Classical Human Leukocyte Antigen Alleles Research Articles

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQβ1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

HLA-C*07:01 and HLA-DQB1*02:01 protect against white matter hyperintensities and deterioration of cognitive function: A population-based cohort study

BackgroundNeuroinflammation and aberrant immune regulation are increasingly implicated in the pathophysiology of white matter hyperintensities (WMH), an imaging marker of cerebrovascular pathologies and predictor of cognitive impairment. The role of human leukocyte antigen (HLA) genes, critical in immunoregulation and associated with susceptibility to neurodegenerative diseases, in WMH pathophysiology remains unexplored. MethodsWe performed association analyses between classical HLA alleles and WMH volume, derived from MRI scans of 38 302 participants in the UK Biobank. To identify independent functional alleles driving these associations, we conducted conditional forward stepwise regression and lasso regression. We further investigated whether these functional alleles showed consistent associations with WMH across subgroups characterized by varying levels of clinical determinants. Additionally, we validated the clinical relevance of the identified alleles by examining their association with cognitive function (n = 147 549) and dementia (n = 460 029) in a larger cohort. FindingsFour HLA alleles (DQB1*02:01, DRB1*03:01, C*07:01, and B*08:01) showed an association with reduced WMH volume after Bonferroni correction for multiple comparisons. Among these alleles, DQB1*02:01 exhibited the most significant association (β = −0.041, 95 % CI: −0.060 to −0.023, p = 1.04 × 10−5). Forward selection and lasso regression analyses indicated that DQB1*02:01 and C*07:01 primarily drove this association. The protective effect against WMH conferred by DQB1*02:01 and C*07:01 persisted in clinically relevant subgroups, with a stronger effect observed in older participants. Carrying DQB1*02:01 and C*07:01 was associated with higher cognitive function, but no association with dementia was found. InterpretationOur population-based findings support the involvement of immune-associated mechanisms, particularly both HLA class I and class II genes, in the pathogenesis of WMH and subsequent consequence of cognitive functions.

Partitioning genetic effects on birthweight at classical human leukocyte antigen loci into maternal and fetal components, using structural equation modelling.

Single nucleotide polymorphisms in the human leukocyte antigen (HLA) region in both maternal and fetal genomes have been robustly associated with birthweight (BW) in previous genetic association studies. However, no study to date has partitioned the association between BW and classical HLA alleles into maternal and fetal components. We used structural equation modelling (SEM) to estimate the maternal and fetal effects of classical HLA alleles on BW. Our SEM leverages the data structure of the UK Biobank (UKB), which includes ∼270 000 participants' own BW and/or the BW of their firstborn child. We show via simulation that our model yields asymptotically unbiased estimates of the maternal and fetal allelic effects on BW and appropriate type I error rates, in contrast to simple regression models. Asymptotic power calculations show that we have sufficient power to detect moderate-sized maternal or fetal allelic effects of common HLA alleles on BW in the UKB. Applying our SEM to imputed classical HLA alleles and own and offspring BW from the UKB replicated the previously reported association at the HLA-C locus and revealed strong evidence for maternal (HLA-A*03:01, B*35:01, B*39:06, P <0.001) and fetal allelic effects (HLA-B*39:06, P <0.001) of non-HLA-C alleles on BW. Our model yields asymptotically unbiased estimates, appropriate type I error rates and appreciable power to estimate maternal and fetal effects on BW. These novel allelic associations between BW and classical HLA alleles provide insight into the immunogenetics of fetal growth in utero.

Abstract 3013: The immunogenetic basis of hepatitis B virus-related hepatocellular carcinoma

