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• W2051118414 abstract "Increased dietary ratios of ω6/ω3 polyunsaturated fatty acids have been implicated in the pathogenesis of Crohn's disease (CD), but epidemiologic data are limited. We investigated whether variants of genes that control polyunsaturated fatty acid metabolism (CYP4F3, FADS1, and FADS2), along with the dietary ratio of ω6/ω3, confers susceptibility to CD. Based on data from 182 children newly diagnosed with CD and 250 controls, we found that children who consumed a higher dietary ratio of ω6/ω3 were susceptible for CD if they were also carriers of specific variants of CYP4F3 and FADS2 genes. Our findings implicate diet–gene interactions in the pathogenesis of CD. Increased dietary ratios of ω6/ω3 polyunsaturated fatty acids have been implicated in the pathogenesis of Crohn's disease (CD), but epidemiologic data are limited. We investigated whether variants of genes that control polyunsaturated fatty acid metabolism (CYP4F3, FADS1, and FADS2), along with the dietary ratio of ω6/ω3, confers susceptibility to CD. Based on data from 182 children newly diagnosed with CD and 250 controls, we found that children who consumed a higher dietary ratio of ω6/ω3 were susceptible for CD if they were also carriers of specific variants of CYP4F3 and FADS2 genes. Our findings implicate diet–gene interactions in the pathogenesis of CD. Although many studies suggest that a high dietary ratio of ω6/ω3 polyunsaturated fatty acids (PUFAs) is potentially risk-conferring for CD, evidence across studies is equivocal.1Cabré E. et al.Br J Nutr. 2012; 107: S240-S252Crossref PubMed Scopus (113) Google Scholar Notwithstanding methodologic issues, a key phenomenon overlooked in most studies is that risk or protection from dietary PUFA may depend on an individual's ability to appropriately metabolize them. Recent studies have shown that genes involved in PUFA metabolism are associated with endogenous levels of PUFA metabolites.2Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (246) Google Scholar, 3Kettunen J. et al.Nat Genet. 2012; 44: 269-276Crossref PubMed Scopus (431) Google Scholar It is thus possible that risk of CD associated with a high ω6/ω3 PUFA ratio depends on variation in the PUFA metabolic genes. There are 2 main families of PUFA, classified as ω3 and ω6, based on the location of the last double bond relative to the terminal methyl end of the molecule.4Wall R. et al.Nutr Rev. 2010; 68: 280-289Crossref PubMed Scopus (824) Google Scholar The human body can produce all but 2 of the PUFAs it requires: linoleic acid (precursor to the ω6 series) and α-linolenic acid (ALA) (precursor to the ω3 series). Lipid mediators generated from long-chain (LCN) PUFAs such as ω-6 arachidonic acid, and ω3 eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), have important roles in immune regulation and inflammation.5Calder P.C. Biochimie. 2009; 91: 791-795Crossref PubMed Scopus (564) Google Scholar For the most part, metabolism of ω6 PUFA leads to the production of proinflammatory lipid mediators, whereas those produced via ω3 metabolism are less proinflammatory. As a result of nutritional trends, Western society diets presently are characterized by high ω6 PUFA, as well as an overall low ω3 PUFA intake.6Simopoulos A.P. Mol Neurobiol. 2011; 44: 203-215Crossref PubMed Scopus (390) Google Scholar Optimal dietary intakes of the ω6/ω3 ratio are suggested to be approximately 1–4:1. However, in Western diets it now is between 10:1 and 20:1.7Olivier M.C. et al.Gastroenterol Res Pract. 2011; 2011: 364040PubMed Google Scholar This high ratio could influence the PUFA metabolic pathway in favor of the ω6 path that, in the presence of genetic susceptibility, predisposes to chronic inflammation, which is a characteristic of CD. We explored this gene–diet interaction hypothesis in the present study. We studied 182 newly diagnosed CD cases and 250 controls of Caucasian origin (Table 1). Most patients had ileocolonic disease (47%). We investigated 15 single-nucleotide polymorphisms (SNPs) across 3 PUFA metabolic genes (FADS1, 1; FADS2, 10; and CYP4F3, 4). The genes/SNPs were chosen based on their significant associations with plasma levels of different PUFA metabolites as reported in the recent meta-analyses of genome-wide association studies (GWAS)2Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (246) Google Scholar (see the Supplementary Materials and Methods section). All genotyped SNPs were in Hardy–Weinberg equilibrium (P > .01) in our controls. Usual dietary consumption during the 12 months before disease diagnosis was acquired using a validated food frequency questionnaire as was reported previously.8Amre D.K. et al.Am J Gastroenterol. 