TY - JOUR
T1 - Genes involved in the metabolism of poly-unsaturated fatty-acids (PUFA) and risk for Crohn's disease in children & young adults
AU - Costea, Irina
AU - Mack, David R.
AU - Israel, David
AU - Morgan, Kenneth
AU - Krupoves, Alfreda
AU - Seidman, Ernest
AU - Deslandres, Colette
AU - Lambrette, Philippe
AU - Grimard, Guy
AU - Levy, Emile
AU - Amre, Devendra K.
PY - 2010
Y1 - 2010
N2 - Background and Objectives:Epidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn's disease (CD) is unclear, although the key metabolite leucotriene B4 (LTB4) is closely linked to the inflammatory process. We hypothesized that inherited variation in key PUFA metabolic enzymes may modify susceptibility for CD. Methods and Principal Results: A case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children ≤20 yrs diagnosed with CD and controls were recruited. 19 single nucleotide polymorphisms (SNPs) across the ALOX5 (4) CYP4F3 (5) and CYP4F2 (10) genes, were genotyped. Associations between SNPs/haplotypes and CD were examined. A total of 431 cases and 507 controls were studied. The mean (±SD) age of the cases was 12.4 (±3.3) years. Most cases were male (56.4%), had ileo-colonic disease (L3±L4, 52.7%) and inflammatory behavior (B1±p, 87%) at diagnosis. One genotyped CYP4F3 SNP (rs2683037) not in Hardy-Weinberg Equilibrium was excluded. No associations with the remaining 4 CYP4F3 SNPs with CD were evident. However haplotype analysis revealed associations with a two-marker haplotype (TG) (rs3794987 & rs1290617) (p = 0.02; permuted p = 0.08). CYP4F2 SNPs, rs3093158 (OR (recessive)= 0.56, 95% CI=0.35-0.89; p = 0.01), rs2074902 (OR (trend)= 1.26, 95% CI = 1.00-1.60; p = 0.05), and rs2108622 (OR (recessive) =1.6, 95% CI = 1.00-2.57; p = 0.05) were significantly associated whereas rs1272 (OR (recessive) = 0.58, 95% CI = 0.30-1.13; p = 0.10) showed suggestions for associations with CD. A haplotype comprising these 4 SNPs was significantly associated (p = 0.007, permuted p = 0.02) with CD. Associations with SNP rs3780901 in the ALOX5 gene were borderline non-significant (OR (dominant) =1.29, 95% CI=0.99-1.67; p=0.056). A haplotype comprising the 4 ALOX5 SNPs (TCAA, p= 0.036) was associated with CD, but did not withstand corrections for multiple comparisons (permuted p = 0.14). Conclusions: Inherited variation in enzymes involved in the synthesis/metabolism of LTB4 may be associated with CD. These findings implicate PUFA metabolism as a important pathway in the CD pathogenesis.
AB - Background and Objectives:Epidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn's disease (CD) is unclear, although the key metabolite leucotriene B4 (LTB4) is closely linked to the inflammatory process. We hypothesized that inherited variation in key PUFA metabolic enzymes may modify susceptibility for CD. Methods and Principal Results: A case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children ≤20 yrs diagnosed with CD and controls were recruited. 19 single nucleotide polymorphisms (SNPs) across the ALOX5 (4) CYP4F3 (5) and CYP4F2 (10) genes, were genotyped. Associations between SNPs/haplotypes and CD were examined. A total of 431 cases and 507 controls were studied. The mean (±SD) age of the cases was 12.4 (±3.3) years. Most cases were male (56.4%), had ileo-colonic disease (L3±L4, 52.7%) and inflammatory behavior (B1±p, 87%) at diagnosis. One genotyped CYP4F3 SNP (rs2683037) not in Hardy-Weinberg Equilibrium was excluded. No associations with the remaining 4 CYP4F3 SNPs with CD were evident. However haplotype analysis revealed associations with a two-marker haplotype (TG) (rs3794987 & rs1290617) (p = 0.02; permuted p = 0.08). CYP4F2 SNPs, rs3093158 (OR (recessive)= 0.56, 95% CI=0.35-0.89; p = 0.01), rs2074902 (OR (trend)= 1.26, 95% CI = 1.00-1.60; p = 0.05), and rs2108622 (OR (recessive) =1.6, 95% CI = 1.00-2.57; p = 0.05) were significantly associated whereas rs1272 (OR (recessive) = 0.58, 95% CI = 0.30-1.13; p = 0.10) showed suggestions for associations with CD. A haplotype comprising these 4 SNPs was significantly associated (p = 0.007, permuted p = 0.02) with CD. Associations with SNP rs3780901 in the ALOX5 gene were borderline non-significant (OR (dominant) =1.29, 95% CI=0.99-1.67; p=0.056). A haplotype comprising the 4 ALOX5 SNPs (TCAA, p= 0.036) was associated with CD, but did not withstand corrections for multiple comparisons (permuted p = 0.14). Conclusions: Inherited variation in enzymes involved in the synthesis/metabolism of LTB4 may be associated with CD. These findings implicate PUFA metabolism as a important pathway in the CD pathogenesis.
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U2 - 10.1371/journal.pone.0015672
DO - 10.1371/journal.pone.0015672
M3 - Article
C2 - 21187935
AN - SCOPUS:78650920450
SN - 1932-6203
VL - 5
JO - PloS one
JF - PloS one
IS - 12
M1 - e15672
ER -