BACKGROUND: IBD5, IL23R, and ATG16L1 genetic variations are established Crohn's disease (CD) risks alleles. We evaluated these in a population-based case-control study within a cohort to determine their penetrance, population attributable risk, independence, and relationship to other established CD risk factors, including NOD2. METHODS: DNA from 213 CD, 118 [corrected] ulcerative colitis, and 315 [corrected] healthy control subjects from the population based University of Manitoba IBD Research Registry were genotyped for IBD5 and IL23R single-nucleotide polymorphisms (SNPs),and for the Thr 300Ala ATG16L1 SNP. Univariate and multivariate analyses were performed for these and nongenetic risk factors.We introduce multidimensionality reduction (MDR) to explore gene– gene interactions. RESULTS: ATG16L1, IBD5, and IL23R SNPs were significantly associated with CD. Multivariate analysis showed independent CD association for carriers of ATG16L1 (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.09-3.24), IBD5-IGR2230 (OR = 2.16, 95% CI 1.30-3.59), and IL23R-rs10889677 (OR = 2.13, 95% CI 1.39-3.28) while retaining association for NOD2 mutation carriers (OR = 4.45, 95% CI 2.68-7.38), IBD family history (OR = 2.75, 95% CI 1.42-5.31), tobacco (OR = 2.06, 95% CI 1.35-3.14), and Jewish ethnicity (OR = 20.1, 95% CI 2.16-186.8). IL23R minor variants for Arg381Gln and Intron 6 rs7517848 showed independent, CD protection and 3' untranslated variant rs108896778 showed risk. MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles. Penetrance values for ATG16L1 and IBD5 were 0.27% for heterozygotes, and 0.35% and 0.44%, respectively, for homozygotes. IL23R rs108896778 penetrance was 0.37%. CONCLUSIONS: A population-based analysis of CD risk factors is useful for characterizing the epidemiology of multiple CD genetic and nongenetic risk factors. Gene-gene interactions are likely, but require further evaluation in large population-based cohorts.
BACKGROUND:IBD5, IL23R, and ATG16L1 genetic variations are established Crohn's disease (CD) risks alleles. We evaluated these in a population-based case-control study within a cohort to determine their penetrance, population attributable risk, independence, and relationship to other established CD risk factors, including NOD2. METHODS: DNA from 213 CD, 118 [corrected] ulcerative colitis, and 315 [corrected] healthy control subjects from the population based University of Manitoba IBD Research Registry were genotyped for IBD5 and IL23R single-nucleotide polymorphisms (SNPs),and for the Thr 300Ala ATG16L1 SNP. Univariate and multivariate analyses were performed for these and nongenetic risk factors.We introduce multidimensionality reduction (MDR) to explore gene– gene interactions. RESULTS:ATG16L1, IBD5, and IL23R SNPs were significantly associated with CD. Multivariate analysis showed independent CD association for carriers of ATG16L1 (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.09-3.24), IBD5-IGR2230 (OR = 2.16, 95% CI 1.30-3.59), and IL23R-rs10889677 (OR = 2.13, 95% CI 1.39-3.28) while retaining association for NOD2 mutation carriers (OR = 4.45, 95% CI 2.68-7.38), IBD family history (OR = 2.75, 95% CI 1.42-5.31), tobacco (OR = 2.06, 95% CI 1.35-3.14), and Jewish ethnicity (OR = 20.1, 95% CI 2.16-186.8). IL23R minor variants for Arg381Gln and Intron 6 rs7517848 showed independent, CD protection and 3' untranslated variant rs108896778 showed risk. MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles. Penetrance values for ATG16L1 and IBD5 were 0.27% for heterozygotes, and 0.35% and 0.44%, respectively, for homozygotes. IL23Rrs108896778 penetrance was 0.37%. CONCLUSIONS: A population-based analysis of CD risk factors is useful for characterizing the epidemiology of multiple CD genetic and nongenetic risk factors. Gene-gene interactions are likely, but require further evaluation in large population-based cohorts.
Authors: Daniel J Schaid; Charles M Rowland; David E Tines; Robert M Jacobson; Gregory A Poland Journal: Am J Hum Genet Date: 2001-12-27 Impact factor: 11.025
Authors: A Armuzzi; T Ahmad; K-L Ling; A de Silva; S Cullen; D van Heel; T R Orchard; K I Welsh; S E Marshall; D P Jewell Journal: Gut Date: 2003-08 Impact factor: 23.059
Authors: Cosmas Giallourakis; Monika Stoll; Katie Miller; Jochen Hampe; Eric S Lander; Mark J Daly; Stefan Schreiber; John D Rioux Journal: Am J Hum Genet Date: 2003-05-29 Impact factor: 11.025
Authors: K Negoro; D P B McGovern; Y Kinouchi; S Takahashi; N J Lench; T Shimosegawa; A Carey; L R Cardon; D P Jewell; D A van Heel Journal: Gut Date: 2003-04 Impact factor: 23.059
Authors: Peter J P Croucher; Silvia Mascheretti; Jochen Hampe; Klaus Huse; Henning Frenzel; Monika Stoll; Tim Lu; Susanna Nikolaus; Suk-Kyun Yang; Michael Krawczak; Won Ho Kim; Stefan Schreiber Journal: Eur J Hum Genet Date: 2003-01 Impact factor: 4.246
Authors: Manuel Alvarez-Lobos; Daniela P Pizarro; Christian E Palavecino; Abner Espinoza; Valentina P Sebastián; Juan C Alvarado; Patricio Ibañez; Carlos Quintana; Orlando Díaz; Alexis M Kalergis; Susan M Bueno Journal: World J Gastroenterol Date: 2013-09-21 Impact factor: 5.742
Authors: Lynn Cotterill; Debbie Payne; Scott Levinson; John McLaughlin; Emma Wesley; Mark Feeney; Hilary Durbin; Simon Lal; Alistair Makin; Simon Campbell; Stephen A Roberts; Catherine O'Neill; Cathryn Edwards; William G Newman Journal: Can J Gastroenterol Date: 2010-05 Impact factor: 3.522
Authors: Bu'Hussain Hayee; Farooq Z Rahman; Gavin Sewell; Andrew M Smith; Anthony W Segal Journal: Expert Rev Clin Immunol Date: 2010-07 Impact factor: 4.473