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Response to Infliximab in Crohn's Disease: Genetic Analysis Supporting Expression Profile.

Medrano LM, Taxonera C, González-Artacho C, Pascual V, Gómez-García M, Barreiro-de Acosta M, Pérez-Calle JL, Bermejo F, López-Sanromán A, Martín Arranz D, Gisbert JP, Mendoza JL, Martín J, Núñez C, Urcelay E - Mediators Inflamm. (2015)

Bottom Line: Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07).These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients.Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

View Article: PubMed Central - PubMed

Affiliation: Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.

ABSTRACT
Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

No MeSH data available.


Related in: MedlinePlus

Linkage disequilibrium (D′ and r2) between the studied SNPs located in the same genetic region: S100A9-S100A8, G0S2, TNFAIP6, and IL11.
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Related In: Results  -  Collection


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fig1: Linkage disequilibrium (D′ and r2) between the studied SNPs located in the same genetic region: S100A9-S100A8, G0S2, TNFAIP6, and IL11.

Mentions: Demographic and baseline characteristics were compared between responders and nonresponders by using the Mann-Whitney U test or the chi-square test, whether continuous or categorical variables were considered. The statistical analysis to compare allelic and genotypic distributions was performed using chi-square test or Fisher's exact test (when expected values were below 5). Odds ratios (ORs) were calculated and their 95% confidence intervals were estimated using the Cornfield method. Haplotypic frequencies were inferred with the expectation-maximization algorithm implemented in the Haploview 4.1 software. Linkage disequilibrium was measured by calculating two parameters: r2 and D′ (Figure 1). Demographic characteristics were analyzed as potential confounding factors of the IFX response using logistic regression.


Response to Infliximab in Crohn's Disease: Genetic Analysis Supporting Expression Profile.

Medrano LM, Taxonera C, González-Artacho C, Pascual V, Gómez-García M, Barreiro-de Acosta M, Pérez-Calle JL, Bermejo F, López-Sanromán A, Martín Arranz D, Gisbert JP, Mendoza JL, Martín J, Núñez C, Urcelay E - Mediators Inflamm. (2015)

Linkage disequilibrium (D′ and r2) between the studied SNPs located in the same genetic region: S100A9-S100A8, G0S2, TNFAIP6, and IL11.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4539178&req=5

fig1: Linkage disequilibrium (D′ and r2) between the studied SNPs located in the same genetic region: S100A9-S100A8, G0S2, TNFAIP6, and IL11.
Mentions: Demographic and baseline characteristics were compared between responders and nonresponders by using the Mann-Whitney U test or the chi-square test, whether continuous or categorical variables were considered. The statistical analysis to compare allelic and genotypic distributions was performed using chi-square test or Fisher's exact test (when expected values were below 5). Odds ratios (ORs) were calculated and their 95% confidence intervals were estimated using the Cornfield method. Haplotypic frequencies were inferred with the expectation-maximization algorithm implemented in the Haploview 4.1 software. Linkage disequilibrium was measured by calculating two parameters: r2 and D′ (Figure 1). Demographic characteristics were analyzed as potential confounding factors of the IFX response using logistic regression.

Bottom Line: Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07).These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients.Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

View Article: PubMed Central - PubMed

Affiliation: Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain.

ABSTRACT
Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

No MeSH data available.


Related in: MedlinePlus