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1.
Eur J Hum Genet ; 28(3): 313-323, 2020 03.
Article in English | MEDLINE | ID: mdl-31591516

ABSTRACT

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.


Subject(s)
Celiac Disease/genetics , Genetic Loci , Polymorphism, Single Nucleotide , Argentina , Celiac Disease/pathology , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 22/genetics , Europe , Genome-Wide Association Study , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Humans , Intestinal Mucosa/metabolism , Lymphotoxin beta Receptor/genetics , Lymphotoxin beta Receptor/metabolism , NADPH Oxidases/genetics , NADPH Oxidases/metabolism , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/metabolism , rac GTP-Binding Proteins/genetics , rac GTP-Binding Proteins/metabolism , RAC2 GTP-Binding Protein
2.
Genome Med ; 10(1): 97, 2018 12 20.
Article in English | MEDLINE | ID: mdl-30572963

ABSTRACT

BACKGROUND: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. METHODS: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. RESULTS: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. CONCLUSIONS: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.


Subject(s)
Autoimmune Diseases/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Arthritis, Rheumatoid/genetics , Celiac Disease/genetics , Diabetes Mellitus, Type 1/genetics , Genome-Wide Association Study , Humans , Molecular Sequence Annotation , Scleroderma, Systemic/genetics
3.
Methods Mol Biol ; 1793: 111-134, 2018.
Article in English | MEDLINE | ID: mdl-29876894

ABSTRACT

The MHC/HLA region has been consistently associated with a large number of complex traits, including but not limited to, most immune-mediated ones. Efforts to pinpoint drivers of this commonly encountered association peak at the short arm of chromosome 6, however, have been challenging, owing to the high density of genes and the long and extended linkage disequilibrium that are characteristic of this region.The development of methods to impute classical HLA alleles and amino acids from SNP genotyping data has offered an important additional layer of information to the investigators seeking to fine map the signal in the region. As a result, imputation-aided association analyses are now typically employed to shed light on the relationship of this locus with disease susceptibility and response to drugs.In this chapter we discuss how the signal in the HLA region can be interrogated in practice, from performing the imputation to understanding its output and to incorporating it into downstream analysis. In addition, we recount some of the analytical approaches that are commonly used and suggest ways in which the findings from such imputation-aided analyses can be interpreted.


Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , HLA Antigens/genetics , Alleles , Computational Biology/methods , Disease Susceptibility , Genetic Association Studies/methods , Genetic Variation , Genome-Wide Association Study , Genotype , HLA Antigens/immunology , Humans
4.
Eur J Gastroenterol Hepatol ; 30(8): 828-837, 2018 08.
Article in English | MEDLINE | ID: mdl-29787419

ABSTRACT

BACKGROUND: Approximately 5% of patients with celiac disease (CeD) do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T lymphocytes. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. It is not known whether genetic variations play a role in severe progression of CeD to RCDII. PATIENTS AND METHODS: We performed the first genome-wide association study to identify the causal genes for RCDII and the molecular pathways perturbed in RCDII. The genome-wide association study was performed in 38 Dutch patients with RCDII, and the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P<5×10) were replicated in 56 independent French and Dutch patients with RCDII. RESULTS: After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36) but not with CeD susceptibility. SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratification of RCDII biopsies based on rs2041570 genotype showed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells. CONCLUSION: We have identified a novel SNP associated with the severe progression of CeD to RCDII. Our data suggest that genetic susceptibility to CeD might be distinct from the progression to RCDII and suggest a role for Paneth cells in RCDII progression.


Subject(s)
Celiac Disease/genetics , Chromosomes, Human, Pair 7/genetics , Polymorphism, Single Nucleotide , Biopsy , Case-Control Studies , Celiac Disease/diagnosis , Celiac Disease/diet therapy , Celiac Disease/immunology , Diet, Gluten-Free , Disease Progression , Female , France , Gastrointestinal Microbiome/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Immunity, Innate/genetics , Intestine, Small/immunology , Intestine, Small/microbiology , Intestine, Small/pathology , Male , Membrane Proteins/genetics , Multivariate Analysis , Netherlands , Odds Ratio , Paneth Cells/immunology , Paneth Cells/microbiology , Paneth Cells/pathology , Phenotype , Risk Factors , Severity of Illness Index , Treatment Failure
5.
Nat Genet ; 49(2): 256-261, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28067908

ABSTRACT

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.


