Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway

Lee, James C.; Espéli, Marion; Anderson, Carl A.; Linterman, Michelle A.; Pocock, Joanna; Williams, Naomi; Roberts, Rebecca; Viatte, Sébastien; Fu, Bo; Peshu, Norbert; Hien, Tran Tinh; Phu, Nguyen Hoan; Wesley, Emma; Edwards, Cathryn; Ahmad, Tariq; Mansfield, John C.; Gearry, Richard B.; Dunstan, Sarah J.; Williams, Thomas N.; Barton, Anne; Vinuesa, Carola G.; Parkes, Miles; Lyons, Paul; Smith, Kenneth G. C.

doi:10.1016/j.cell.2013.08.034

Cited by 201 publications

(222 citation statements)

References 60 publications

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“…Integrative analyses of autoimmune disease genetics have helped to prioritize likely causal genes in GWAS loci, suggesting not only key biological pathways, but perhaps even drug targets and candidate therapies (113). Looking forward, there is hope that such studies will uncover effects of genetic variants that contribute not only to disease risk, but also to heterogeneity in disease progression (114) and responses to therapy.…”

Section: Resultsmentioning

confidence: 99%

Genetic basis of autoimmunity

Marson¹,

Housley²,

Hafler³

2015

J. Clin. Invest.

100

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Section: Resultsmentioning

confidence: 99%

Genetic basis of autoimmunity

Marson¹,

Housley²,

Hafler³

2015

J. Clin. Invest.

100

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“…They have been evaluated for association with several diseases including GVHD. [7][8][9][10] Our group has previously shown a risk model using SNPs to predict patients with high risk of developing aGVHD and hence decreased OS. 11 Other studies have also examined SNPs to predict the onset of GVHD, but not their response to steroid therapy or development of SR aGVHD.…”

Section: Introductionmentioning

confidence: 99%

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD

Alam

Atenafu

et al. 2015

Bone Marrow Transplant

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Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n = 180) and validation sets (n = 88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P o0.0001) and donor genotypes of IL6 (rs1800797; P = 6.2 × 10 −4 ) and IFNG (rs2069727; P = 4.4 × 10 −4 ) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n = 74) vs high risk (scores 1-3; n = 106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P o 0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P = 0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

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“…We would then like to follow that up with a controlled intervention in two characterised populations, one with the G allele and the other with the wild type, to confirm the effect of the G allele. The minor G allele of FOXO3 has been shown to down-regulate pro-inflammatory cytokines including TNF and to up-regulate the anti-inflammatory cytokine IL-10, which accounts for the less severe symptoms of CD [27]. This reduced inflammatory response may account for the positive association of FOXO3 with tolerance to some foods, but it does not explain why it is associated with an adverse response to other foods.…”

Section: Discussionmentioning

confidence: 97%

“…Lee et al [27] reported that the minor G allele of rs12212067 is associated with less severe symptoms and a less severe course in CD and rheumatoid arthritis, due to the down-regulation of pro-inflammatory cytokines including TNF and the up-regulation of IL-10, an anti-inflammatory cytokine [28,29]. We were interested to consider if this single nucleotide polymorphism also related to dietary intolerances in people with CD.…”

Section: Introductionmentioning

confidence: 99%

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand

et al. 2015

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Background: Diet is known to play a major role in Crohn's disease (CD). It has also been reported that the minor G allele from the rs12212067 polymorphism (T>G) in FOXO3 is associated with milder CD. The aim of this study was to investigate the association between the rs12212067 polymorphism and food intolerances for a total of 253 foods. Methods: Tolerances and intolerances were recorded on a self-reported dietary questionnaire. Each food was scored on a 5-point ordinal scale: beneficial effects as ‘+ +' or ‘+', adverse effects as ‘- -' or ‘-', and ‘makes no difference' as ‘='. Dietary and genotype data were available for a total of 283 CD patients. Results: We identified 17 foods with beneficial effects in our study which were significantly associated with the G allele of the FOXO3 rs12212067 polymorphism. Of these, sweet potatoes had the highest reported frequency of beneficial responses. We also identified 4 foods with detrimental effects in more than 25% of our study population. These were mustard, wasabi, and raw and cooked tomatoes, which again were significantly associated with the G allele in FOXO3. Conclusions: There was strong evidence that adverse effects of mustard, wasabi, and raw and cooked tomatoes were significantly associated with the G allele of FOXO3 and that these foods should be avoided by people carrying this allele.

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Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway

Cited by 201 publications

References 60 publications

Genetic basis of autoimmunity

Genetic basis of autoimmunity

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand

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