQ genotypes and haplotypes associated with rheumatic fever among a clinically homogeneous patient population of Latvian children

The HLA system is being paid more and more attention because it is very significant in polymorphous immunological reactions. Several studies have suggested that genetic susceptibility to rheumatic fever (RF) and rheumatic heart disease (RHD) is linked to HLA class II alleles. We hypothesized that HLA class II associations within RHD may be more consistent if analysed amongst patients with a relatively homogeneous clinical outcome. A total of 70 RF patients under the age of 18 years were surveyed and analysed in Latvia. HLA genotyping of DQA1, DQB1 and DRB1 was performed using PCR with amplification with sequence-specific primers. We also used results from a previous study of DQB1 and DRB1 genotyping. In the RF patients, HLA class II DQA1*0401 was found more frequently compared to DQA1*0102. In the RF homogeneous patient groups, DQA1*0402 has the highest odds ratio. This is also the case in the multivalvular lesion (MVL) group, together with DQA1*0501 and DQA1*0301. In the chorea minor patients, DQA1*0201 was often found. Significant HLA DQA1 protective genotypes were not detected, although DQA1 genotypes *0103/*0201 and *0301/*0501 were found significantly and frequently. In the distribution of HLA DRB1/DQA1 genotypes, *07/*0201 and *01/*0501 were frequently detected; these also occurred significantly often in the MVL group. The genotype *07/*0201 was frequently found in Sydenhamn's chorea patients that had also acquired RHD, but DRB1*04/DQA1*0401 was often apparent in RF patients without RHD. In the distribution of HLA DQA1/DQB1 genotypes, both in RF patients and in the homogeneous patient groups, the least frequent were *0102/*0602-8. The genotype DQA1*0501 with the DQB1 risk allele *0301 was often found in the MVL group. The genotype *0301/*0401-2 was frequently found in the RF and Sydenhamn's chorea patient groups. The haplotype *07-*0201-*0302 was frequently found in RF and homogeneous patient groups, including the MVL group. In addition, haplotypes *04-*0401-*0301 and *04-*0301-*0401-2 were frequent amongst patients with Sydenhamn's chorea. The protective alleles DQA1*0102 and DQB1*0602-8 in the haplotype DRB1*15 were less frequently found in RF patients. The results of the present study support our hypothesis and indicate that certain HLA class II haplotypes are associated with risk for or protection against RHD and that these associations are more evident in patients in clinically homogeneous groups.     

Relationship between Rad51 G135C and G172T Variants and the Susceptibility to Cancer: A Meta-Analysis Involving 54 Case-Control Studies

Background

The associations between Rad51 gene polymorphisms (G135C and G172T) and risk of cancer have been investigated, but the results were inconclusive. To get a comprehensive evaluation of the association above, we performed a meta-analysis of published studies.

Methods

A computerized search of PubMed, Embase and Web of Knowledge databases for all relevant studies was performed and the data were analyzed in a meta-analysis. The overall odds ratio (OR) with the 95% confidence interval (95% CI) was calculated to assess the strength of the association between Rad51 polymorphisms and cancer risk. Data were analyzed using fixed- or random-effects model when appropriate. Sensitivity analysis and publication bias test were also estimated.

Results

Overall, a total of 54 case-control studies were included in the current meta-analysis, among which 42 studies with 19,142 cases and 20,363 controls for RAD51 G135C polymorphism and 12 studies with 6,646 cases and 6,783 controls for G172T polymorphism. For G135C polymorphism, the pooled results indicated that significantly increased risk was found in overall cancers (homozygote model: OR = 1.776, 95% CI = 1.288–2.449; allelic genetic model: OR = 1.169, 95% CI = 1.016–1.345; recessive model: OR = 1.946, 95% CI = 1.336–2.835), especially in breast cancer (homozygote model: OR = 1.498, 95% CI = 1.026–2.189; recessive model: OR = 1.732, 95% CI  =  1.170–2.562). For G172T polymorphism, a decreased cancer risk was observed in head and neck cancer (homozygote model: OR  =  0.621, 95% CI  =  0.460–0.837; allelic genetic model: OR  =  0.824, 95% CI  =  0.716–0.948; recessive model: OR  =  0.639, 95% CI = 0.488–0.837).

Conclusions

Our results suggested that the Rad51 G135C polymorphism is a candidate for susceptibility to overall cancers, especially to breast cancer, and that the Rad51 G172T might play a protective role in the development of head and neck cancer.     

Access to Water Source,Latrine Facilities and Other Risk Factors of Active Trachoma in Ankober,Ethiopia

Objective

This study aims to determine the prevalence and correlates of active trachoma in Ankober, Ethiopia.

Methods

A cross-sectional community-based study was conducted during July 2007. A total of 507 children (ages 1–9 years), from 232 households were included in the study. All children were examined for trachoma by ophthalmic nurses using the WHO simplified clinical grading system. Interviews and observations were used to assess risk factors. Logistic regression procedures were used to determine associations between potential risk factors and signs of active trachoma.

Results

Overall, the prevalence of active trachoma was found to be 53.9% (95%CI 49.6%–58.2%). Presence of fly-eye (fly contact with the eyelid margin during eye examination) (Odds Ratio (OR) = 4.03 95% CI 1.40–11.59), absence of facial cleanliness (OR = 7.59; 95%CI 4.60–12.52), an illiterate mother (OR = 5.88; 95%CI 2.10–15.95), lack of access to piped water (OR = 2.19; 95%CI 1.14–6.08), and lack of access to latrine facilities (OR = 4.36; 95%CI 1.49–12.74) were statistically significantly associated with increased risk of active trachoma.

Conclusion

Active trachoma among children 1–9 years of age in Ankober is highly prevalent and significantly associated with a number of risk factors including access to water and latrine facilities. Trachoma prevention programs that include improved access to water and sanitation, active fly control, and hygiene education are recommended to lower the burden of trachoma in Ankober, Ethiopia.     

Association of CCR2-CCR5 Haplotypes and CCL3L1 Copy Number with Kawasaki Disease,Coronary Artery Lesions,and IVIG Responses in Japanese Children

Background

The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.

Methodology/Principal Findings

We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., < or > four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)  = 2.25, p = 0.004 and OR = 6.26, p = 0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR = 0.21, p = 0.026) and CAL development (OR = 0.44, p = 0.071).

Conclusions/Significance

The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.