Subject(s)
Genetic Predisposition to Disease/genetics , Inflammatory Bowel Diseases/genetics , Integrins/genetics , Alleles , Genome-Wide Association Study/methods , Humans , Inflammation/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics
6.
Nat Genet ; 49(2): 269-273, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27992413

ABSTRACT

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.


Subject(s)
Cholangitis, Sclerosing/genetics , Inflammatory Bowel Diseases/genetics , Adaptor Proteins, Signal Transducing/genetics , Alleles , Colitis, Ulcerative/genetics , Genome-Wide Association Study/methods , Humans , Polymorphism, Single Nucleotide/genetics , RNA, Messenger/genetics , Risk Factors
7.
J Autoimmun ; 68: 62-74, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26898941

ABSTRACT

Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases.


Subject(s)
Autoimmune Diseases/genetics , Chromosome Mapping , Gene Expression , Genetic Variation , Genome-Wide Association Study , Quantitative Trait Loci , RNA, Untranslated , Autoimmune Diseases/metabolism , Autophagy/genetics , Celiac Disease/genetics , Celiac Disease/metabolism , Cytokines/metabolism , Gene Expression Regulation , Genetic Predisposition to Disease , Genome, Human , Genomics , High-Throughput Nucleotide Sequencing , Humans , Linkage Disequilibrium , Polymorphism, Single Nucleotide , RNA, Long Noncoding/genetics
8.
Hum Mol Genet ; 25(1): 180-90, 2016 Jan 01.
Article in English | MEDLINE | ID: mdl-26546613

ABSTRACT

Hundreds of genomic loci have been associated with a significant number of immune-mediated diseases, and a large proportion of these associated loci are shared among traits. Both the molecular mechanisms by which these loci confer disease susceptibility and the extent to which shared loci are implicated in a common pathogenesis are unknown. We therefore sought to dissect the functional components at loci shared between two autoimmune diseases: coeliac disease (CeD) and rheumatoid arthritis (RA). We used a cohort of 12 381 CeD cases and 7827 controls, and another cohort of 13 819 RA cases and 12 897 controls, all genotyped with the Immunochip platform. In the joint analysis, we replicated 19 previously identified loci shared by CeD and RA and discovered five new non-HLA loci shared by CeD and RA. Our fine-mapping results indicate that in nine of 24 shared loci the associated variants are distinct in the two diseases. Using cell-type-specific histone markers, we observed that loci which pointed to the same variants in both diseases were enriched for marks of promoters active in CD14+ and CD34+ immune cells (P < 0.001), while loci pointing to distinct variants in one of the two diseases showed enrichment for marks of more specialized cell types, like CD4+ regulatory T cells in CeD (P < 0.0001) compared with Th17 and CD15+ in RA (P = 0.0029).


Subject(s)
Arthritis, Rheumatoid/genetics , Celiac Disease/genetics , Arthritis, Rheumatoid/immunology , CD4-Positive T-Lymphocytes , Celiac Disease/immunology , Chromosome Mapping , Cohort Studies , Genetic Association Studies , Humans , Quantitative Trait Loci
9.
Eur J Hum Genet ; 24(2): 263-70, 2016 Feb.
Article in English | MEDLINE | ID: mdl-25966632

ABSTRACT

Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.


