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1.  Inflammatory bowel disease: Genetic and epidemiologic considerations 
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.
doi:10.3748/wjg.14.338
PMCID: PMC2679123  PMID: 18200657
Crohn's disease; Ulcerative colitis; Interleukin 23; Autophagy; Complex genetics
2.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/ibd.22931
PMCID: PMC3810419  PMID: 22411504
genetics; epidemiology; Crohn's disease
3.  NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2 
Gut  2011;61(7):1028-1035.
Objective
The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD).
Methods
Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts.
Results
Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10−5, OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67phox to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD.
Conclusion
These studies suggest that the rare novel p67phox variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.
doi:10.1136/gutjnl-2011-300078
PMCID: PMC3806486  PMID: 21900546
4.  A New Approach for the Joint Analysis of Multiple Chip-Seq Libraries with Application to Histone Modification 
Most approaches for analyzing ChIP-Seq data are focused on inferring exact protein binding sites from a single library. However, frequently multiple ChIP-Seq libraries derived from differing cell lines or tissue types from the same individual may be available. In such a situation, a separate analysis for each tissue or cell line may be inefficient. Here, we describe a novel method to analyze such data that intelligently uses the joint information from multiple related ChIP-Seq libraries. We present our method as a two-stage procedure. First, separate single cell line analysis is performed for each cell line. Here, we use a novel mixture regression approach to infer the subset of genes that are most likely to be involved in protein binding in each cell line. In the second step, we combine the separate single cell line analyses using an Empirical Bayes algorithm that implicitly incorporates inter-cell line correlation. We demonstrate the usefulness of our method using both simulated data, as well as real H3K4me3 and H3K27me3 histone methylation libraries.
doi:10.1515/1544-6115.1660
PMCID: PMC3770480  PMID: 22499701
Empirical Bayes; EM; ChIP-Seq; histone methylation
6.  Inflammatory Bowel Disease 
The New England journal of medicine  2009;361(21):2066-2078.
doi:10.1056/NEJMra0804647
PMCID: PMC3491806  PMID: 19923578
7.  Unraveling the Genetics of Autoimmunity 
Cell  2010;140(6):791-797.
The chronic autoimmune diseases include multiple complex genetic disorders. Recently, genome-wide association studies (GWAS) have identified a large number of major loci, with many associations shared between various autoimmune diseases. These associations highlight key roles for lymphocyte activation and prioritize specific cytokine pathways and mechanisms of host-microbe recognition. Despite success in identifying loci, comprehensive models of disease pathogenesis are currently lacking. Future efforts comparing association patterns between autoimmune diseases may be particularly illustrative. New genomic technologies applied to classic genetic studies involving twins, early onset cases, and phenotypic extremes may provide key insights into developmental and gene-environment interactions in autoimmunity.
doi:10.1016/j.cell.2010.03.003
PMCID: PMC3491807  PMID: 20303870
8.  Improved risk prediction for Crohn's disease with a multi-locus approach 
Human Molecular Genetics  2011;20(12):2435-2442.
Genome-wide association studies have identified numerous loci demonstrating genome-wide significant association with Crohn's disease. However, when many single nucleotide polymorphisms (SNPs) have weak-to-moderate disease risks, genetic risk prediction models based only on those markers that pass the most stringent statistical significance testing threshold may be suboptimal. Haplotype-based predictive models may provide advantages over single-SNP approaches by facilitating detection of associations driven by cis-interactions among nearby SNPs. In addition, these approaches may be helpful in assaying non-genotyped, rare causal variants. In this study, we investigated the use of two-marker haplotypes for risk prediction in Crohn's disease and show that it leads to improved prediction accuracy compared with single-point analyses. With large numbers of predictors, traditional classification methods such as logistic regression and support vector machine approaches may be suboptimal. An alternative approach is to apply the risk-score method calculated as the number of risk haplotypes an individual carries, both within and across loci. We used the area under the curve (AUC) of the receiver operating curve to assess the performance of prediction models in large-scale genetic data, and observed that the prediction performance in the validation cohort continues to improve as thousands of haplotypes are included in the model, with the AUC reaching its plateau at 0.72 at ∼7000 haplotypes, and begins to gradually decline after that point. In contrast, using the SNP as predictors, we only obtained maximum AUC of 0.65. Validation studies in independent cohorts further support improved prediction capacity with multi-marker, as opposed to single marker analyses.
doi:10.1093/hmg/ddr116
PMCID: PMC3298027  PMID: 21427131
9.  Genetic Variants in the Region Harbouring IL2/IL21 Associated to Ulcerative Colitis 
Gut  2009;58(6):799-804.
