Assuntos
Queimaduras/microbiologia , Infecção dos Ferimentos/microbiologia , Anti-Infecciosos/uso terapêutico , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Queimaduras/diagnóstico , Queimaduras/tratamento farmacológico , Queimaduras/cirurgia , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Humanos , Metagenômica , Resultado do Tratamento , Infecção dos Ferimentos/diagnóstico , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/cirurgiaRESUMO
We identified a consanguineous kindred, of three affected children with severe autoinflammation, resulting in the death of one sibling and allogeneic stem cell transplantation in the other two. All three were homozygous for MEFV p.S208C mutation; however, their phenotype was more severe than previously reported, prompting consideration of an oligogenic autoinflammation model. Further genetic studies revealed homozygous mutations in TRAP1, encoding the mitochondrial/ER resident chaperone protein tumour necrosis factor receptor associated protein 1 (TRAP1). Identification of a fourth, unrelated patient with autoinflammation and compound heterozygous mutation of TRAP1 alone facilitated further functional studies, confirming the importance of this protein as a chaperone of misfolded proteins with loss of function, which may contribute to autoinflammation. Impaired TRAP1 function leads to cellular stress and elevated levels of serum IL-18. This study emphasizes the importance of considering digenic or oligogenic models of disease in particularly severe phenotypes and suggests that autoinflammatory disease might be enhanced by bi-allelic mutations in TRAP1.
Assuntos
Proteínas de Choque Térmico HSP90/genética , Doenças Hereditárias Autoinflamatórias/genética , Mutação , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Consanguinidade , Evolução Fatal , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Doenças Hereditárias Autoinflamatórias/sangue , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Lactente , Recém-Nascido , Interleucina-18/sangue , Masculino , Linhagem , Pirina/genética , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Protein homology search is an important, yet time-consuming, step in everything from protein annotation to metagenomics. Its application, however, has become increasingly challenging, due to the exponential growth of protein databases. In order to perform homology search at the required scale, many methods have been proposed as alternatives to BLAST that make an explicit trade-off between sensitivity and speed. One such method, SANSparallel, uses a parallel implementation of the suffix array neighbourhood search (SANS) technique to achieve high speed and provides several modes to allow for greater sensitivity at the expense of performance. RESULTS: We present a new approach called asymmetric SANS together with scored seeds and an alternative suffix array ordering scheme called optimal substitution ordering. These techniques dramatically improve both the sensitivity and speed of the SANS approach. Our implementation, TOPAZ, is one of the top performing methods in terms of speed, sensitivity and scalability. In our benchmark, searching UniProtKB for homologous proteins to the Dickeya solani proteome, TOPAZ took less than 3 minutes to achieve a sensitivity of 0.84 compared to BLAST. CONCLUSIONS: Despite the trade-off homology search methods have to make between sensitivity and speed, TOPAZ stands out as one of the most sensitive and highest performance methods currently available.
Assuntos
Bases de Dados de Proteínas , Software , Algoritmos , Sequência de Aminoácidos , Proteínas de Bactérias/química , Enterobacteriaceae/metabolismo , Alinhamento de SequênciaRESUMO
The unprecedented growth of high-throughput sequencing has led to an ever-widening annotation gap in protein databases. While computational prediction methods are available to make up the shortfall, a majority of public web servers are hindered by practical limitations and poor performance. Here, we introduce PANNZER2 (Protein ANNotation with Z-scoRE), a fast functional annotation web server that provides both Gene Ontology (GO) annotations and free text description predictions. PANNZER2 uses SANSparallel to perform high-performance homology searches, making bulk annotation based on sequence similarity practical. PANNZER2 can output GO annotations from multiple scoring functions, enabling users to see which predictions are robust across predictors. Finally, PANNZER2 predictions scored within the top 10 methods for molecular function and biological process in the CAFA2 NK-full benchmark. The PANNZER2 web server is updated on a monthly schedule and is accessible at http://ekhidna2.biocenter.helsinki.fi/sanspanz/. The source code is available under the GNU Public Licence v3.
Assuntos
Biologia Computacional/tendências , Ontologia Genética/tendências , Internet , Software , Algoritmos , Bases de Dados de Proteínas/tendências , Sequenciamento de Nucleotídeos em Larga Escala , Anotação de Sequência MolecularRESUMO
We present AAI-profiler, a web server for exploratory analysis and quality control in comparative genomics. AAI-profiler summarizes proteome-wide sequence search results to identify novel species, assess the need for taxonomic reclassification and detect multi-isolate and contaminated samples. AAI-profiler visualises results using a scatterplot that shows the Average Amino-acid Identity (AAI) from the query proteome to all similar species in the sequence database. Taxonomic groups are indicated by colour and marker styles, making outliers easy to spot. AAI-profiler uses SANSparallel to perform high-performance homology searches, making proteome-wide analysis possible. We demonstrate the efficacy of AAI-profiler in the discovery of a close relationship between two bacterial symbionts of an omnivorous pirate bug (Orius) and a thrip (Frankliniella occidentalis), an important pest in agriculture. The symbionts represent novel species within the genus Rosenbergiella so far described only in floral nectar. AAI-profiler is easy to use, the analysis presented only required two mouse clicks and was completed in a few minutes. AAI-profiler is available at http://ekhidna2.biocenter.helsinki.fi/AAI.
