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1.  Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus 
Nature genetics  2007;40(1):83-89.
Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established1–3. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B6. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs)7,8 and vascular endothelial cells9, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells10. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell–APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.
PMCID: PMC3705866  PMID: 18059267
2.  The Dichotomous Pattern of IL-12R and IL-23R Expression Elucidates the Role of IL-12 and IL-23 in Inflammation 
PLoS ONE  2014;9(2):e89092.
IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans.
PMCID: PMC3931659  PMID: 24586521
3.  Assessment of Complement C4 Gene Copy Number Using the Paralog Ratio Test 
Human mutation  2010;31(7):866-874.
The complement C4 locus is in the class III region of the MHC, and exhibits copy number variation. Complement C4 null alleles have shown association with a number of diseases including systemic lupus erythematosus (SLE). However, most studies to date have used protein immunophenotyping and not direct interrogation of the genome to determine C4 null allele status. Moreover, a lack of accurate C4 gene copy number (GCN) estimation and tight linkage disequilibrium across the disease-associated MHC haplotypes has confounded attempts to establish whether or not these associations are causal. We have therefore developed a high through-put paralog ratio test (PRT) in association with two restriction enzyme digest variant ratio tests (REDVRs) to determine total C4 GCN, C4A GCN, and C4B GCN. In the densely genotyped CEU cohort we show that this method is accurate and reproducible when compared to gold standard Southern blot copy number estimation with a discrepancy rate of 9%. We find a broad range of C4 GCNs in the CEU and the 1958 British Birth Cohort populations under study. In addition, SNP-C4 CNV analyses show only moderate levels of correlation and therefore do not support the use of SNP genotypes as proxies for complement C4 GCN.
PMCID: PMC3567757  PMID: 20506482
complement C4; CNV; lupus; paralog ratio test
4.  MHC region and risk of systemic lupus erythematosus in African-American women 
Human genetics  2011;130(6):807-815.
The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythemathosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case-control study (380 cases, 765 age-matched controls) nested within the prospective Black Women’s Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry in order to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6×10−5) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2×10−4), rs2071349 (OR = 1.53, p = 1.0×10−3), and rs2844580 (OR = 1.43, p = 1.3×10−3) to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p< 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.
PMCID: PMC3215804  PMID: 21695597
systemic lupus erythemathosus; African Americans; major histocompatibility complex; single nucleotide polymorphisms
5.  Contribution of higher risk genes and European admixture to Crohn's disease in African Americans 
Inflammatory bowel diseases  2012;18(12):10.1002/ibd.22931.
Background & Aims
African Americans (AA) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD.
Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 SNPs in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry.
Mean EA was similar among the CD cases and controls (20.9% and 20.4, respectively, p=0.58). No significant admixture differences were observed among cases (211 to 227) stratified by phenotypic sub-classifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, p = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, p=0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (L503F [10.6% CD, 7.6% Controls, p=0.05] and g-207c [41.3% CD, 35.7% Controls, p=0.03], respectively) and IL23R rs2201841 (18.2% CD, 13.8% Controls, p=0.03), but not IRGM variants nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (p=0.05), whereas a more common haplotype isolating g-207c was not.
Specific functional gene variations significantly contribute to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 in recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.
PMCID: PMC3810419  PMID: 22411504
genetics; epidemiology; Crohn's disease
6.  Crohn disease 
Autophagy  2011;7(4):355-374.
Crohn disease (CD) is a chronic and debilitating inflammatory condition of the gastrointestinal tract.1 Prevalence in western populations is 100–150/100,000 and somewhat higher in Ashkenazi Jews. Peak incidence is in early adult life, although any age can be affected and a majority of affected individuals progress to relapsing and chronic disease. Medical treatments rely significantly on empirical corticosteroid therapy and immunosuppression, and intestinal resectional surgery is frequently required. Thus, 80% of patients with CD come to surgery for refractory disease or complications. It is hoped that an improved understanding of pathogenic mechanisms, for example by studying the genetic basis of CD and other forms of inflammatory bowel diseases (IBD), will lead to improved therapies and possibly preventative strategies in individuals identified as being at risk.