Subject(s)
Arthritis, Rheumatoid/genetics , Inflammatory Bowel Diseases/genetics , Receptors, IgG/biosynthesis , Receptors, IgG/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , DNA Copy Number Variations/genetics , Female , GPI-Linked Proteins/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Inflammatory Bowel Diseases/pathology , Male , Phenotype , Polymorphism, Single Nucleotide
10.
Biomark Insights ; 10: 125-31, 2015.
Article in English | MEDLINE | ID: mdl-26715831

ABSTRACT

Bacterial meningitis (BM) is a pyogenic infection present in the subarachnoid space, potentially fatal and frequently associated with neurological sequelae. During BM, cytokines (CTs) are locally produced. We sought to determine the CTs' clinical role as disease severity predictors in adults, which is not completely clear. Using a bead-based flow cytometric assay, levels of six CTs were determined in cerebrospinal fluid (CSF) and plasma from 18 adult BM patients and 19 uninfected controls. Long-term neurological sequelae were evaluated using the Glasgow Outcome Scale (GOS). All evaluated CTs were higher in CSF than in plasma, and the levels of CSF interleukin (IL)-6, IL-8, IL-10, IL-1ß, and tumor necrosis factor-α and plasma IL-10 and IL-12p70 were significantly higher in patients with severe sepsis than with sepsis, suggesting an association with clinical severity. There was a strong negative correlation between CSF IL-6 and plasma IL-12p70 with GOS score, supporting the possible role of these CTs in the development of neurological long-term sequelae. These findings could be helpful to identify candidates to receive neuroprotective treatments and early physiotherapy schemes.

11.
Diabetes Care ; 38 Suppl 2: S37-44, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26405070

ABSTRACT

Type 1 diabetes (T1D) and celiac disease (CeD) cluster in families and can occur in the same individual. Genetic loci have been associated with susceptibility to both diseases. Our aim was to explore the genetic differences between individuals developing both these diseases (double autoimmunity) versus those with only one. We hypothesized that double autoimmunity individuals carry more of the genetic risk markers that are shared between the two diseases independently. SNPs were genotyped in loci associated with T1D (n=42) and CeD (n=28) in 543 subjects who developed double autoimmunity, 2,472 subjects with T1D only, and 2,223 CeD-only subjects. For identification of loci that were specifically associated with individuals developing double autoimmunity, two association analyses were conducted: double autoimmunity versus T1D and double autoimmunity versus CeD. HLA risk haplotypes were compared between the two groups. The CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CeD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5/DQ8, provided the highest risk for developing double autoimmunity (odds ratio 5.22, P=2.25×10(-29)). We identified a strong HLA risk genotype (DQ2.5/DQ8) predisposing to double autoimmunity, suggesting a dominant role for HLA. Non-HLA loci, CTLA4 and IL2RA, may also confer risk to double autoimmunity. Thus, CeD patients who carry the DQ2.5/DQ8 genotype may benefit from periodic screening of autoantibodies related to T1D.


Subject(s)
Celiac Disease/genetics , Diabetes Mellitus, Type 1/genetics , Autoimmunity/genetics , CTLA-4 Antigen/genetics , Case-Control Studies , Celiac Disease/immunology , Diabetes Mellitus, Type 1/immunology , Female , Gene Frequency , Genetic Association Studies , Genetic Background , Genetic Loci , Genetic Predisposition to Disease , HLA Antigens/genetics , Haplotypes , Humans , Interleukin-2 Receptor alpha Subunit/genetics , Linkage Disequilibrium , Male , Odds Ratio , Polymorphism, Single Nucleotide , Risk
12.
Nat Genet ; 47(9): 1085-90, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26258845

ABSTRACT

Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10(-12); T1D, P = 2.4 × 10(-10); psoriasis, P = 5.9 × 10(-6); celiac disease, P = 1.2 × 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10(-3); T1D, P = 8.6 × 10(-27); celiac disease, P = 6.0 × 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.


Subject(s)
Autoimmune Diseases/genetics , HLA-C Antigens/genetics , HLA-D Antigens/genetics , Histocompatibility Antigens Class I/genetics , Case-Control Studies , Epistasis, Genetic , Genetic Association Studies , Genetic Loci , Genetic Predisposition to Disease , Haplotypes , Humans , Polymorphism, Single Nucleotide , Risk Factors
13.
Best Pract Res Clin Gastroenterol ; 29(3): 399-412, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26060105

ABSTRACT

New insights into the underlying molecular pathophysiology of celiac disease (CeD) over the last few years have been guided by major advances in the fields of genetics and genomics. The development and use of the Immunochip genotyping platform paved the way for the discovery of 39 non-HLA loci associated to CeD, and for follow-up functional genomics studies that pinpointed new disease genes, biological pathways and regulatory elements. By combining information from genetics with gene expression data, it has become clear that CeD is a disease with a dysregulated immune response, which can probably occur in a variety of immune cells. This type of information is crucial for our understanding of the disease and for providing leads for developing alternative therapies to the current gluten-free diet. In this review, we place these genetic findings in a wider context and suggest how they can assist the clinical care of CeD patients.


