ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study...

Author's reply to: Ankylosing spondylitis: evidence for a non-HLA-B*27 protective effect, Sjef Van Der Linden, Desieree Van Der Heijde

As mentioned in the letter by van der Linden and van der Heijde, Jurgen Braun’s excellent recent paper describing a survey of blood donors by questionnaire, clinical, and magnetic resonance imaging examinations revealed a prevalence of ankylosing spondylitis in B27 positive blood donors (6.4%)1-1 very similar to that reported by Gran et al(6.7%).1-2 It is probable that some of the differences in reported prevalence of ankylosing spondylitis by the various studies are because of methodological differences.

The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis

Objective. To analyze the effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis (AS). Methods. Three hundred sixty- three white British AS patients were studied; 149 were carefully assessed for a range of clinical manifestations, and disease severity was assessed using a structured questionnaire. Limited HLA class I typing and complete HLA-DR typing were performed using DNA-based methods. HLA data from 13,634 healthy white British bone marrow donors were used for comparison. Results. A significant association between DR1 and AS was found, independent of HLA-B27 (overall odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8, P = 0.02; relative risk [RR] 2.7, 95% CI 1.5-4.8, P = 6 x 10-4 among homozygotes; RR 2.1, 95% CI 1.5-2.8, P = 5 x 10-6 among heterozygotes). A large but weakly significant association between DR8 and AS was noted, particularly among DR8 homozygotes (RR 6.8, 95% CI 1.6-29.2, P = 0.01 among homozygotes; RR 1.6, 95% CI 1.0-2.7, P = 0.07 among heterozygotes). A negative association with DR12 (OR 0.22, 95% CI 0.09-0.5, P = 0.001) was noted. HLA-DR7 was associated with younger age at onset of disease (mean age at onset 18 years for DR7-positive patients and 23 years for DR7-negative patients; Z score 3.21, P = 0.001). No other HLA class I or class H associations with disease severity or with different clinical manifestations of AS were found. Conclusion. The results of this study suggest that HLA-DR genes may have a weak effect on susceptibility to AS independent of HLA-B27, but do not support suggestions that they affect disease severity or different clinical manifestations.

Susceptibility to ankylosing spondylitis in twins: The role of genes, HLA, and the environment

Objective To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). Methods Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence- specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. Results Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co- twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. Conclusion Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

The effect of HLA-DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin α-tumor necrosis factor haplotype

Objective. HLA-DRB1, a major genetic determinant of susceptibility to rheumatoid arthritis (RA), is located within 1,000 kb of the gene encoding tumor necrosis factor (TNF). Because certain HLA-DRB1*04 subtypes increase susceptibility to RA, investigation of the role of the TNF gene is complicated by linkage disequilibrium (LD) between TNF and DRB1 alleles. By adequately controlling for this LD, we aimed to investigate the presence of additional major histocompatibility complex (MHC) susceptibility genes. Methods. We identified 274 HLA-DRB1*04-positive cases of RA and 271 HLA-DRB1*04-positive population controls. Each subject was typed for 6 single-nucleotide polymorphisms within a 4.5-kb region encompassing TNF and lymphotoxin a (LTA). LTA-TNF haplotypes in these unrelated individuals were determined using a combination of family data and the PHASE software program. Results. Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04. The LTA-TNF haplotypes observed were very restricted, with only 4 haplotypes constituting 81% of all haplotypes present. Among individuals carrying DRB1*0401, the LTA-TNF 2 haplotype was significantly underrepresented in cases compared with controls (odds ratio 0.5 [95% confidence interval 0.3-0.8], P = 0.007), while in those with DRB1*0404, the opposite effect was observed (P = 0.007). Conclusion. These findings suggest that the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to RA.

A method for matching patients to advanced prostate cancer clinical trials

Objective: To illustrate a new method for simplifying patient recruitment for advanced prostate cancer clinical trials using natural language processing techniques. Background: The identification of eligible participants for clinical trials is a critical factor to increase patient recruitment rates and an important issue for discovery of new treatment interventions. The current practice of identifying eligible participants is highly constrained due to manual processing of disparate sources of unstructured patient data. Informatics-based approaches can simplify the complex task of evaluating patient’s eligibility for clinical trials. We show that an ontology-based approach can address the challenge of matching patients to suitable clinical trials. Methods: The free-text descriptions of clinical trial criteria as well as patient data were analysed. A set of common inclusion and exclusion criteria was identified through consultations with expert clinical trial coordinators. A research prototype was developed using Unstructured Information Management Architecture (UIMA) that identified SNOMED CT concepts in the patient data and clinical trial description. The SNOMED CT concepts model the standard clinical terminology that can be used to represent and evaluate patient’s inclusion/exclusion criteria for the clinical trial. Results: Our experimental research prototype describes a semi-automated method for filtering patient records using common clinical trial criteria. Our method simplified the patient recruitment process. The discussion with clinical trial coordinators showed that the efficiency in patient recruitment process measured in terms of information processing time could be improved by 25%. Conclusion: An UIMA-based approach can resolve complexities in patient recruitment for advanced prostate cancer clinical trials.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. © 2013 Nature America, Inc. All rights reserved.