2007; 102: 2016-2025Crossref PubMed Scopus (200) Google ScholarTable 1Sociodemographic Characteristics of the Study PopulationCharacteristicCases (n = 182)Controls (n = 250)P valueMean age, y (±SD)12.8 (3.2)13.3 (3.2).05Sex, n (%) Males111 (61.0)122 (48.8) Females71 (39.0)128 (51.2).01Study site, n (%) Montreal83 (45.6)150 (60.0) Ottawa78 (42.9)83 (33.2) Vancouver21 (11.5)17 (6.8).009Mean energy intake (±SD)2437.3 (681.1)2214.9 (615.0)<.001Mean BMI (±SD)21.5 (10.9)20.5 (4.7).23Family history, n (%)aInflammatory bowel disease in first- or second-degree relatives. No145 (79.7)231 (92.4) Yes37 (20.3)19 (7.6)<.001BMI, body mass index.a Inflammatory bowel disease in first- or second-degree relatives. Open table in a new tab BMI, body mass index. Logistic regression analysis using energy-adjusted nutrients (using the residual method,9Willett W.C. et al.Am J Clin Nutr. 1997; 65: 1220sCrossref PubMed Scopus (2181) Google Scholar energy measured in kilocalories) and accounting for potential confounders such as age, sex, body mass index, family history of inflammatory bowel disease, and study center, showed that a higher ratio of LCN ω6/ω3 was associated with increased risks for CD (Q4 vs Q1–3: odds ratio, 1.63; 95% confidence interval, 1.01–2.64; P = .044). None of the 15 SNPs were associated independently with CD (Supplementary Table 1), as previously reported.10Jostins L. et al.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3261) Google Scholar When interactions were examined, no SNP/ω6 interactions were evident, whereas interaction between 1 FADS2 SNP rs11230815 and dietary ω3 was observed (P = .042). When the dietary ratio of LCN ω6/ω3 was considered, we observed significant interactions (P < .05) involving 6 SNPs (Table 2), suggesting that associations between the dietary ratio and CD varied according to CYP4F3 and FADS2 genotypes. For example, in children who carried the GG genotype in SNP rs1290617 or the CC genotype in SNP rs1290620 in the CYP4F3 gene, a higher LCN ω6/ω3 dietary ratio was associated with a greater risk for CD. Because the G and C alleles of these 2 SNPs are associated with high levels of DPA2Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (246) Google Scholar and because the CYP4F3 gene is involved in the metabolism of DHA, children who are carriers of these alleles and consume a higher LCN ω6/ω3 dietary ratio may produce and metabolize DHA less efficiently into anti-inflammatory resolvins and protectins, resulting in a higher risk for CD. Similarly for the FADS2 gene, the alleles of 3 SNPs (rs11230815, rs968567, and rs174627) involved in the interactions (Table 2) are associated with high levels of ALA and low levels of EPA and DPA.2Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (246) Google Scholar We hypothesize that in carriers of these alleles, a higher LCN ω6/ω3 dietary ratio might divert the pathway to the metabolism of ω6 PUFA and further compromise the metabolism of ω3 PUFA. This may result in an increased production of potentially proinflammatory mediators and a greater risk of CD. However, given that these effects are not consistent for the FADS2 SNP rs17831757, complex interactions are likely to be in play.Table 2Association Between the Dietary PUFA Ratio and CD According to Genotypes in the CYP4F3 and FADS2 GenesSNP (gene)OR (95% CI) associated with the ratio (low ratio as reference)Interaction, P valueAssociation with PUFA plasma levelsaPublished and unpublished data from Lemaitre et al.2rs1290617 (CYP4F3)G allele TT0.92 (0.44–1.89).04DPA: high GT1.37 (0.78–2.42) GG2.91 (0.90–9.39)rs1290620 (CYP4F3)C allele TT0.52 (0.13–2.04).025DPA: high CT0.98 (0.54–1.77) CC2.53 (1.29–4.96)rs11230815 (FADS2)bGenotypes were combined owing to small numbers.G allele CC + CG0.50 (0.20–1.22).007ALA: high GG1.77 (1.11–2.82)EPA: lowDPA: lowrs17831757 (FADS2)bGenotypes were combined owing to small numbers.T allele CC + CT0.52 (0.21–1.27).011ALA: low TT1.75 (1.10–2.78)EPA: highDPA: highrs968567 (FADS2)bGenotypes were combined owing to small numbers.T allele CC0.99 (0.62–1.60).028ALA: high CT + TT2.68 (1.17–6.19)EPA: lowDPA: lowrs174627 (FADS2)bGenotypes were combined owing to small numbers.A allele GG1.08 (0.68–1.71).029ALA: high AG + AA2.99 (1.12–7.99)EPA: lowDPA: lowNOTE. Associations were adjusted for age, sex, family history of inflammatory bowel disease, study site, and body mass index.AA, arachidonic acid; CI, confidence interval; OR, odds ratio.a Published and unpublished data from Lemaitre et al.2Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (246) Google Scholarb Genotypes were combined owing to small numbers. Open table in a new tab NOTE. Associations were adjusted for age, sex, family history of inflammatory bowel disease, study site, and body mass index. AA, arachidonic acid; CI, confidence interval; OR, odds ratio. The CYP4F3 gene is an important modulator of the inflammatory process via its ability to inactivate leukotriene B4 (LTB4).11Corcos L. et al.Drug Metabol Drug Interact. 