Assuntos
Proteínas de Bactérias/genética , Chlamydia trachomatis/classificação , Erwinia/classificação , Filogenia , Proteoma/genética , Software , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/classificação , Proteínas de Bactérias/metabolismo , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , Erwinia/genética , Erwinia/isolamento & purificação , Expressão Gênica , Genômica/métodos , Heterópteros/microbiologia , Internet , Anotação de Sequência Molecular , Proteoma/classificação , Proteoma/metabolismo , Homologia de Sequência de Aminoácidos , Simbiose/fisiologia , Tisanópteros/microbiologiaRESUMO
Despite metabarcoding being widely used to analyse bacterial community composition, its application in parasitological research remains limited. What interest there has been has focused on previously intractable research settings where traditional methods are inappropriate, for example, in longitudinal studies and studies involving endangered species. In settings such as these, non-invasive sampling combined with metabarcoding can provide a fast and accurate assessment of component communities. In this paper we review the use of metabarcoding in the study of helminth communities in wild mammals, outlining the necessary procedures from sample collection to statistical analysis. We highlight the limitations of the metabarcoding approach and speculate on what type of parasitological study would benefit from such methods in the future.
Assuntos
Animais Selvagens/parasitologia , Código de Barras de DNA Taxonômico/métodos , DNA de Helmintos/genética , Helmintos/genética , Mamíferos/parasitologia , Animais , Biota , DNA de Helmintos/isolamento & purificação , Helmintos/classificação , Manejo de EspécimesRESUMO
MOTIVATION: Haplotype reconstruction is an important tool for understanding the aetiology of human disease. Haplotyping infers the most likely phase of observed genotypes conditional on constraints imposed by the genotypes of other pedigree members. The results of haplotype reconstruction, when visualized appropriately, show which alleles are identical by descent despite the presence of untyped individuals. When used in concert with linkage analysis, haplotyping can help delineate a locus of interest and provide a succinct explanation for the transmission of the trait locus. Unfortunately, the design choices made by existing haplotype visualization programs do not scale to large numbers of markers. Indeed, following haplotypes from generation to generation requires excessive scrolling back and forth. In addition, the most widely used program for haplotype visualization produces inconsistent recombination artefacts for the X chromosome. RESULTS: To resolve these issues, we developed HaploForge, a novel web application for haplotype visualization and pedigree drawing. HaploForge takes advantage of HTML5 to be fast, portable and avoid the need for local installation. It can accurately visualize autosomal and X-linked haplotypes from both outbred and consanguineous pedigrees. Haplotypes are coloured based on identity by descent using a novel A* search algorithm and we provide a flexible viewing mode to aid visual inspection. HaploForge can currently process haplotype reconstruction output from Allegro, GeneHunter, Merlin and Simwalk. AVAILABILITY AND IMPLEMENTATION: HaploForge is licensed under GPLv3 and is hosted and maintained via GitHub. https://github.com/mtekman/haploforge. CONTACT: r.kleta@ucl.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Haplótipos , Linhagem , Software , Algoritmos , Alelos , Gráficos por Computador , Ligação Genética , Genótipo , HumanosRESUMO
The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1ß, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1ß, and their cells also secreted more IL-18 but not IL-1ß in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.
Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Síndromes de Imunodeficiência/genética , Proteínas dos Microfilamentos/genética , Mutação de Sentido Incorreto , Trombocitopenia/genética , Actinas/metabolismo , Criança , Feminino , Doenças Hereditárias Autoinflamatórias/etiologia , Humanos , Síndromes de Imunodeficiência/etiologia , Inflamassomos/fisiologia , Interleucina-18/sangue , Proteínas dos Microfilamentos/fisiologia , Fagocitose , Trombocitopenia/etiologiaRESUMO
BACKGROUND: Competitive gene set analysis is a standard exploratory tool for gene expression data. Permutation-based competitive gene set analysis methods are preferable to parametric ones because the latter make strong statistical assumptions which are not always met. For permutation-based methods, we permute samples, as opposed to genes, as doing so preserves the inter-gene correlation structure. Unfortunately, up until now, sample permutation-based methods have required a minimum of six replicates per sample group. RESULTS: We propose a new permutation-based competitive gene set analysis method for multi-group gene expression data with as few as three replicates per group. The method is based on advanced sample permutation technique that utilizes all groups within a data set for pairwise comparisons. We present a comprehensive evaluation of different permutation techniques, using multiple data sets and contrast the performance of our method, mGSZm, with other state of the art methods. We show that mGSZm is robust, and that, despite only using less than six replicates, we are able to consistently identify a high proportion of the top ranked gene sets from the analysis of a substantially larger data set. Further, we highlight other methods where performance is highly variable and appears dependent on the underlying data set being analyzed. CONCLUSIONS: Our results demonstrate that robust gene set analysis of multi-group gene expression data is permissible with as few as three replicates. In doing so, we have extended the applicability of such approaches to resource constrained experiments where additional data generation is prohibitively difficult or expensive. An R package implementing the proposed method and supplementary materials are available from the website http://ekhidna.biocenter.helsinki.fi/downloads/pashupati/mGSZm.html .
Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Animais , Interpretação Estatística de Dados , Humanos , CamundongosRESUMO
Wasabi is an open source, web-based environment for evolutionary sequence analysis. Wasabi visualizes sequence data together with a phylogenetic tree within a modern, user-friendly interface: The interface hides extraneous options, supports context sensitive menus, drag-and-drop editing, and displays additional information, such as ancestral sequences, associated with specific tree nodes. The Wasabi environment supports reproducibility by automatically storing intermediate analysis steps and includes built-in functions to share data between users and publish analysis results. For computational analysis, Wasabi supports PRANK and PAGAN for phylogeny-aware alignment and alignment extension, and it can be easily extended with other tools. Along with drag-and-drop import of local files, Wasabi can access remote data through URL and import sequence data, GeneTrees and EPO alignments directly from Ensembl. To demonstrate a typical workflow using Wasabi, we reproduce key findings from recent comparative genomics studies, including a reanalysis of the EGLN1 gene from the tiger genome study: These case studies can be browsed within Wasabi at http://wasabiapp.org:8000?id=usecases. Wasabi runs inside a web browser and does not require any installation. One can start using it at http://wasabiapp.org. All source code is licensed under the AGPLv3.
Assuntos
Evolução Molecular , Filogenia , Análise de Sequência/métodos , Software , Algoritmos , Genoma , Internet , Alinhamento de Sequência , Análise de Sequência de DNA , NavegadorRESUMO
While it is known that intestinal parasite communities vary in their composition over time, there is a lack of studies addressing how variation in component communities (between-hosts) manifests in infracommunities (within-host) during the host lifespan. In this study, we investigate the changes in the intestinal parasite infracommunities in wild-living rufous mouse lemurs (Microcebus rufus) from Ranomafana National Park in southeastern Madagascar from 2010 to 2012. We used high-throughput barcoding of the 18S rRNA gene to interrogate parasite community structure. Our results show that in these nematode communities, there were two frequently occurring putative species and four rarer putative species. All putative species were randomly distributed over host individuals and they did not occur in clear temporal patterns. For the individuals caught in at least two different years, there was high turnover of putative species and high variation in fecal egg counts. Our study shows that while there was remarkable variation in infracommunities over time, the component community was relatively stable. Nevertheless, the patterns of prevalence varied substantially between years in each component community.
Assuntos
Cheirogaleidae/parasitologia , Nematoides/fisiologia , Infecções por Nematoides/veterinária , Animais , Fezes/parasitologia , Feminino , Madagáscar/epidemiologia , Masculino , Infecções por Nematoides/epidemiologia , Infecções por Nematoides/parasitologia , Contagem de Ovos de Parasitas/veterinária , Estações do AnoRESUMO
BACKGROUND: Marker gene studies often use short amplicons spanning one or more hypervariable regions from an rRNA gene to interrogate the community structure of uncultured environmental samples. Target regions are chosen for their discriminatory power, but the limited phylogenetic signal of short high-throughput sequencing reads precludes accurate phylogenetic analysis. This is particularly unfortunate in the study of microscopic eukaryotes where horizontal gene flow is limited and the rRNA gene is expected to accurately reflect the species phylogeny. A promising alternative to full phylogenetic analysis is phylogenetic placement, where a reference phylogeny is inferred using the complete marker gene and iteratively extended with the short sequences from a metagenetic sample under study. RESULTS: Based on the phylogenetic placement approach we built Séance, a community analysis pipeline focused on the analysis of 18S marker gene data. Séance combines the alignment extension and phylogenetic placement capabilities of the Pagan multiple sequence alignment program with a suite of tools to preprocess, cluster and visualise datasets composed of many samples. We showcase Séance by analysing 454 data from a longitudinal study of intestinal parasite communities in wild rufous mouse lemurs (Microcebus rufus) as well as in simulation. We demonstrate both improved OTU picking at higher levels of sequence similarity for 454 data and show the accuracy of phylogenetic placement to be comparable to maximum likelihood methods for lower numbers of taxa. CONCLUSIONS: Séance is an open source community analysis pipeline that provides reference-based phylogenetic analysis for rRNA marker gene studies. Whilst in this article we focus on studying nematodes using the 18S marker gene, the concepts are generic and reference data for alternative marker genes can be easily created. Séance can be downloaded from http://wasabiapp.org/software/seance/ .