PMCID: PMC3842289  PMID: 20729636
Atg16L1; dendritic cells; gastrointestinal; genome-wide association; gut microbiota; inflammatory bowel diseases; IRGM; Paneth cell; ulcerative colitis
7.  Evidence for CRHR1 in multiple sclerosis using supervised machine learning and meta-analysis in 12 566 individuals 
Human Molecular Genetics  2010;19(21):4286-4295.
The primary genetic risk factor in multiple sclerosis (MS) is the HLA-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has yet to be elucidated. Several lines of evidence support a role for neuroendocrine system involvement in autoimmunity which may, in part, be genetically determined. Here, we comprehensively investigated variation within eight candidate hypothalamic–pituitary–adrenal (HPA) axis genes and susceptibility to MS. A total of 326 SNPs were investigated in a discovery dataset of 1343 MS cases and 1379 healthy controls of European ancestry using a multi-analytical strategy. Random Forests, a supervised machine-learning algorithm, identified eight intronic SNPs within the corticotrophin-releasing hormone receptor 1 or CRHR1 locus on 17q21.31 as important predictors of MS. On the basis of univariate analyses, six CRHR1 variants were associated with decreased risk for disease following a conservative correction for multiple tests. Independent replication was observed for CRHR1 in a large meta-analysis comprising 2624 MS cases and 7220 healthy controls of European ancestry. Results from a combined meta-analysis of all 3967 MS cases and 8599 controls provide strong evidence for the involvement of CRHR1 in MS. The strongest association was observed for rs242936 (OR = 0.82, 95% CI = 0.74–0.90, P = 9.7 × 10−5). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted.
PMCID: PMC2951862  PMID: 20699326
8.  Occupational and environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents 
Rheumatology (Oxford, England)  2010;49(11):2172-2180.
Objectives. We examined occupational and non-occupational exposures in relation to risk of SLE in a case–control study conducted through the Canadian Network for Improved Outcomes in SLE (CaNIOS).
Methods. SLE cases (n = 258) were recruited from 11 rheumatology centres across Canada. Controls (without SLE, n = 263) were randomly selected from phone number listings and matched to cases by age, sex and area of residence. Data were collected using a structured telephone interview.
Results. An association was seen with outdoor work in the 12 months preceding diagnosis [odds ratio (OR) 2.0; 95% CI 1.1, 3.8]; effect modification by sun reaction was suggested, with the strongest effect among people who reported reacting to midday sun with a blistering sunburn or a rash (OR 7.9; 95% CI 0.97, 64.7). Relatively strong but imprecise associations were seen with work as an artist working with paints, dyes or developing film (OR 3.9; 95% CI 1.3, 12.3) and work that included applying nail polish or nail applications (OR 10.2; 95% CI 1.3, 81.5). Patients were more likely than controls to report participation in pottery or ceramics work as a leisure activity, with an increased risk among individuals with a total frequency of at least 26 days (OR 2.1; 95% CI 1.1, 3.9). Analyses of potential respirable silica exposures suggested an exposure–response gradient (OR 1.0, 1.4. and 2.1 for zero, one and two or more sources of exposure, respectively; trend test P < 0.01).
Conclusions. This study supports the role of specific occupational and non-occupational exposures in the development of SLE.
PMCID: PMC2954367  PMID: 20675707
Systemic lupus erythematosus; Risk factors; Silica; Ultraviolet radiation; Solvents; Occupation; Environment
9.  LRRK2 Is Involved in the IFN-γ Response and Host Response to Pathogens 
LRRK2 was previously identified as a defective gene in Parkinson’s disease, and it is also located in a risk region for Crohn’s disease. In this study, we aim to determine whether LRRK2 could be involved in immune responses. We show that LRRK2 expression is enriched in human immune cells. LRRK2 is an IFN-γ target gene, and its expression increased in intestinal tissues upon Crohn’s disease inflammation. In inflamed intestinal tissues, LRRK2 is detected in the lamina propria macrophages, B-lymphocytes, and CD103-positive dendritic cells. Furthermore, LRRK2 expression enhances NF-κB–dependent transcription, suggesting its role in immune response signaling. Endogenous LRRK2 rapidly translocates near bacterial membranes, and knockdown of LRRK2 interferes with reactive oxygen species production during phagocytosis and bacterial killing. These observations indicate that LRRK2 is an IFN-γ target gene, and it might be involved in signaling pathways relevant to Crohn’s disease pathogenesis.