2012; 27: 63-71Crossref PubMed Google Scholar The CYP4F3 pre–messenger RNA is spliced into 2 mature transcripts (CYP4F3B and CYP4F3A), of which CYP4F3A is expressed in neutrophils/monocytes and in the intestines, and is more than 25 times as efficient as CYP4F3B for the ω-hydroxylation and inactivation of LTB4 to 20-OH LTB4.4Wall R. et al.Nutr Rev. 2010; 68: 280-289Crossref PubMed Scopus (824) Google Scholar CYP4F3A also ω-hydroxylates fatty acid epoxides and lipoxins A and B. This ability of the gene to detoxify fatty acids that are associated intimately with inflammation makes it a relevant candidate for CD.12Hawthorne A.B. et al.Gut. 1992; 33: 513-517Crossref PubMed Scopus (29) Google Scholar, 13Sharon P. et al.Gastroenterology. 1984; 86: 453-460Abstract Full Text PDF PubMed Scopus (633) Google Scholar, 14Nielsen O.H. et al.Gut. 1987; 28: 181-185Crossref PubMed Scopus (49) Google Scholar, 15Devchand P.R. et al.Nature. 1996; 384: 39-43Crossref PubMed Scopus (1210) Google Scholar However, we noted that variation in this gene appears to impact the association between the dietary ratio of LCN ω6/ω3 and CD, whereby only children with certain genotypes are at higher risk for CD if they consume a high ratio. In such individuals a higher LCN ω6/ω3 dietary ratio conceivably may lead to inefficient clearance of LTB4, promoting prolonged tissue inflammation. The FADS2 gene is a key PUFA metabolic gene influencing the pathway at multiple steps. It is a desaturase that catalyzes the first step in the conversion of both ω6 linoleic acid and ω3 ALA into longer chain ω6 and ω3 PUFAs. Not surprisingly, variations in the gene are associated with endogenous plasma/serum levels of EPA, DHA, and DPA,2Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (246) Google Scholar and different PUFA ratios.3Kettunen J. et al.Nat Genet. 2012; 44: 269-276Crossref PubMed Scopus (431) Google Scholar The higher risk for CD that is associated with a higher dietary ratio of LCN ω6/ω3 in individuals with particular FADS2 SNPs suggest that lower endogenous production of ω3 PUFAs may influence risk when combined with a higher LCN ω6/ω3 dietary ratio. Certainly any postulated mechanism can be considered speculative at this time. Nonetheless, taken together, our findings do support the possibility of an altered fatty acid metabolic status that facilitates chronic inflammation in response to diet. These findings suggest that preventive dietary intervention could be targeted to specific subgroups (based on PUFA metabolic genes) that might benefit the most. Studies to replicate these findings are needed. We performed a case-control study including children with CD diagnosed before age 19, recruited from 3 pediatric gastroenterology clinics across Canada. Details of the study have been reported previously.1Amre D.K. et al.Am J Gastroenterol. 2007; 102: 2016-2025Crossref PubMed Scopus (230) Google Scholar In brief, for this study children newly diagnosed with CD using standard criteria were included. As controls, children visiting the orthopedic clinics of the respective study hospitals (Montreal and Vancouver) for minor fractures/scoliosis or population-based controls (Montreal and Ottawa) were recruited. Both cases and controls were restricted to those of Caucasian ancestry (self-report). Dietary consumption during the 12 months before disease diagnosis (for cases) and before the date of recruitment (for controls) was acquired using a self-administered, validated, food-frequency questionnaire Youth Adolescent Questionnaire.2Rockett H.R. et al.J Am Diet Assoc. 