Assuntos
RNA Ribossômico 18S/genética , Software , Animais , Análise por Conglomerados , Intestinos/parasitologia , Lemur/parasitologia , Funções Verossimilhança , Estudos Longitudinais , Parasitos/classificação , Parasitos/genética , Parasitos/isolamento & purificação , Filogenia , Fluxo de TrabalhoRESUMO
The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.
Assuntos
Glomerulonefrite Membranosa/genética , Receptores da Fosfolipase A2/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Variação Estrutural do Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the ß-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the ß-tubulin autoregulatory MREI (methionine-arginine-glutamic acid-isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild-type ß-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis.
Assuntos
Distúrbios Distônicos/genética , Predisposição Genética para Doença/genética , Mutação/genética , Tubulina (Proteína)/genética , Adulto , Animais , Austrália , Encéfalo/patologia , Distúrbios Distônicos/patologia , Inglaterra , Exoma , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
MOTIVATION: Linkage analysis remains an important tool in elucidating the genetic component of disease and has become even more important with the advent of whole exome sequencing, enabling the user to focus on only those genomic regions co-segregating with Mendelian traits. Unfortunately, methods to perform multipoint linkage analysis scale poorly with either the number of markers or with the size of the pedigree. Large pedigrees with many markers can only be evaluated with Markov chain Monte Carlo (MCMC) methods that are slow to converge and, as no attempts have been made to exploit parallelism, massively underuse available processing power. Here, we describe SWIFTLINK, a novel application that performs MCMC linkage analysis by spreading the computational burden between multiple processor cores and a graphics processing unit (GPU) simultaneously. SWIFTLINK was designed around the concept of explicitly matching the characteristics of an algorithm with the underlying computer architecture to maximize performance. RESULTS: We implement our approach using existing Gibbs samplers redesigned for parallel hardware. We applied SWIFTLINK to a real-world dataset, performing parametric multipoint linkage analysis on a highly consanguineous pedigree with EAST syndrome, containing 28 members, where a subset of individuals were genotyped with single nucleotide polymorphisms (SNPs). In our experiments with a four core CPU and GPU, SWIFTLINK achieves a 8.5× speed-up over the single-threaded version and a 109× speed-up over the popular linkage analysis program SIMWALK. AVAILABILITY: SWIFTLINK is available at https://github.com/ajm/swiftlink. All source code is licensed under GPLv3.
Assuntos
Ligação Genética , Software , Algoritmos , Genômica , Perda Auditiva Neurossensorial/genética , Humanos , Deficiência Intelectual/genética , Cadeias de Markov , Método de Monte Carlo , Linhagem , Polimorfismo de Nucleotídeo Único , Convulsões/genéticaRESUMO
BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
Assuntos
Amelogênese Imperfeita/genética , Proteínas do Esmalte Dentário/genética , Predisposição Genética para Doença/genética , Mutação , Nefrocalcinose/genética , Adolescente , Adulto , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/patologia , Criança , Consanguinidade , Exoma/genética , Saúde da Família , Feminino , Genes Recessivos/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Nefrocalcinose/complicações , Nefrocalcinose/patologia , Linhagem , Análise de Sequência de DNA/métodos , Síndrome , Adulto JovemRESUMO
A revolution is happening in genetics! The decoding of the first genome in 2003 was a large international collaborative effort that took about 13 years at a cost of around $2.7 billion. Now, only a few years later, new technology allows the sequencing of an entire genome within a few weeks--and at a cost of less than $10,000. The vaunted $1000 genome is within reach. These extraordinary advances will undoubtedly transform the way we practice medicine. But, like any new technology, it carries risks, as well as benefits. As physicians, we need to understand the implications in order to best utilise these advances for our patients and to provide informed advice. In this review, our aim is to explain these new technologies, to separate the hype from the reality and to address some of the resulting questions and implications. The practical objective is to provide a simple overview of the available technologies and of purpose to which they are best suited.
Assuntos
Testes Genéticos , Nefropatias/diagnóstico , Nefropatias/genética , Aconselhamento Genético , Predisposição Genética para Doença , Privacidade Genética , Testes Genéticos/métodos , Humanos , Nefropatias/fisiopatologia , Nefropatias/terapia , Farmacogenética , Fenótipo , Medicina de Precisão , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
BACKGROUND: Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population. METHODS: We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method). RESULTS: In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2). CONCLUSIONS: An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.