Objectives
Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBD) known as Crohn’s disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in celiac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that IL2 and IL21 play in the immune response also make them attractive candidates for inflammatory bowel disease. Our objective was to test for association between the IL2/IL21 locus and the inflammatory bowel diseases.
Methods
The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated to celiac disease were genotyped in 1590 IBD cases and 929 controls from the Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed.
Results
All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p= 1.35×10−10, rs13119723 p= 8.60×10−8, rs6840978 p= 3.07×10−8, rs6822844 p= 2.77×10−9). We also found a moderate association with CD in the pooled analysis (p value range 0.0016–9.86×10−5).
Conclusions
We found a strong association for the IL2/IL21 locus with UC, which also confirms it as a general susceptibility locus for inflammatory disease.
doi:10.1136/gut.2008.166918
PMCID: PMC2757103  PMID: 19201773
Inflammatory bowel disease; ulcerative colitis; Crohn’s disease; IL2; IL21
10.  Finding the missing heritability of complex diseases 
Nature  2009;461(7265):747-753.
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
doi:10.1038/nature08494
PMCID: PMC2831613  PMID: 19812666
11.  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.
doi:10.1038/ng.215
PMCID: PMC2731799  PMID: 19165925
12.  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).
doi:10.1038/ng.275
PMCID: PMC2652837  PMID: 19122664
13.  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.
doi:10.1038/NG.175
PMCID: PMC2574810  PMID: 18587394
14.  MAST3: a Novel IBD Risk Factor that Modulates TLR4 Signaling 
Genes and immunity  2008;9(7):602-612.
Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genomewide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage one, 1530 SNPs were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage two). One intronic variant, rs273506 located in the MAST3 gene was found to be associated in both stages (pooled P=2×10−4). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated to IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays which showed abundant expression of MAST3 in antigen presenting cells and in lymphocytes. The knockdown of MAST3 specifically decreased TLR4 dependent NF-κB activity. Our findings are additional proof of the pivotal role played by modulators of NF-κB activity in IBD pathogenesis.
doi:10.1038/gene.2008.57
PMCID: PMC2574831  PMID: 18650832
MAST3; Inflammatory Bowel Disease; TLR4; NF-κB
15.  Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy 
Journal of Clinical Investigation  2004;113(6):826-835.
Whether and how T cells contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN) has not been well defined. Here, we explore a murine model that spontaneously develops T cell–mediated intestinal inflammation accompanied by pathological features similar to those of human IgAN. Intestinal inflammation mediated by LIGHT, a ligand for lymphotoxin β receptor (LTβR), not only stimulates IgA overproduction in the gut but also results in defective IgA transportation into the gut lumen, causing a dramatic increase in serum polymeric IgA. Engagement of LTβR by LIGHT is essential for both intestinal inflammation and hyperserum IgA syndrome in our LIGHT transgenic model. Impressively, the majority of patients with inflammatory bowel disease showed increased IgA-producing cells in the gut, elevated serum IgA levels, and severe hematuria, a hallmark of IgAN. These observations indicate the critical contributions of dysregulated LIGHT expression and intestinal inflammation to the pathogenesis of IgAN.
doi:10.1172/JCI200420096
PMCID: PMC362120  PMID: 15067315
16.  Clinical Aspects and Pathophysiology of Inflammatory Bowel Disease 
Clinical Microbiology Reviews  2002;15(1):79-94.
doi:10.1128/CMR.15.1.79-94.2002
PMCID: PMC118061  PMID: 11781268
17.  Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice 
Journal of Clinical Investigation  2001;107(5):585-593.
The epithelial cells of the gastrointestinal tract are exposed to toxins and infectious agents that can adversely affect protein folding in the endoplasmic reticulum (ER) and cause ER stress. The IRE1 genes are implicated in sensing and responding to ER stress signals. We found that epithelial cells of the gastrointestinal tract express IRE1β, a specific isoform of IRE1. BiP protein, a marker of ER stress, was elevated in the colonic mucosa of IRE1β–/– mice, and, when exposed to dextran sodium sulfate (DSS) to induce inflammatory bowel disease, mutant mice developed colitis 3–5 days earlier than did wild-type or IRE1β+/– mice. The inflammation marker ICAM-1 was also expressed earlier in the colonic mucosa of DSS-treated IRE1β–/– mice, indicating that the mutation had its impact early in the inflammatory process, before the onset of mucosal ulceration. These findings are consistent with a model whereby perturbations in ER function, which are normally mitigated by the activity of IRE1β, participate in the development of colitis.