Abstract Background: The reported associations of genetic variants within the human leukocyte antigen (HLA) region with hepatis B virus (HBV)-related hepatocellular carcinoma (HCC) are not consistent, and the structure-function patterns involved in this disease remain unclear. Methods: Utilizing genotype data from 706 HBV-related HCC cases and 6197 chronic HBV carriers without HCC collected from three resources in Taiwan, we imputed the classical HLA alleles at 2-field resolution and analyzed the molecular landscape of HLA complexes by deeply dissecting their genotypic configurations, functional divergence, and HBV-antigen binding capabilities in associations with the HCC risk. Logistic regression models were used, and all models were adjusted for sex, age, and population structure using the top 10 principal components. We also tested the underlying biological implications of our findings by investigating the HLA binding affinities and HLA effect on control of viral replication (i.e, HBV DNA load), viral population diversity (i.e, quasispecies), and inflammation (i.e, chemokines, cytokines, and soluble programmed cell death 1 [sPD-1]-associated T cell exhaustion). Results: We found high accuracy (≥95% concordance) of HLA imputation at all HLA class I and class II alleles. The strongest evidence for an association with HCC was observed for HLA-DQB1*03:01 (adjusted OR= 1.35 in an additive genetic model, P=1.3×10-6). Three amino acids at specific positions within or near the peptide-binding groove of DQB1 molecules might explain the observed allele association, which leads to loss of binding HBV nucleocapsid protein (i.e., low binding affinity predicted by NetMHCIIpan 4.0 for HLA-DQB1*03:01). HLA-DQB1*03:01 was significantly associated with a higher HBV DNA load (P= 4.3×10-4) and an increased level of serum sPD-1 (P=6.8×10-4), but not with increased levels of chemokines, cytokines, and viral complexity (i.e., Shannon entropy for HBV quasispecies, all P values&amp;gt;0.05). Analysis of HLA zygosity confirmed that HLA-DQB1 heterozygosity was associated with a decreased risk of HCC (adjusted OR=0.77, P= 0.015). Analysis of HLA evolutionary divergence (HED) showed that high HED at HLA-DRB1 loci was marginally associated with a decreased risk of HCC among HLA-DQB1*03:01 non-carriers (P=0.05). Conclusion: Our data shed light on the immunogenetic risk associated with HBV-related HCC. The effect of HLA-DQB1*03:01 could be partly explained by its low binding affinity with HBV nucleocapsid antigen, and/or its effect on viral load control and sPD-1, but not by its control on other inflammation markers (chemokines and cytokines) and viral population diversity. The association between HLA-DQB1 heterozygosity and HCC risk could be independent of the HLA-DQB1*03:01 effect, which indicates underlying mechanisms related to increased immunosurveillance in clearing potential viral antigens or neoantigens. Citation Format: Zhiwei Liu, Chih-Jen Huang, Yu-Han Huang, Mei-Hung Pan, Mei-Hsuan Lee, Mathias Viard, Allan Hildesheim, Ruth M. Pfeiffer, Mary Carrington, Chien-Jen Chen, Tobias L. Lenz, Hwai-I Yang. The immunogenetic basis of hepatitis B virus-related hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3013.

Association of Human Leukocyte Antigen Variants with Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Background: Multiple Myeloma (MM), a neoplasm of terminally differentiated plasma cells that produce a monoclonal immunoglobulin, represents 10% of hematologic malignancies. Virtually all MM arises from monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant phase, at a rate of progression of about 1% annually. However, the risk of progression is not uniform as some individuals with MGUS could have progression rates as high as 58% in 20 years. Novel predictive markers are critically needed to accurately identify MGUS patients at high-risk of malignant transformation, so that early intervention can be implemented to prevent end-organ damage associated with frank myeloma. Genome-wide association studies (GWAS) have repeatedly identified loci at the major histocompatibility complex (MHC) that are associated with the risk of many cancers including MM. However, the impact of specific MHC loci on the MGUS-to-MM progression risk has not been elucidated. Methods: We used the Illumina Infinium Global Screening Array to scan the buffy coat samples of 259 MGUS and 654 MM patients enrolled from the Medical College of Wisconsin (MCW) Tissue Bank. All MGUS and MM patients have been chart reviewed and confirmed diagnosis. After a standard quality control (QC), 249 MGUS and 619 MM patients with 11,882 genotyped single nucleotide polymorphisms (SNPs) in the MHC region (20 to 40 mb at chromosome 6) were used for analysis. The SNP2HLA v1.0.3 software and HLA*IMP:03 were applied to impute classical human leukocyte antigen (HLA) alleles at a four-digit resolution based on SNP genotyping. SNP2HLA uses Beagle to impute all missing SNPs, classical HLA alleles, and amino acid polymorphisms to the HapMap reference panel. HLA*IMP:03 uses the Michigan Imputation Server to impute phased haplotypes to a multi-ethnic panel of 10,561 individuals with SNP genotype data and lab-based typing of alleles at 11 HLA genes. A post-imputation QC was conducted to remove variants with low imputation quality score (R2 < 0.3). Logistic regression analysis was performed using PLINK, a whole genome association analysis toolset, which adjusted for age, race, sex, and top principal components. Results: As evidenced by the quantile-quantile (QQ) plot (Figure 1), there was no evidence for hidden substructure or cryptic relatedness in the GWAS (λ=1.02). The final set of imputed variants from both tools used in association analysis were of high quality (R2 ≥0.9). Although we did not observe any HLA variants showing associations with the progression of MGUS to MM at Bonferroni adjusted significance level for SNP2HLA (P = 0.05/5865 = 8.53 × 10-6) and for HLA*IMP:03 (P = 0.05/215 = 2.33 × 10-4), we found 4 classical HLA alleles and 30 HLA Amino Acids were associated with MGUS progression at a P-value of < 0.05 via association analysis with SNP2HLA. Association analysis for HLA*IMP:03 imputation data identified 8 classical HLA alleles were associated with MGUS progression at P value < 0.05. Among them, two classical HLA alleles were identified in both tools, they are HLA_B*08:01 (odds ratio, OR=0.38, 95% confidence interval, CI =0.19-0.77 and OR=0.43, 95% CI=0.21-0.86 for SNP2HLA and HLA*IMP:03, respectively) and HLA_C*07:01 (OR=0.61, 95% CI=0.41-0.89 and OR=0.63, 95% CI=0.41-0.98 for SNP2HLA and HLA*IMP:03, respectively) (Table 1). Conclusions: These results implicate that HLA alleles may contribute to the progression of MGUS to MM. Further studies are needed to validate our findings with larger sample sizes and explore the biological mechanisms. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Human Leukocyte Antigen Contributes to Childhood Endemic Burkitt Lymphoma in Eastern Africa: A Case-Control Association Study

