Genetic predictors of medically refractory ulcerative colitis.
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.
Haritunians
Talin
T
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Talin.Haritunians@cshs.org
Taylor
Kent D
KD
Targan
Stephan R
SR
Dubinsky
Marla
M
Ippoliti
Andrew
A
Kwon
Soonil
S
Guo
Xiuqing
X
Melmed
Gil Y
GY
Berel
Dror
D
Mengesha
Emebet
E
Psaty
Bruce M
BM
Glazer
Nicole L
NL
Vasiliauskas
Eric A
EA
Rotter
Jerome I
JI
Fleshner
Phillip R
PR
McGovern
Dermot P B
DP
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D003082:Colectomy; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics; D055815:Young Adult
C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15