PMCID: PMC199427  PMID: 11238559
18.  Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3 
Genes and immunity  2013;14(5):310-316.
The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease etiology in this population, most notably at NOD2, in which three causal, uncommon, and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to a non-Jewish population (145 haplotypes and no haplotypes with P-value < 10−3, respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established Crohn’s disease loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare Crohn’s disease-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.
doi:10.1038/gene.2013.19
PMCID: PMC3785105  PMID: 23615072
haplotype association; Ashkenazi Jewish; Crohn’s disease; NF-κB signaling; synthetic association
19.  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.
doi:10.1371/journal.pgen.1003723
PMCID: PMC3772057  PMID: 24068945
20.  Genome-wide Association Study of N370S Homozygous Gaucher Disease Reveals the Candidacy of CLN8 gene as a Genetic Modifier Contributing to Extreme Phenotypic Variation 
American journal of hematology  2012;87(4):377-383.
Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesized that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate or severe disease category using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for associations using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at p value 1.26 × 10−6. Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients in whom CLN8 risk alleles were over-represented. In an in vitro cell model of GD, CLN8 expression was increased which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.
doi:10.1002/ajh.23118
PMCID: PMC3684025  PMID: 22388998
Gaucher disease; GWAS; genotype/phenotype correlations; phenotypic diversity; modifier genes; CLN8; N370S; GBA mutations
21.  Age and CD161 Expression Contribute to Inter-Individual Variation in Interleukin-23 Response in CD8+ Memory Human T Cells 
PLoS ONE  2013;8(3):e57746.
The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson’s correlation coefficient, r = −0.37, p = 0.001) source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R), RORC (RORγt) and CD161 (KLRB1), whereas RORA (RORα) and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001). Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = −0.34, p = 0.05). Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes.
doi:10.1371/journal.pone.0057746
PMCID: PMC3585933  PMID: 23469228
22.  Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease 
Nature Genetics  2011;43(11):1066-1073.
More than a thousand disease susceptibility loci have been identified via genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings generally remain to be defined. We utilize pooled next-generation sequencing to study 56 genes in regions associated to Crohn’s Disease in 350 cases and 350 controls. Follow up genotyping of 70 rare and low-frequency protein-altering variants (MAF ~ .001-.05) in nine independent case-control series (16054 CD patients, 12153 UC patients, 17575 healthy controls) identifies four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association to a novel, protective splice variant in CARD9 (p < 1e-16, OR ~ 0.29), as well as additional associations to coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by providing novel, rare, and likely functional variants that will empower functional experiments and predictive models.
doi:10.1038/ng.952
PMCID: PMC3378381  PMID: 21983784
23.  Effector CD4+ T Cell Expression Signatures and Immune-Mediated Disease Associated Genes 
PLoS ONE  2012;7(6):e38510.
Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune–mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis.
doi:10.1371/journal.pone.0038510
PMCID: PMC3371029  PMID: 22715389
24.  A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci 
PLoS Genetics  2012;8(3):e1002559.
Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.
Author Summary
Crohn's disease causes inflammation of the digestive tract resulting from the interaction of normal gut bacteria with the host immune system in genetically predisposed individuals. People of Jewish heritage have an increased risk of developing Crohn's disease compared to non-Jewish Europeans. So far, 71 genetic variants that increase the risk of Crohn's disease have been identified in individuals of European ancestry. Here, we take advantage of recent technical and methodological advances to explore Crohn's diseases-related genetic variants specific to the Ashkenazi Jewish population. We examined 6,347 individuals whose Jewish ancestry was confirmed by a large number of genetic markers and detected several variants associated with the increased risk of Crohn' disease. We confirmed the involvement of 12 known Crohn's disease risk variants in Ashkenazi Jews and identified novel genetic regions not previously found in non-Jewish European populations. Further studies of these regions may help discover biological pathways affecting susceptibility to Crohn's disease and lead to the development of novel treatments. This study also demonstrates the complementary value of genetic studies in isolated populations, like the Ashkenazim.
doi:10.1371/journal.pgen.1002559
PMCID: PMC3297573  PMID: 22412388
25.  l-Histidine Decarboxylase and Tourette's Syndrome 
The New England journal of medicine  2010;362(20):1901-1908.
Summary
Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding l-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics.
doi:10.1056/NEJMoa0907006
PMCID: PMC2894694  PMID: 20445167

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