1995; 95: 336-340Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar, 3Rockett H.R. et al.Prev Med. 1997; 26: 808-816Crossref PubMed Scopus (576) Google Scholar The Youth Adolescent Questionnaire has been validated and tested for reproducibility in children. Good correlations have been reported between 24-hour dietary recalls and the Youth Adolescent Questionnaire–based consumption levels of different fatty acids including PUFAs (r = 0.30), saturated fatty acids (r = 0.54), monounsaturated fatty acids (r = 0.52), and total fats (r = 0.56).3Rockett H.R. et al.Prev Med. 1997; 26: 808-816Crossref PubMed Scopus (576) Google Scholar Children reporting major changes in diet (eg, reducing fat intake) in the 12-month period were excluded. Peripheral blood and/or saliva samples were collected as a source for DNA. The DNA was genotyped for SNPs in the CYP4F3 (n = 4), FADS1 (n = 1), and FADS2 (n = 10) genes using the Sequenom-based platform (San Diego, California). The 15 SNPs were selected based on their reported associations with plasma/serum levels of key PUFA metabolites (such as EPA, DPA, and DHA) as reported in a recent meta-analysis of GWAS4Lemaitre R.N. et al.PLoS Genet. 2012; 7: e1002193Crossref Scopus (273) Google Scholar that examined genome-wide associations with ω3 fatty acids. In this genome-wide association study, 28 CYP4F3 SNPs were reported to be associated with serum levels of either EPA, DPA, or DHA (P < .05). We selected 4 SNPs that showed the highest linkage disequilibrium with other associated SNPs for genotyping.5Carlson C.S. et al.Am J Hum Genet. 2004; 74: 106-120Abstract Full Text Full Text PDF PubMed Scopus (1333) Google Scholar For the FADS2 gene, in the same study, 38 SNPs were found to be associated with serum levels of either EPA, DPA, or DHA (P < 10-5). We randomly selected 10 of these SNPs for genotyping. For the FADS1 gene, 9 SNPs were reported to be associated similarly with the earlier-mentioned serum PUFA levels. We chose for genotyping the single SNP that was in maximum linkage disequilibrium with the other associated SNPs. Informed consent was acquired from all participants and the ethics boards of the 3 study hospitals approved the study. The children's responses to the Youth Adolescent Questionnaire were analyzed for acquiring information on the daily consumption of specific nutrients. For nutrients of relevance to the current study (PUFA), the daily intake (grams or micrograms as the case may be) was estimated. The raw intakes of the LCN ω-3 (EPA, DPA, and DHA) and LCN ω-6 (arachidonic acid) were adjusted for energy intake using the residual method.6Willett W.C. et al.Am J Clin Nutr. 1997; 65: 1220sCrossref PubMed Scopus (2524) Google Scholar The ratio of arachidonic acid/(EPA, DPA, DHA) then was calculated. The quartiles were used for studying independent associations and the median was used for analyzing gene–diet interactions. The genotyping data on the 15 SNPs first was examined for deviation from Hardy–Weinberg equilibrium using chi-square tests. SNPs in Hardy–Weinberg equilibrium in the controls were retained. Associations between the arachidonic acid/(EPA, DPA, DHA) ratio and CD adjusting for age, sex, family history, study center, and body mass index were estimated using logistic regression. Associations between the 15 SNPs and CD were examined separately (1 model for each SNP) using univariate logistic regression models assuming additive inheritance. Subsequently, multivariate analysis was performed to assess for interactions. Single models (per SNP) that included the variables representing the ratio (low, below the median; high, above the median), the SNP (coded as 0, 1, or 2), an interaction term comprising the ratio and the SNP, along with potential confounders, were fit. Models wherein the interaction term was statistically significant (P < .05) were considered to represent important interactions. Because the study was exploratory, no corrections for multiple comparisons were made. For SNP-ratio interactions that appeared to be prominent, the odds ratios, and their respective 95% confidence intervals for the association between the ratio and CD were estimated based on stratification of specific genotypes in the study SNPs.Supplementary Table 1Associations Between SNPs in the CYP4F3, FADS1, and FADS2 Genes and CDSNP (gene)Odds ratio (95% confidence interval)P valuers1290617 (CYP4F3)1.17 (0.88–1.55).28rs1290620 (CYP4F3)1.08 (0.82–1.44).57rs2283612 (CYP4F3)1.36 (0.92–1.99).11rs8106799 (CYP4F3)1.14 (0.87–1.52).34rs11230815 (FADS2)0.72 (0.45–1.14).16rs17831757 (FADS2)0.68 (0.42–1.08).11rs968567 (FADS2)1.01 (0.67–1.53).95rs174579 (FADS2)1.01 (0.71–1.43).94rs174627 (FADS2)1.09 (0.72–1.66).68rs174577 (FADS2)1.03 (0.76–1.38).86rs174601 (FADS2)0.99 (0.74–1.33).96rs174602 (FADS2)0.92 (0.66–1.27).60rs498793 (FADS2)1.03 (0.77–1.39).82rs174547 (FADS2)0.91 (0.68–1.22).54rs174575 (FADS1)0.94 (0.68–1.29).69 Open table in a new tab" @default.
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• W2051118414 title "Interactions Between the Dietary Polyunsaturated Fatty Acid Ratio and Genetic Factors Determine Susceptibility to Pediatric Crohn's Disease" @default.
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