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Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A—C—B—DRB1—DQA—DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA– B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA–C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men1,2, whereas schizophrenia affects men more frequently and severely3–5. All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from HLA alleles6–13. Here we show that the complement component 4 (C4) genes in the MHC locus, recently found to increase risk for schizophrenia14, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10−117 in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59-30.89; p < 10−23 in total), with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjögren’s syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid (p < 10−5 for both C4 and C3) and plasma among adults ages 20-5015–17, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

© 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

© 2015 Nature America, Inc. All rights reserved.Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Objective This paper describes the development of the tests of competence used as part of the General Medical Council’s assessment of potentially seriously deficient doctors. It is illustrated by reference to tests of knowledge and clinical and practical skills created for general practice. Subjects and tests A notional sample of 30 volunteers in ‘good standing’ in the specialty (reference group), 27 practitioners referred to the procedures and four practitioners not referred but who were the focus of concern over their performance. Tests were constructed using available guidelines and a specially convened working group in the specialty. Methods Standards were set using Angoff, modified contrasting group and global judgement methods, as appropriate. Results Tests performed highly reliably, showed evidence of construct validity, intercorrelated at appropriate levels and, at the standards employed, demonstrated good separation of reference and referred groups. Likelihood ratios for above and below standard performance based on competence were large for each test. Seven of 27 doctors referred were shown not to be deficient in both phases of the performance assessment.

Introduction We describe the steps taken to develop an appropriate list of ‘clinical problems’ used to define the content of the objective structured clinical examination (OSCE) component of the Professional and Linguistic Assessments Board (PLAB) examination. Method A blueprint and list of 255 clinical problems was compiled by reviewing PLAB questions, published curricula of the UK Royal Colleges and other sources such as the General Medical Council’s own guidelines. This list was sent to a random sample of 251 successful PLAB candidates who were asked to rate the clinical problems using a scale of ‘seen frequently/seldom/never’ and to 120 members of the accident and emergency (A&E) specialists’ association who were asked to identify ‘important’ tasks. The list was further validated using activity data obtained for consecutive A&E attendances (934) and admissions (6130) at three hospitals. Results After two mailings, 131/251 (52%) former PLAB candidates and 89/120 (74%) A&E specialists replied. All of the 255 clinical problems were seen by some former candidates and were felt to be important by some A&E specialists. Of the 255 problems, 40 were neither rated as important nor as seen frequently/seldom by over 50% of respondents. The 255 clinical problems covered a mean 94% consecutive A&E attendances and 97·6% reasons for hospital admission. The correlation between clinical problems that were frequently encountered and those felt to be important was rho=0·38 (P