PMCID: PMC3156100  PMID: 20921534
10.  Variation Within DNA Repair Pathway Genes and Risk of Multiple Sclerosis 
American Journal of Epidemiology  2010;172(2):217-224.
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system with a prominent genetic component. The primary genetic risk factor is the human leukocyte antigen (HLA)-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has not been elucidated. The authors investigated the relation between variation in DNA repair pathway genes and risk of MS. Single-locus association testing, epistatic tests of interactions, logistic regression modeling, and nonparametric Random Forests analyses were performed by using genotypes from 1,343 MS cases and 1,379 healthy controls of European ancestry. A total of 485 single nucleotide polymorphisms within 72 genes related to DNA repair pathways were investigated, including base excision repair, nucleotide excision repair, and double-strand breaks repair. A single nucleotide polymorphism variant within the general transcription factor IIH, polypeptide 4 gene, GTF2H4, on chromosome 6p21.33 was significantly associated with MS (odds ratio = 0.7, P = 3.5 × 10−5) after accounting for multiple testing and was not due to linkage disequilibrium with HLA-DRB1*1501. Although other candidate genes examined here warrant further follow-up studies, collectively, these results derived from a well-powered study do not support a strong role for common variation within DNA repair pathway genes in MS.
PMCID: PMC3658128  PMID: 20522537
decision trees; DNA repair; epistasis, genetic; genetic variation; multiple sclerosis
11.  Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis 
PLoS Genetics  2013;9(9):e1003723.
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.
Author Summary
Genetic studies of common diseases have seen tremendous progress in the last half-decade primarily due to recent technologies that enable a systematic examination of genetic markers across the entire genome in large numbers of patients and healthy controls. The studies, while identifying genomic regions that influence a person's risk for developing disease, often do not pinpoint the actual gene or gene variants that account for this risk (called a causal gene/variant). A prime example of this can be seen with the 163 genetic risk factors that have recently been associated with the chronic inflammatory bowel diseases known as Crohn's disease and ulcerative colitis. For less than a handful of these 163 is the causative change in the genetic code known. The current study used an approach to directly look at the genetic code for a subset of these and identified a causative change in the genetic code for eight risk factors for ulcerative colitis. This finding is particularly important because it directs biological studies to understand the mechanisms that lead to this chronic life-long inflammatory disease.
PMCID: PMC3772057  PMID: 24068945
12.  CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis 
Human Molecular Genetics  2010;19(11):2331-2340.
The MHC class II transactivator gene (CIITA) is an important transcription factor regulating gene required for HLA class II MHC-restricted antigen presentation. Association with HLA class II variation, particularly HLA-DRB1*1501, has been well-established for multiple sclerosis (MS). In addition, the −168A/G CIITA promoter variant (rs3087456) has been reported to be associated with MS. Thus, a multi-stage investigation of variation within CIITA, DRB1*1501 and MS was undertaken in 6108 individuals. In stage 1, 24 SNPs within CIITA were genotyped in 1320 cases and 1363 controls (n = 2683). Rs4774 (missense +1614G/C; G500A) was associated with MS (P = 4.9 × 10−3), particularly in DRB1*1501 +individuals (P = 1 × 10−4). No association was observed for the −168A/G promoter variant. In stage 2, rs4774 was genotyped in 973 extended families; rs4774*C was also associated with increased risk for MS in DRB1*1501+ families (P = 2.3 × 10−2). In a third analysis, rs4774 was tested in cases and controls (stage 1) combined with one case per family (stage 2) for increased power. Rs4774*C was associated with MS (P = 1 × 10−3), particularly in DRB1*1501+ cases and controls (P = 1 × 10−4). Results obtained from logistic regression analysis showed evidence for interaction between rs4774*C and DRB1*1501 associated with risk for MS (ratio of ORs = 1.72, 95% CI 1.28–2.32, P = 3 × 10−4). Furthermore, rs4774*C was associated with DRB1*1501+ MS when conditioned on the presence (OR = 1.67, 95% CI = 1.19–2.37, P = 1.9 × 10−3) and absence (OR = 1.49, 95% CI = 1.15–1.95, P = 2.3 × 10−3) of CLEC16A rs6498169*G, a putative MS risk allele adjacent to CIITA. Our results provide strong evidence supporting a role for CIITA variation in MS risk, which appears to depend on the presence of DRB1*1501.
