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. 2010 Nov;16(11):1830-40.
doi: 10.1002/ibd.21293.

Genetic predictors of medically refractory ulcerative colitis

Talin Haritunians  1 , Kent D Taylor, Stephan R Targan, Marla Dubinsky, Andrew Ippoliti, Soonil Kwon, Xiuqing Guo, Gil Y Melmed, Dror Berel, Emebet Mengesha, Bruce M Psaty, Nicole L Glazer, Eric A Vasiliauskas, Jerome I Rotter, Phillip R Fleshner, Dermot P B McGovern
Affiliations

Genetic predictors of medically refractory ulcerative colitis

Talin Haritunians et al. Inflamm Bowel Dis. 2010 Nov.

Abstract

Background: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.

Methods: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.

Results: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)).

Conclusions: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.

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Conflict of interest statement

Disclosures: Authors have no disclosures to declare. No conflicts of interest exist.

Figures

Figure 1
Figure 1
Schematic describing MR-UC vs. Non-MR-UC survival analysis and risk modeling
Figure 2
Figure 2
A) Higher risk score categories are associated with MR-UC (χ 2 test for trend p <2.2×10−16). Risk score (observed range: 28–60) was divided into quarters: scores 28–38 (risk-A); scores 39–45 (risk-B); scores 46–52 (risk-C); and scores 53–60 (risk-D). MR-UC, dark grey; Non-MR-UC, light gray. Percentage of MR-UC is noted, along with the total number of UC subjects in each risk category. B) Higher risk score categories are associated with an earlier progression to colectomy at 24 and 60 months. Risk score was divided into quarters (see A above). At 24 months, risk of colectomy was 3.1%, 19.1% and 62% for risk-B, -C, and -D, respectively. Risk of colectomy at 60 months increased to 8.3%, 48.4%, 84% for risk-B, -C, and -D, respectively. Total number of UC subjects in each risk category is given.
Figure 2
Figure 2
A) Higher risk score categories are associated with MR-UC (χ 2 test for trend p <2.2×10−16). Risk score (observed range: 28–60) was divided into quarters: scores 28–38 (risk-A); scores 39–45 (risk-B); scores 46–52 (risk-C); and scores 53–60 (risk-D). MR-UC, dark grey; Non-MR-UC, light gray. Percentage of MR-UC is noted, along with the total number of UC subjects in each risk category. B) Higher risk score categories are associated with an earlier progression to colectomy at 24 and 60 months. Risk score was divided into quarters (see A above). At 24 months, risk of colectomy was 3.1%, 19.1% and 62% for risk-B, -C, and -D, respectively. Risk of colectomy at 60 months increased to 8.3%, 48.4%, 84% for risk-B, -C, and -D, respectively. Total number of UC subjects in each risk category is given.
Figure 3
Figure 3
Manhattan plot depicting MR-UC vs. Control analysis, which confirms a significant contribution of the MHC region (chromosome 6) to UC severity, with suggestive significance observed for TNFSF15 (TL1A) region on chromosome 9. Red line denotes 10−7, a level of genome-wide significance; blue line denotes suggestive significance at 10−5. (Generated using Haploview .)
Figure 4
Figure 4
A) P-values and LD plot of 82 SNPs (p <1×10−3) on chromosome 6p of MHC region from MR-UC vs. healthy controls (analysis-III). Ten SNPs reached genome-wide significance (p ≤5×10−7), with an association peak at rs17207986 (p= 1.4×10−16). Leading and trailing SNPs, and SNPs bordering haplotype blocks are further identified (see Table S3 for complete list of SNPs). B) P-values and LD plot of 17 SNPs (p <1×10−3) within the TL1A/TNFSF15 and TNFSF8 regions on chromosome 9q from MR-UC vs. healthy controls (analysis-III). Three SNPs reached genome-wide suggestive significance (p <5×10−5): rs2145929 (p= 3.7×10−5), rs2093403 (p= 1.9×10−5), with an association peak at rs11554257 (p= 1.4×10−6). SNPs are represented as red triangles. LD heat map indicates level of linkage disequilibrium (r-squared) between SNPs. Chromosomal position of leading and trailing SNPs, and genes of interest located within this region are noted. (Generated with R package snp.plotter; http://cbdb.nimh.nih.gov/~kristin/snp.plotter.html)
Figure 4
Figure 4
A) P-values and LD plot of 82 SNPs (p <1×10−3) on chromosome 6p of MHC region from MR-UC vs. healthy controls (analysis-III). Ten SNPs reached genome-wide significance (p ≤5×10−7), with an association peak at rs17207986 (p= 1.4×10−16). Leading and trailing SNPs, and SNPs bordering haplotype blocks are further identified (see Table S3 for complete list of SNPs). B) P-values and LD plot of 17 SNPs (p <1×10−3) within the TL1A/TNFSF15 and TNFSF8 regions on chromosome 9q from MR-UC vs. healthy controls (analysis-III). Three SNPs reached genome-wide suggestive significance (p <5×10−5): rs2145929 (p= 3.7×10−5), rs2093403 (p= 1.9×10−5), with an association peak at rs11554257 (p= 1.4×10−6). SNPs are represented as red triangles. LD heat map indicates level of linkage disequilibrium (r-squared) between SNPs. Chromosomal position of leading and trailing SNPs, and genes of interest located within this region are noted. (Generated with R package snp.plotter; http://cbdb.nimh.nih.gov/~kristin/snp.plotter.html)
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