Combined Evidence From Three Large British Association Studies Rejects TUCAN/CARD8 as an IBD Susceptibility Gene
2007; Elsevier BV; Volume: 132; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2007.03.086
ISSN1528-0012
AutoresSheila Fisher, Muddassar M. Mirza, Clive M. Onnie, Dianne Soars, Cathryn M. Lewis, Natalie J. Prescott, Christopher G. Mathew, Jeremy Sanderson, Alastair Forbes, Catherine E Todhunter, Peter T. Donaldson, John Mansfield,
Tópico(s)IL-33, ST2, and ILC Pathways
ResumoThe importance of CARD15 mutations in susceptibility to Crohn's disease (CD)1Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Interleukin-23 drives innate and T cell-mediated intestinal inflammation.J Exp Med. 2001; 203: 2473-2483Google Scholar, 2Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nunez G. Cho J.H. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (4171) Google Scholar, 3Hampe J. Cuthbert A. Croucher P.J.P. Mirza M.M. Mascheretti S. Fisher S. Frenzel H. King K. Hasselmeyer A. MacPherson A.J.S. Bridger S. van Deventer S. Forbes A. Nikolaus S. Lennard-Jones J.E. Foelsch U.R. Krawczak M. Lewis C. Schreiber S. Mathew C.G. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.Lancet. 2001; 357: 1925-1928Abstract Full Text Full Text PDF PubMed Scopus (1016) Google Scholar and its role in the activation of nuclear factor-κB provides a compelling case for the involvement of other genes in this signaling pathway. We therefore read with interest the recent report by McGovern et al4McGovern D.P. Butler H. Ahmad T. Paolucci M. van Heel D.A. Negoro K. Hysi P. Ragoussis J. Travis S.P. Cardon L.R. Jewell D.P. TUCAN (CARD8) genetic variants and inflammatory bowel disease.Gastroenterology. 2006; 131: 1190-1196Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar of a novel association between a variant in the CARD8 gene and inflammatory bowel disease (IBD). The CARD8 protein, also known as TUCAN (tumour–up-regulated CARD-containing antagonist of caspase nine) is a 48-kDa peptide (TUCAN-48; T48) expressed mainly in monocytes, placenta, lymph nodes, and spleen; it interacts directly with caspase-1 and can induce apoptosis. Recently, a second, larger, alternatively spliced isoform of TUCAN, TUCAN-54 (T54), that is over-expressed in some cancer tissues and suppresses caspase-mediated apoptosis, has been described.5Yamamoto M. Torigoe T. Kamiguchi K. Hirohashi Y. Nakanishi K. Nabeta C. Asanuma H. Tsuruma T. Sato T. Hata F. Ohmura T. Yamaguchi K. Kurotaki T. Hirata K. Sato N. A novel isoform of TUCAN is overexpressed in human cancer tissues and suppresses both caspase-8- and caspase-9-mediated apoptosis.Cancer Res. 2005; 65: 8706-8714Crossref PubMed Scopus (25) Google Scholar We undertook screening of the CARD8 gene for sequence variants by sequencing all exons, splice sites, 5′ and 3′ untranslated regions (UTRs) in 24 unrelated IBD patients. Six known single nucleotide polymorphisms (SNPs) were detected: rs10500299 (T54:c.1102G/A or T48:c.938 G/A), rs13745718 (T54:c.1278A/G or T48:c.1114A/G), rs8112588 (T54:c.1395C/T or T48:c.1231C/T), rs2288876 (T54:c.96T/C or T48:c.-29T/C), rs2043211 which causes a premature STOP codon at Cys10 of T48 or a Phe>Ile at residue 52 of T54; and rs12984612 (T54: c.-295A/C only). In addition, 2 novel variants were detected: an insertion AA frameshift mutation at residue 43 of T48 (or residue 98 of T54), resulting in a premature stop codon 25 amino acids downstream, and a -318G/T substitution in exon 1 of T54 5′UTR. The stop codon and frame shift mutations apart, none of the other variants would be predicted to alter the amino acid sequence of the protein. Evaluation of linkage disequilibrium (LD) in an extended sample of 47 patients revealed strong LD (r2 = 0.93) between T54 c.-318G/T and rs12984612, and therefore T54 c.-318G/T was identified as a tagging SNP for rs12984612. All other pairwise values of r2 were <0.6 and no further tagging SNPs could be identified. One SNP, rs8112588, was observed in only 1 individual out of 47 and was therefore not considered further as our study would provide insufficient power to detect association. The remaining 6 SNPs were genotyped in a total of 1399 IBD patients (851 CD, 548 ulcerative colitis [UC]) recruited from Guy's, King's and St Thomas' Hospitals and St Mark's Hospital (London, England) and 652 normal healthy controls, as previously described.6Cuthbert A.P. Fisher S.A. Mirza M.M. King K. Hampe J. Croucher P.J.P. Mascheretti S. Sanderson J. Forbes A. Mansfield J. Schreiber S. Lewis C.M. Mathew C.G. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.Gastroenterology. 