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1.
PLoS Genet ; 9(9): e1003723, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24068945

RESUMO

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.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Receptores de Interleucina/genética , Ubiquitina-Proteína Ligases/genética , Canadá , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Etnicidade , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único
2.
PLoS Genet ; 7(1): e1001283, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21298027

RESUMO

Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0 x 10⁻5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10⁻² in CelD and < 1 x 10⁻³ in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10⁻8 and 6.39 x 10⁻9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55 x 10⁻¹° and 1.38 x 10⁻¹¹ respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.


Assuntos
Doença Celíaca/genética , Doença de Crohn/genética , Proteínas Ativadoras de GTPase/genética , Predisposição Genética para Doença , Hidroliases/genética , Subunidade beta de Receptor de Interleucina-18/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Interpretação Estatística de Dados , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco
3.
PLoS Genet ; 7(6): e1002158, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21738491

RESUMO

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).


Assuntos
Cromossomos Humanos Par 2/genética , Morte Súbita Cardíaca , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , População Branca/genética , Adulto , Idoso , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/genética , Polimorfismo de Nucleotídeo Único/genética
4.
Nat Genet ; 43(11): 1066-73, 2011 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-21983784

RESUMO

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.


Assuntos
Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Análise de Sequência de DNA , Estudos de Casos e Controles , Linhagem Celular , Predisposição Genética para Doença , Humanos , Proteína Adaptadora de Sinalização NOD2/genética , Splicing de RNA , Receptores de Interleucina/genética
5.
Nat Genet ; 43(3): 246-52, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21297633

RESUMO

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Humanos , Risco
6.
Nat Genet ; 42(4): 332-7, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20228799

RESUMO

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.


Assuntos
Colite Ulcerativa/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana/genética , Metanálise como Assunto , Receptores de IgG/genética
7.
Neurobiol Aging ; 27(5): 691-701, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-15993984

RESUMO

Microglial activation is a key player in the degenerative process that accompanies the deposition of amyloid-beta (Abeta) peptide into senile plaques in Alzheimer's disease (AD) patients. The goal of this study is to identify novel genes involved in microglial activation in response to Abeta peptide. Prompted by the fact that soluble Abeta(1-42) (sAbeta(1-42))-stimulated primary rat microglia produce more tumor necrosis factor-alpha (TNF-alpha) than fibrillar Abeta(1-42) (fAbeta(1-42))-stimulated microglia, we examined gene expression in these cells following stimulation using cDNA arrays. This analysis confirms the upregulation caused by both sAbeta(1-42) and fAbeta(1-42) of pro-inflammatory molecules such as TNF-alpha, interleukin-1beta and macrophage inflammatory protein-1alpha. In addition, other transcripts not previously described in the context of Abeta-induced microglial activation were identified. The modulation of some of these genes within microglial cells seems to be specific to sAbeta(1-42) as compared to fAbeta(1-42) suggesting that different forms of Abeta may activate distinct pathways during the progression of AD. Importantly, we demonstrate that Pde4B, a cAMP-specific phosphodiesterase, is upregulated by Abeta and results in an increased production of TNF-alpha. Inhibition of Pde4B reduces by up to 70% the release of TNF-alpha from sAbeta-stimulated microglial cells, implicating cAMP as an important mediator of Abeta-induced microglial activation.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/fisiologia , Peptídeos beta-Amiloides/farmacologia , Microglia/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Separação Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Citocinas/metabolismo , DNA Complementar/biossíntese , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Isoenzimas/metabolismo , Isoenzimas/fisiologia , Microglia/efeitos dos fármacos , Microglia/enzimologia , Microscopia Eletrônica de Transmissão , Hibridização de Ácido Nucleico , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rolipram/farmacologia
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