Background Endemic Burkitt lymphoma (eBL), which occurs at a disproportionately high rate among children in Africa, is associated with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV). Genetic factors, including Human leukocyte antigen (HLA) system, are hypothesized to play a role in eBL by modulating the immune response or susceptibility to associated pathogens. However, the association between HLA and eBL has not been comprehensively evaluated to-date. Methods We investigated the association between HLA variants and eBL among 800 cases and 3,845 controls aged 0-15 years enrolled in two studies: the Epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) study conducted in Uganda, Tanzania and Kenya (2010-2016) and the Infections and Childhood Cancer Study conducted in Malawi (2005-2008). HLA alleles from eight classical HLA genes were imputed from genome wide data (Illumina 5 M array) with the SNP2HLA program using an updated multi-ancestry HLA reference panel (n=21,456). We demonstrated accurate imputation at 2-field resolution by comparing the imputed HLA alleles against HLA alleles obtained by sequence-based typing of 600 EMBLEM participants (200 cases and 400 controls) from Uganda. We performed country-specific association tests using generalized linear mixed models (GLMMs), adjusting for sex (genetic confirmed), age, falciparum positivity, and population structure using the top 3 principal components and accounting for genetic relatedness. Odds ratios (OR) were used to estimate the effect size for each HLA variant and significance was assessed by Wald tests. Meta-analyses were performed to obtain summary effects across countries. For 12 HLA alleles with previously reported associations with severe malaria (e.g., HLA-B*53), EBV antibodies (e.g., HLA-DRB1*15:01) or eBL (e.g., HLA-A*02), were hypothesized, apriori, that we would observe associations with eBL mirroring biologic effects of prior associations. Thus, a P value of 0.05 was considered sufficient for statistical significance. For all other associations, we adjusted for multiple testing with P<2.7×10-4 (correction for 187 tested HLA alleles) used to determine statistical significance for classical HLA alleles at 1- and 2-field resolution and P<1.1×10-6 (correction for 46,350 HLA variants) for all other variants in the HLA region. Conditional analyses were performed to identify HLA variants that independently influence eBL susceptibility. Results We found high concordance rates (>85%) of HLA imputation at all HLA class I and class II alleles of 2-field resolution. The frequency distribution of imputed HLA alleles was similar to that based on sequencing-based HLA typing in a subset of Ugandan participants (Pearson r=0.97). The expected associations between eBL and HLA alleles were only observed for HLA-A*02 and -B*41 based on a nominal p<0.05. More importantly, we found significant associations between eBL and HLA-DQA1*04:01 (adjusted odds ratio [aOR]= 1.61, 95% confidence interval [CI]=1.32 to 1.97, P=3.71×10-6) and SNP rs2040406, located in the HLA-DQA1 region (aOR=1.43 (95%CI=1.26 to 1.63), P=4.62×10-8) (Figure 1). No other HLA alleles or non-allele variants were significantly associated with eBL in conditional analysis on HLA-DQA*04:01 or rs2040406. The novel association with SNP rs2040406 corresponds to a single residue Gln53 within the HLA-DQA1 peptide-binding groove that tracks with rs2040406 (r2 = 0.88) and showed the strongest association among all residues (aOR=1.36, P=2.06×10-6). Conclusions We present a comprehensive investigation of the associations between eBL and HLA variants utilizing imputed HLA data. Consistent associations were observed for two eBL-based apriori-stipulated hypotheses (HLA-A*02 and-B*41); however, contrary to our expectations, the malaria-based apriori hypotheses were not confirmed. Our agnostic analysis identified new associations between eBL and variants in the HLA-DQB1/DQA1 region, thereby providing new directions to explore the underlying relationship between HLA, immunity and eBL risk. In particular, the association of eBL with rs2040406 was attributed to residue Gln53 within the HLA-DQA1 peptide-binding groove. These associations hint at functional effects, perhaps mediated by stronger binding of EBV glycoproteins. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.

Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

A large-scale investigation into the role of classical HLA loci in multiple types of severe infections, with a focus on overlaps with autoimmune and mental disorders

BackgroundInfections are a major disease burden worldwide. While they are caused by external pathogens, host genetics also plays a part in susceptibility to infections. Past studies have reported diverse associations between human leukocyte antigen (HLA) alleles and infections, but many were limited by small sample sizes and/or focused on only one infection.MethodsWe performed an immunogenetic association study examining 13 categories of severe infection (bacterial, viral, central nervous system, gastrointestinal, genital, hepatitis, otitis, pregnancy-related, respiratory, sepsis, skin infection, urological and other infections), as well as a phenotype for having any infection, and seven classical HLA loci (HLA-A, B, C, DPB1, DQA1, DQB1 and DRB1). Additionally, we examined associations between infections and specific alleles highlighted in our previous studies of psychiatric disorders and autoimmune disease, as these conditions are known to be linked to infections.ResultsAssociations between HLA loci and infections were generally not strong. Highlighted associations included associations between DQB1*0302 and DQB1*0604 and viral infections (P = 0.002835 and P = 0.014332, respectively), DQB1*0503 and sepsis (P = 0.006053), and DQA1*0301 with “other” infections (a category which includes infections not included in our main categories e.g. protozoan infections) (P = 0.000369). Some HLA alleles implicated in autoimmune diseases showed association with susceptibility to infections, but the latter associations were generally weaker, or with opposite trends (in the case of HLA-C alleles, but not with alleles of HLA class II genes). HLA alleles associated with psychiatric disorders did not show association with susceptibility to infections.ConclusionsOur results suggest that classical HLA alleles do not play a large role in the etiology of severe infections. The discordant association trends with autoimmune disease for some alleles could contribute to mechanistic theories of disease etiology.

The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian population: evidence from the MyEIRA case-control study

BackgroundFine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy.MethodsWe imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region.ResultsWe confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30–5.49, PGWAS = 7.22 × 10−29) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37–0.62, PGWAS = 2.58 × 10−08). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09–0.30, PGWAS = 1.60 × 10−09). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia.ConclusionsOur results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

BackgroundThe prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. MethodsWe fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). ResultsNo HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). ConclusionsWe found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Common Genetic Variations Associated with the Persistence of Immunity following Childhood Immunization

Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood.Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA) locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1∗0301, HLA DQB1∗0201, HLA DQB1∗0602, and HLA DRB1∗1501, associated with TT-specific immunity, independent of the lead SNP association.

Genome-wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis.

Anti‐nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome‐wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single‐nucleotide polymorphisms rs492899 (P = 3.27 × 10−22; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34‐3.66) and rs1794280 (P = 5.78 × 10−28; OR, 3.89; 95% CI, 3.05‐4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti‐sp100‐positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA‐DRβ1‐Asn77/Arg74, DRβ1‐Ser37, and DPβ1‐Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10−9; OR, 2.97; 95% CI, 2.06‐4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles.

Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina’s Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5. Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A, -B, -C, -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Imputation-Based HLA Typing with SNPs in GWAS Studies.

SNP-based imputation approaches for human leukocyte antigen (HLA) typing take advantage of the extended haplotype structure within the major histocompatibility complex (MHC) to predict classical HLA alleles using dense SNP genotypes, such as those available on chip panels of genome-wide association study (GWAS). These methods enable HLA analyses of classical alleles on existing SNP datasets genotyped in GWAS studies at no extra cost. Here, I describe the workflow of HIBAG, an imputation method with attribute bagging, for obtaining a sample's HLA class I and II genotypes of two-field resolution using SNP data. Two examples are provided to illustrate with a publicly available HLA and SNP dataset: genotype imputation with pre-fit classifiers in GWAS, and model training to build a new classifier.

Human Leukocyte Antigen (HLA) and Immune Regulation: How Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections?

The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the major histocompatibility complex in viral pathogenesis in particular human immunodeficiency virus (HIV) and hepatitis C virus (HCV), is very well documented. We, recently, added a novel insight into the field by identifying the molecular mechanism associated with the protective role of human leukocyte antigen (HLA)-B27/B57 CD8+ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA alleles, including class Ia (HLA-A, -B, -C), class Ib (HLA-E, -F, -G, -H), and class II (HLA-DR, -DQ, -DM, and -DP) in immune regulation and viral pathogenesis (e.g., HIV and HCV). To our knowledge, this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.

Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus

Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 × 10−24; rs2516448, 1.1 × 10−15; and rs3130196, 2.3 × 10−9, respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54–0.67, P = 3.0 × 10−19), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.

Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration.

Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD.

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.