Saviour Siblings and the Regulation of Assisted Reproductive Technology: Harm, Ethics and Law

Advances in the field of Assisted Reproductive Technology (ART) have been revolutionary. This book focuses on the use of ARTs in the context of families who seek to conceive a matching sibling donor as a source of tissue to treat an existing sick child. Such children have been referred to as ‘saviour siblings’. Considering the legal and regulatory frameworks that impact on the accessibility of this technology in Australia and the UK, the work analyses the ethical and moral issues that arise from the use of the technology for this specific purpose. The author claims the only justification for limiting a family’s reproductive liberty in this context is where the exercise of reproductive decision-making results in harm to others. It is argued that the harm principle is the underlying feature of legislative action in Western democratic society, and as such, this principle provides the grounds upon which a strong and persuasive argument is made for a less-restrictive regulatory approach in the context of ‘saviour siblings’.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

A genome-wide asociation study identifies new psoriasis susceptibility loci and an interaction betwEn HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertOk a genome-wide asociation study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified asociations at eight previously unreported genomic loci. Seven loci harbored genes with recognized iMune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These asociations were replicated in 9,079 European samples (six loci with a combined P < 5-10 -8 and two loci with a combined P < 5-10-7). We also report compeLing evidence for an interaction betwEn the HLA-C and ERAP1 loci (combined P = 6.95-10-6). ERAP1 plays an important role in MHC claS I peptide proceSing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk aLele. Our findings implicate pathways that integrate epidermal barrier dysfunction with iNate and adaptive iMune dysregulation in psoriasis pathogenesis.

Predominant association of HLA-B*2704 with ankylosing spondylitis in Chinese Han patients

The HLA-B27 subtypes have a varied racial and ethnic prevalence throughout the world. However, the association of B27-subtypes with ankylosing spondylitis (AS) in the mainland China is unknown. To determine the association of B27-subtypes with AS in the Mainland Chinese Han population, a total of unrelated 153 patients with AS were enrolled in a large case-control association study, and 1545 unrelated, healthy, ethnically matched blood donors were included as controls. The genotyping of B27 and its subtypes was performed using the polymerase chain reaction with sequence specific primers (PCR-SSP). A total of 130 (84.97%) AS patients and 61 (3.95%) healthy controls were B27 positive. Three B27-subtypes, B*2704, B*2705 and B*2710, were further identified, of which both B*2704 and B*2705 were strongly AS associated. B*2710 was only detected in one AS patient and two other healthy controls. Considering only B27-positive cases and controls, a statistically different frequency of B27-subtypes was observed, with an over-representation of B*2704 (P = 0.018). B*2704 was clearly more strongly associated than B*2705 with AS [odds ratio (OR) = 2.4, P = 0.011]. Furthermore, a combined analysis including three previous studies of B27-subtype distributions in Chinese AS cases confirmed the stronger association of B*2704 with AS than B*2705 (OR = 2.5, P = 0.00094).

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Non-inherited maternal HLA alleles are associated with rheumatoid arthritis

Background. Rheumatoid arthritis (RA) is strongly associated with a series of HLA-DRB1 alleles that encode a conserved sequence of amino acids (70Q/R K/R R A A74) in the DRβ1 chain, known as the shared epitope (SE). However 30% of patients are negative for DRB1*04 and 15% are SE-negative. Exposure to these alleles as non-inherited maternal antigens (NIMA) might explain this discrepancy. We undertook a family study to investigate the role of NIMA in RA. Methods. One hundred families, including the RA proband and both parents, were recruited. HLA-DRB1 genotyping was performed using an allele-specific polymerase chain reaction by standard methods. The frequencies of NIMA and non-inherited paternal antigens (NIPA) were compared using contingency tables and a two-tailed P test. We then reviewed four previously published studies of NIMA in RA and conducted an analysis of the combined data Results. We identified 36 families in which the proband was DRB1*04-negative and 13 in which the proband lacked the SE. There was an excess of DRB1*04 and SE NIMA (P=0.05) compared with NIPA. Combined analysis with previous studies showed that 53/231 mothers (23%) versus 25/205 fathers (12%) had a non-inherited DRB1*04 (P=0.003) and 30/99 mothers versus 18/101 fathers had a non-inherited SE allele (P=0.03). Conclusion. A role for HLA NIMA in RA is suggested by these results.