TM Connelly MB, BCh, MS; B Sanders BS; A Berg PhD; L Harris III BS, E Williams MD, S Deiling, BA; A Tinsley MD, MS

WA Koltun MD

Genetic Predictors of Quality of Life Post Ileal Pouch Anal Anastomosis for

Ulcerative Colitis

No Disclosures

Total proctocolectomy and Ileal Pouch Anal Anastomosis (IPAA) for ulcerative colitis (UC) allows for the resection of the diseased rectum and colon whilst preserving continence

Procedure outcomes and patient satisfaction are varied

Many studies have attempted to predict pouch function preoperatively or evaluate pouch function through objective measures such as pouchitis and frequency of bowel motions

INTRODUCTION

Ileal Pouch Anal Anastomosis

Regardless of pouch function, patient satisfaction or well-being post IPAA is what is desired

Factors to predict such well-being post IPAA are not well defined

We hypothesized that a correlation between a genetic marker and pouch satisfaction may be

identifiable

INTRODUCTION

To determine predictors of post IPAA well-being or satisfaction in the form of:1. Demographic and

perioperative variables2. Genetic markers

AIM

To determine ‘patient satisfaction’ we created a modified questionnaire based on the validated:

1. Modified Pouchitis Activity Score2. IBD quality of life questionnaire (IBDQ)

Added questions on steroid and antibiotic use

Adapted to be pouch specific by adding the phrase “Since your pouch operation…”

METHODS: Questionnaire Design

The Modified Pouchitis Activity Score=4 questions on clinical condition: stool frequency, rectal bleeding, urgency and pyrexia

IBDQ=32 questions covering 4 categories• Bowel symptoms • Emotional well-being • Social well-being • Systemic symptoms

METHODS: Questionnaire Design

**These 4 categories were combined for an ‘overall QOL’ score

The 220 adult UC-IPAA patients with stored DNA samples were identified from our divisional Biobank and mailed surveys

-Excluded pouch failure/excision patients

14 surveys were returned to sender and 142 (69%) patients responded

METHODS: Patient Selection

Patient DNA was genotyped on the HMC Division of Colon and Rectal Surgery’s custom designed Illumina® BeadExpress VeraCode platform

-307 IBD associated SNPs

Genotyping was performed at the HMC Genomics Core Facility

METHODS: Genotyping

Questionnaire Analysis For each category, the median overall score of all

patients was calculated Individual patient scores were then separated into

above or below the median Fisher’s exact test and the Mann Whitney test were

used Variables with a p<.05 in each category were entered

into multivariate analyses

METHODS: Statistical Evaluation

Genotyping Analysis

Logistic Regression

Bonferroni correction to correct for multiple comparisons of 307 SNPs

METHODS: Statistical Evaluation

RESULTS

FEMALE 39%EX OR CURRENT SMOKER 41%AGE AT DX (YEARS, SD) 32 ± 12

POUCH DURATION (YEARS, SD) 10 ± 6

DURATION BETWEEN DIAGNOSIS AND COLECTOMY (YEARS, SD)

8 ± 8

Patient Demographics

UNIVARIATE MULTIVARIATE

p value OR 95% CI pFemales .003 2.6 1.1-6.0 .02Readmitted within 30 days post colectomy

.05 5.3

1.8-16.7 .005

History of pouchitis

.00008 5.6 1.12-20 .003

Intermittent pyrexia .009 5.9 1.3-50 .03

Intermittent steroid use

.03

Intermittent antibiotic use

.04

Urgency .004

FACTORS CORRELATING WITH POOR OVERALL QOL

UNIVARIATE MULTIVARIATE

p value OR 95% CI pFemales .003 2.6 1.1-6.0 .02Readmitted within 30 days post colectomy

.05 5.3

1.8-16.7 .005

History of pouchitis

.00008 5.6 1.12-20 .003

Intermittent pyrexia .009 5.9 1.3-50 .03

Intermittent steroid use

.03

Intermittent antibiotic use

.04

Urgency .004

FACTORS CORRELATING WITH POOR OVERALL QOL SCORE

UNIVARIATEp value

Urgent Colectomy .0063Readmitted within 30 days post colectomy

.05

History of pouchitis

.00002

Intermittent pyrexia .05

Intermittent steroid use .03

Intermittent antibiotic use

.04

Urgency .0065

Younger age at colectomy .05

Shorter duration between UC diagnosis and colectomy

.006

FACTORS CORRELATING WITH POOR EMOTIONAL WELL-BEING

UNIVARIATE MULTIVARIATEp value OR 95% CI p

Urgent Colectomy .0063 3.6 1.2-12.5 .02

Readmitted within 30 days post colectomy

.05 5.6

1.8-20 .004

History of pouchitis

.00002 5.6

1.8-20 .004

Intermittent pyrexia .05

Intermittent steroid use .03

Intermittent antibiotic use

.04

Urgency .0065

Younger age at colectomy .05

Shorter duration between UC diagnosis and colectomy

.006

FACTORS CORRELATING WITH POOR EMOTIONAL WELL-BEING

UNIVARIATEp value

Positive Smoking History .02History of pouchitis

.02

Intermittent pyrexia .02

Urgency .007

FACTORS CORRELATING WITH POOR SOCIAL WELL-BEING

UNIVARIATE MULTIVARIATE

p value OR 95% CI pPositive Smoking History .02 2.1 .99-4.5 .053

History of pouchitis

.02 2.1 1.0-4.3 .04

Intermittent pyrexia .02

Urgency .007

FACTORS CORRELATING WITH POOR SOCIAL WELL-BEING

SNP Gene p value Bonferroni corrected p value

rs2279627 TNFSF14 .0001 .033rs7837328 8q24 .00034 NSDrs7014346 8q24 .0018 NSDrs7712957 S100Z .002 NSD

OVERALL QOL : GENETICS

BOWEL SYMPTOMS: GENETICS

SNP Gene p value

Bonferroni corrected p value

rs2279627 TNFSF14 .0001 .033rs7712957 S100Z .0004 NSDrs1297265 Gene Desert .002 NSDrs9647373 CLDN1 .005 NSD

SNP Gene p value Bonferroni corrected p value

rs7837328 POU5F1B .00002 .0061

rs2279627 TNFSF14 .00014 .046

rs7014346 POU5F1B .00014 .0146

rs7712957 S100Z .002 NSD

EMOTIONAL WELL-BEING: GENETICS

TNFSF14 and POU5F1BTNFSF14 (LIGHT) -Stimulation of T cell proliferation-VEGF induced apoptosis of macrophages for the resolution of inflammation -Increased in colonic mucosa of IBD patients

POU5F1 (OCT4)-Embryonic stem cell pluripotency-Inhibits the differentiation of progenitor cells-Adult stem cell renewal-Associated with UC and CRC

CONCLUSIONS:

CONCLUSIONS:1. Worse overall QOL (emotional and social well-being + bowel

and systemic symptoms) was associated with: Female gender, readmission post colectomy, pouchitis intermittent pyrexia SNP rs2279627 within the TNFSF14 gene

2. Poor emotional well-being was associated with:Readmission post colectomy, pouchitis, urgent colectomySNPs within the TNFSF14 and POU5F1 genes

3. Poor social well-being was associated with: Pouchitis and a smoking history

CONCLUSIONS:

Outcomes of patients with pouches are largely determined by postoperative variables

However, genetic markers such as POU5F1 and TNFSF14 SNPs are present preoperatively and may potentially be used to assist in surgical decision making

THANK YOU