2002; 131: 1190-1196Google Scholar, 7Onnie C.M. Fisher S.A. Pattni R. Sanderson J. Forbes A. Lewis C.M. Mathew C.F. Associations of allelic variants of the Multidrug Resistance Gene (ABCB1 or MDR1) and inflammatory bowel disease and their effects on disease behaviour: a case-control study and meta-analysis.Inflamm Bowel Dis. 2006; 12: 263-271Crossref PubMed Scopus (74) Google Scholar No evidence for association was found with SNPs T54 c.-318G/T, rs2288876, T48 p.43 Valfs, rs10500299 or rs3745718. In particular, the frequency of the T48 p.43 Valfs frameshift mutation was 5.1% in IBD cases compared with 6.2% in controls (P = .24). However, a significant increase in the frequency of the stop codon mutation C10X (rs2043211) was observed in both CD (33.3%) and UC cases (32.7%) compared with controls (29.1%) with a combined P value of 0.012 for IBD (Table 1). Our results are in contrast to those of McGovern et al; in their study, the common allele, which encodes a cysteine, rather than the rare stop codon allele, was associated with an increased risk of CD, with the frequency of the stop codon being 35.6% in the Oxford controls compared with 29.1% in the controls from our study. We therefore genotyped C10X_rs2043211 in a second cohort of 791 IBD cases (494 CD, 298 UC) from Newcastle, England,6Cuthbert A.P. Fisher S.A. Mirza M.M. King K. Hampe J. Croucher P.J.P. Mascheretti S. Sanderson J. Forbes A. Mansfield J. Schreiber S. Lewis C.M. Mathew C.G. The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.Gastroenterology. 2002; 131: 1190-1196Google Scholar and 764 British controls, including 249 from Newcastle8Hartland S. Newton J.L. Griffin S.M. Donaldson P.T. A functional polymorphism in the Interleukin-1 receptor gene is associated with increased risk of Helicobacter pylori infection but not with gastric cancer.Dig Dis Sci. 2004; 49: 1545-1550Crossref PubMed Scopus (32) Google Scholar and 515 from the 1958 British Birth Cohort (www.cls.ioe.ac.uk). In this second, independent, case-control cohort, the frequency of the stop codon allele was significantly higher in CD (35%) and UC (35.1%) compared with controls (30.4%) (P = .0037 for IBD; Table 1). Combining our original and replication cohorts, the overall evidence for an association with IBD was highly significant (P = .0003). The pooled odds ratio for the stop codon allele was 1.21 (95% confidence interval [CI], 1.09–1.34) for IBD; similar risks were observed for CD and UC.Table 1CARD8 rs2043211 (C10X) Stop Codon Allele Frequencies in Original, Replication, and Pooled Case Control Cohorts (P value for difference in allele frequency between cases and controls)StudyControlsCDUCIBDN%N%PN%PN%POriginal65229.180933.3.01650232.7.069131133.1.012Replication72930.449535.1.01929736.2.01379235.5.0037Pooled138129.8130434.0.001179934.0.0046210334.0.0003 Open table in a new tab In light of the conflicting results between our cohorts and that of McGovern et al,4McGovern D.P. Butler H. Ahmad T. Paolucci M. van Heel D.A. Negoro K. Hysi P. Ragoussis J. Travis S.P. Cardon L.R. Jewell D.P. TUCAN (CARD8) genetic variants and inflammatory bowel disease.Gastroenterology. 2006; 131: 1190-1196Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar we undertook a meta-analysis across all 3 studies. Using a random effects model,9DerSimonian R. Laird N. Meta-analysis in clinical trials.Control Clin Trials. 1986; 7: 177-188Abstract Full Text PDF PubMed Scopus (29196) Google Scholar the combined odds ratio for IBD associated with the rare stop codon allele was 1.06 (95% CI, 0.81–1.39; P = .65). The corresponding odds ratios for CD and UC were 1.05 (95% CI, 0.78–1.40; P = .77) and 1.09 (95% CI, 0.84–1.40; P = .52), respectively. In summary, our results do not support the conclusions made by McGovern et al4McGovern D.P. Butler H. Ahmad T. Paolucci M. van Heel D.A. Negoro K. Hysi P. Ragoussis J. Travis S.P. Cardon L.R. Jewell D.P. TUCAN (CARD8) genetic variants and inflammatory bowel disease.Gastroenterology. 2006; 131: 1190-1196Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar of an association of the common allele encoding cysteine with CD. Furthermore, we have shown a significant association of the less common allele of this SNP encoding the stop codon with IBD in 2 independent studies. None of the other variants detected from screening of the CARD8 gene have shown any evidence for association. On the basis of the combined evidence across studies, we conclude that CARD8/TUCAN is not likely to be a major susceptibility locus for IBD. TUCAN (CARD8) Genetic Variants and Inflammatory Bowel DiseaseGastroenterologyVol. 131Issue 4PreviewBackground & Aims: The identification of the association between Crohn's disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor κB (NFκB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFκB, making it an excellent candidate gene for gastrointestinal inflammation. Methods: Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. Full-Text PDF
Referência(s)