Subject(s)
Celiac Disease/genetics , Genetic Predisposition to Disease/genetics , Genotype , Humans
14.
Nat Genet ; 47(6): 577-8, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25894500

ABSTRACT

Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and observed five new associations that account for 18% of the genetic risk. Taking these new loci together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.


Subject(s)
Celiac Disease/genetics , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Case-Control Studies , Chromosome Mapping , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Risk , Risk Factors
15.
Eur J Hum Genet ; 23(4): 530-5, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25052311

ABSTRACT

Studies in European populations have contributed to a better understanding of the genetics of complex diseases, for example, in coeliac disease (CeD), studies of over 23 000 European samples have reported association to the HLA locus and another 39 loci. However, these associations have not been evaluated in detail in other ethnicities. We sought to better understand how disease-associated loci that have been mapped in Europeans translate to a disease risk for a population with a different ethnic background. We therefore performed a validation of European risk loci for CeD in 497 cases and 736 controls of north Indian origin. Using a dense-genotyping platform (Immunochip), we confirmed the strong association to the HLA region (rs2854275, P=8.2 × 10(-49)). Three loci showed suggestive association (rs4948256, P=9.3 × 10(-7), rs4758538, P=8.6 × 10(-5) and rs17080877, P=2.7 × 10(-5)). We directly replicated five previously reported European variants (P<0.05; mapping to loci harbouring FASLG/TNFSF18, SCHIP1/IL12A, PFKFB3/PRKCQ, ZMIZ1 and ICOSLG). Using a transferability test, we further confirmed association at PFKFB3/PRKCQ (rs2387397, P=2.8 × 10(-4)) and PTPRK/THEMIS (rs55743914, P=3.4 × 10(-4)). The north Indian population has a higher degree of consanguinity than Europeans and we therefore explored the role of recessively acting variants, which replicated the HLA locus (rs9271850, P=3.7 × 10(-23)) and suggested a role of additional four loci. To our knowledge, this is the first replication study of CeD variants in a non-European population.


Subject(s)
Celiac Disease/genetics , White People/genetics , Alleles , Carrier Proteins/genetics , Chromosome Mapping , Fas Ligand Protein/genetics , Genetic Loci , Genetic Predisposition to Disease , Genotyping Techniques , Humans , India , Inducible T-Cell Co-Stimulator Ligand/genetics , Interleukin-12 Subunit p35/genetics , Isoenzymes/genetics , Phosphofructokinase-2/genetics , Polymorphism, Single Nucleotide , Protein Kinase C/genetics , Protein Kinase C-theta , Reproducibility of Results , Risk Factors , Transcription Factors/genetics , Tumor Necrosis Factors/genetics
16.
Hum Mol Genet ; 24(2): 397-409, 2015 Jan 15.
Article in English | MEDLINE | ID: mdl-25190711

ABSTRACT

Although genome-wide association studies and fine mapping have identified 39 non-HLA loci associated with celiac disease (CD), it is difficult to pinpoint the functional variants and susceptibility genes in these loci. We applied integrative approaches to annotate and prioritize functional single nucleotide polymorphisms (SNPs), genes and pathways affected in CD. CD-associated SNPs were intersected with regulatory elements categorized by the ENCODE project to prioritize functional variants, while results from cis-expression quantitative trait loci (eQTL) mapping in 1469 blood samples were combined with co-expression analyses to prioritize causative genes. To identify the key cell types involved in CD, we performed pathway analysis on RNA-sequencing data from different immune cell populations and on publicly available expression data on non-immune tissues. We discovered that CD SNPs are significantly enriched in B-cell-specific enhancer regions, suggesting that, besides T-cell processes, B-cell responses play a major role in CD. By combining eQTL and co-expression analyses, we prioritized 43 susceptibility genes in 36 loci. Pathway and tissue-specific expression analyses on these genes suggested enrichment of CD genes in the Th1, Th2 and Th17 pathways, but also predicted a role for four genes in the intestinal barrier function. We also discovered an intricate transcriptional connectivity between CD susceptibility genes and interferon-γ, a key effector in CD, despite the absence of CD-associated SNPs in the IFNG locus. Using systems biology, we prioritized the CD-associated functional SNPs and genes. By highlighting a role for B cells in CD, which classically has been described as a T-cell-driven disease, we offer new insights into the mechanisms and pathways underlying CD.


