Abstract
Background and ObjectivesEpidemiological 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 ResultsA 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).ConclusionsInherited 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.
Highlights
Crohn’s disease (CD) a chronic inflammatory bowel disease (IBD) is common in children and appears to be on the rise in most developing countries including Canada [1,2]
In this study we examined whether key enzymes within the fatty-acid metabolic pathway were associated with risk for CD
As individuals will differ in their capacities to metabolize dietary polyunsaturated fatty-acids (PUFA), we hypothesized that DNA variation in key genes that metabolize PUFA may be important and may modify any associations between dietary PUFA and CD
Summary
Crohn’s disease (CD) a chronic inflammatory bowel disease (IBD) is common in children and appears to be on the rise in most developing countries including Canada [1,2]. We have recently shown that in Canadian children an imbalance in consumption of dietary polyunsaturated fatty acids (PUFA) may be associated with risk for CD [10]. Many epidemiological studies [13] and clinical trials [14] using sources of v fatty acids have not provided consistent results. We hypothesized that inherited variation in the ability to metabolize dietary PUFA may mediate development of CD and may have contributed to the previously observed inconsistent results. Epidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn’s disease (CD) is unclear, 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
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