PMCID: PMC2865376  PMID: 20211854
13.  Optimus Primer: A PCR enrichment primer design program for next-generation sequencing of human exonic regions 
BMC Research Notes  2010;3:185.
Polymerase chain reaction (PCR) remains a simple, flexible, and inexpensive method for enriching genomic regions of interest for next-generation sequencing. In order to utilize PCR in this context, a major challenge facing researchers is how to generate a very large number of functional PCR primers that will successfully generate useable amplicons. For instance, in an exon-only re-sequencing project targeting 100 genes, each with 10 exons, 1,000 pairs of primers are required. In fact, the reality is often more complex as each gene might have several isoforms and large exons need to be divided to maintain the desired amplicon size. With only a list of gene names, our program Optimus Primer (OP) automatically takes into account all these variables, and can generate primers with no need to provide genome coordinates. More importantly however, OP, unlike other primer design programs, uniquely utilizes Primer3 in an iterative manner that allows the user to progressively design up to four iterations of primer designs. Through a single interface, the user can specify up to four different design parameters with different stringencies, thus increasing the probability that a functional PCR primer pair will be designed for all regions of interest in a single pass of the pipeline.
To demonstrate the effectiveness of the program, we designed PCR primers against 77 genes located in loci associated with ulcerative colitis as part of a candidate gene re-sequencing experiment. We achieved an experimental success rate of 93% or 472 out of 508 amplicons spanning the exonic regions of the 77 genes. Moreover, by automatically passing amplicons that failed primer design through three additional iterations of design parameters, we achieved an additional 170 successful primer pairs or 34% more in a single pass of OP than by conventional methods.
With only a gene list and PCR parameters, a user can produce hundreds of PCR primer designs for regions of interest with a high probability of success in a very short amount of time. Optimus Primer is an essential tool for researchers who want to pursue PCR-based enrichment strategies for next-generation re-sequencing applications. The program can be accessed via website at
PMCID: PMC2916007  PMID: 20609249
14.  A Major Histocompatibility Class I Locus Contributes to Multiple Sclerosis Susceptibility Independently from HLA-DRB1*15:01 
PLoS ONE  2010;5(6):e11296.
In Northern European descended populations, genetic susceptibility for multiple sclerosis (MS) is associated with alleles of the human leukocyte antigen (HLA) Class II gene DRB1. Whether other major histocompatibility complex (MHC) genes contribute to MS susceptibility is controversial.
Methodology/Principal Findings
A case control analysis was performed using 958 single nucleotide polymorphisms (SNPs) spanning the MHC assayed in two independent datasets. The discovery dataset consisted of 1,018 cases and 1,795 controls and the replication dataset was composed of 1,343 cases and 1,379 controls. The most significantly MS-associated SNP in the discovery dataset was rs3135391, a Class II SNP known to tag the HLA-DRB1*15:01 allele, the primary MS susceptibility allele in the MHC (O.R. = 3.04, p<1×10−78). To control for the effects of the HLA-DRB1*15:01 haplotype, case control analysis was performed adjusting for this HLA-DRB1*15:01 tagging SNP. After correction for multiple comparisons (false discovery rate = .05) 52 SNPs in the Class I, II and III regions were significantly associated with MS susceptibility in both datasets using the Cochran Armitage trend test. The discovery and replication datasets were merged and subjects carrying the HLA-DRB1*15:01 tagging SNP were excluded. Association tests showed that 48 of the 52 replicated SNPs retained significant associations with MS susceptibility independently of the HLA-DRB1*15:01 as defined by the tagging SNP. 20 Class I SNPs were associated with MS susceptibility with p-values ≤1×10−8. The most significantly associated SNP was rs4959039, a SNP in the downstream un-translated region of the non-classical HLA-G gene (Odds ratio 1.59, 95% CI 1.40, 1.81, p = 8.45×10−13) and is in linkage disequilibrium with several nearby SNPs. Logistic regression modeling showed that this SNP's contribution to MS susceptibility was independent of the Class II and Class III SNPs identified in this screen.