Subject(s)
Celiac Disease/genetics , Interferon-gamma/metabolism , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Celiac Disease/metabolism , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Interferon-gamma/genetics , Molecular Sequence Annotation
17.
Ann Rheum Dis ; 74(4): 762-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-24336335

ABSTRACT

OBJECTIVE: Certain HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) are associated with rheumatoid arthritis (RA). Our objective was to examine the combined effect of these associated variants, calculated as a cumulative genetic risk score (GRS) on RA predisposition, as well as the number of autoantibodies (none, one or two present). METHOD: We calculated four GRSs in 4956 patients and 4983 controls from four European countries. All four scores contained data on 22 non-HLA-risk SNPs, and three scores also contained HLA-DRB1 genotypes but had different HLA typing resolution. Most patients had data on both rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPA). The GRSs were standardised (std.GRS) to account for population heterogeneity. Discrimination between patients and controls was examined by receiveroperating characteristics curves, and the four std.GRSs were compared across subgroups according to autoantibody status. RESULTS: The std.GRS improved its discriminatory ability between patients and controls when HLA-DRB1 data of higher resolution were added to the combined score. Patients had higher mean std.GRS than controls (p=7.9×10(-156)), and this score was significantly higher in patients with autoantibodies (shown for both RF and ACPA). Mean std.GRS was also higher in those with two versus one autoantibody (p=3.7×10(-23)) but was similar in patients without autoantibodies and controls (p=0.12). CONCLUSIONS: The GRS was associated with the number of autoantibodies and to both RF and ACPA positivity. ACPA play a more important role than RF with regards to the genetic risk profile, but stratification of patients according to both RF and ACPA may optimise future genetic studies.


Subject(s)
Arthritis, Rheumatoid/genetics , Autoantibodies/immunology , HLA-DRB1 Chains/genetics , Alleles , Arthritis, Rheumatoid/immunology , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Male , Peptides, Cyclic/immunology , Rheumatoid Factor/immunology , Risk Assessment , Risk Factors , White People
18.
J Pediatr Gastroenterol Nutr ; 59 Suppl 1: S4-7, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24979196

ABSTRACT

In the past few years there has been enormous progress in unraveling the genetic basis of celiac disease (CD). Apart from the well-known association to HLA, there are currently 40 genomic loci associated to CD. Most of these loci show pleiotropic effects across many autoimmune diseases and highlight the importance of a dysregulated immune system in the predisposition to CD. It is still too early, however, to use genetics in clinical practice for predicting individual risk. The major challenge for the future is to translate genetic findings into a better understanding of the underlying disease mechanism and to design new ways to treat CD and prevent its development.


Subject(s)
Celiac Disease/genetics , Genetic Loci , Genetic Predisposition to Disease , Autoimmune Diseases/genetics , Celiac Disease/immunology , Genetic Pleiotropy , HLA Antigens/genetics , Humans , Risk Factors
19.
Eur J Hum Genet ; 22(11): 1321-6, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24896149

ABSTRACT

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with 'true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05-0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r(2), increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r(2) improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r(2) increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results.


Subject(s)
Gene Frequency , Genome, Human , Genome-Wide Association Study , Polymorphism, Single Nucleotide , White People/genetics , Case-Control Studies , Cluster Analysis , Denmark , Genotype , Genotyping Techniques , Humans , Italy , Netherlands , Phenotype , Principal Component Analysis , United Kingdom
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