A MHC Class I locus contributes to MS susceptibility independently of the HLA-DRB1*15:01 haplotype.
PMCID: PMC2892470  PMID: 20593013
15.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
PMCID: PMC3712260  PMID: 18204446
16.  Genetic Variants Near TNFAIP3 on 6q23 are Associated with Systemic Lupus Erythematosus (SLE) 
Nature genetics  2008;40(9):1059-1061.
SLE is an autoimmune disease influenced by genetic and environmental components. We performed a genome-wide association scan (GWAS) and observed novel association evidence with a variant inTNFAIP3(rs5029939, P = 2.89×10−12, OR = 2.29). We also found evidence of two independent signals of association to SLE risk, including one described in Rheumatoid Arthritis. These results establish that genetic variation inTNFAIP3contributes to differential risk for SLE and RA.
PMCID: PMC2772171  PMID: 19165918
17.  Autoimmune diseases: insights from genome-wide association studies 
Human Molecular Genetics  2008;17(R2):R116-R121.
Autoimmune diseases occur when an individual's own immune system attacks and destroys his or her healthy cells and tissues. Although it is clear that environmental stimuli can predispose someone to develop autoimmune diseases, twin- and family-based studies have shown that genetic factors also play an important role in modifying disease risk. Because many of these diseases are relatively common (prevalence in European-derived populations: 0.01–1%) and exhibit a complex mode of inheritance, many DNA sequence variants with modest effect on disease risk contribute to the genetic burden. Recently, the completion of the HapMap project, together with the development of new genotyping technologies, has given human geneticists the tools necessary to comprehensively, and in an unbiased manner, search our genome for DNA polymorphisms associated with many autoimmune diseases. Here we review recent progress made in the identification of genetic risk factors for celiac disease, Crohn's disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and type-1 diabetes using genome-wide association studies (GWAS). Strikingly, GWAS have increased the number of genetic risk variants associated with these autoimmune diseases from 15 before 2006 to 68 now. We summarize what this new genetic landscape teaches us in terms of the pathogenesis of these diseases, and highlight some of the outstanding challenges ahead. Finally, we open a discussion on ways to best maximize the impact of these genetic discoveries where it matters the most, that is for autoimmune disease patients.
PMCID: PMC2782355  PMID: 18852199
18.  Genome-wide association study identifies five novel susceptibility loci for Crohn's disease and implicates a role for autophagy in disease pathogenesis. 
Nature genetics  2007;39(5):596-604.
We present a genome-wide association study of ileal Crohn's disease (CD) and two independent replication studies that identify five novel regions of association to CD. Specifically, in addition to the previously established CARD15 and IL23R associations, we report strong associations with independent replication to variation in the genomic regions encoding the PHOX2B, NCF4 and ATG16L1 genes, as well as a predicted gene on 16q24.1 (FAM92B) and an intergenic region on 10q21.1. We further demonstrate that the ATG16L1 gene is expressed in intestinal epithelial cell lines and that functional knock down of this gene abrogates autophagy of Salmonella typhimurium. Together these findings suggest that autophagy and host cell responses to intra-cellular microbes are involved in the pathogenesis of CD.
PMCID: PMC2757939  PMID: 17435756
19.  Genome-wide association studies: a new window into immune-mediated diseases 
Nature reviews. Immunology  2008;8(8):631-643.
Given the recent explosion of genetic discoveries, 2007 is becoming known to human geneticists as the ‘year of genome-wide association studies’. In fact, more genetic risk factors for common diseases were identified in one year than had been collectively reported prior to 2007. In particular, this year witnessed the uncovering of many susceptibility genes that influence the susceptibility to individual immune-mediated diseases, and others that are shared across more than one disease. Although much work remains to be done, we discuss what effect these studies are having on our understanding of disease pathogenesis and their potential impact on future immunology studies.
PMCID: PMC2750781  PMID: 18654571
Gut  2008;57(6):717-720.
Recent genome-wide association studies in Crohn’s Disease have identified genetic variation within two genes involved in a biological process known as autophagy. These genetic findings reveal an important role for autophagic processes in both gut homeostasis and in the development of chronic inflammation of the gastrointestinal tract.
PMCID: PMC2735854  PMID: 18272545
Crohn’s disease; genetics; autophagy; inflammation
21.  Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease 
Nature genetics  2008;40(9):1107-1112.
Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn’s disease (CD) is associated with SNPs around IRGM1,2, but coding-sequence variation has been excluded as a source of this association2. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
PMCID: PMC2731799  PMID: 19165925
22.  Common variants in the NLRP3 region contribute to Crohn's disease susceptibility 
Nature genetics  2008;41(1):71-76.
We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3), that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (Pcombined = 3.49 × 10−9, odds ratio = 1.78, confidence interval = 1.47–2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1β production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders1,2. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease.
PMCID: PMC2728932  PMID: 19098911
23.  Ulcerative colitis loci on chromosomes 1p36 and 12q15 identified by genome-wide association study 
Nature genetics  2009;41(2):216-220.
Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and pre-existing data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1×10−13, combined OR = 0.73) and 12q15 (rs1558744, combined P = 2.5×10−12, combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0×10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3×10−8, combined OR = 0.56; rs10889677, combined P = 1.3×10−8, combined OR = 1.29).
PMCID: PMC2652837  PMID: 19122664
24.  Genome-wide association defines more than thirty distinct susceptibility loci for Crohn's disease 
Nature genetics  2008;40(8):955-962.
Several new risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further we have combined the data from three studies (a total of 3,230 cases and 4,829 controls) and performed replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 new loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1, and ITLN1. The expanded molecular understanding of the basis of disease offers promise for informed therapeutic development.
PMCID: PMC2574810  PMID: 18587394
25.  Genome-wide Expression Profiling Implicates a MAST3-Regulated Gene Set in Colonic Mucosal Inflammation of Ulcerative Colitis Patients 
Inflammatory Bowel Diseases  2011;18(6):1072-1080.
Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) presumably caused by dysregulated immune responses to the gut microbiota. Genetic association studies have implicated dozens of chromosomal regions or loci in IBD susceptibility. The next challenge is to explain the individual role of each of these modest effect loci in disease state. We have previously identified MAST3 as an IBD susceptibility gene through genetic fine-mapping of the 19p linkage region. Testing MAST3 in a reporter assay provided preliminary evidence that MAST3 modulates the activity of inflammation-related transcription factor nuclear factor kappa B (NF-κB). Here, we further characterized the function of MAST3 through an examination of the influence of the modulation of MAST3 expression on endogenous genome-wide expression patterns. More specifically, we looked at differential gene expression resulting from overexpression and knockdown of the MAST3 gene in epithelial and macrophage cell lines. We highlight a group of genes whose expression is modulated by MAST3 and correlate their expression with NF-κB activity. Their expression was found to be enriched in inflamed mucosal tissue of UC patients, confirming the importance of these genes in IBD. These MAST3-regulated genes are central to mucosal immune responses. Among them are pro-inflammatory cytokines (e.g. CCL20, IL8), regulators of NF-κB (e.g. TNFAIP3, LY96, NFKBIA), genes involved in interferon-induced defense against pathogen invasion (e.g. IFIT1, ISG15) and genes involved in cell adhesion and/or migration (e.g. CD44, TMOD1). Taken together, these results confirm MAST3 as a modulator of the inflammatory response through regulation of immune gene expression in the gut of IBD patients.
PMCID: PMC3269563  PMID: 21994190
MAST3; Inflammatory Bowel Disease; NF-κB

Results 1-25 (39)