Abstract: PD01-05
Sources of Funding: Interstitial Cystitis Association

Introduction

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic pain condition with unknown etiology. Family history is one of the strongest known risk factors, suggesting a genetic contribution. We hypothesized that related IC/PBS cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis for IC/PBS.

Methods

Using the Utah Population Database (a population-based genealogy resource linked to medical records at the largest Utah healthcare provider), 13 high-risk pedigrees (defined as having a statistical excess (p<0.05) of IC/PBS cases among relatives who were hospital patients compared to expected number of cases using age- and sex-matched hospital rates for IC/PBS) were used for this analysis. Each pedigree had at least two sampled cases; case status was confirmed in the medical record using natural language processing. DNA was obtained from stored, non-cancerous, formalin-fixed, paraffin-embedded (FFPE) tissue blocks (e.g., appendix). Pedigrees ranged in size from 2 to 12 genotyped cases (n=48). Genotype data were obtained from Illumina OmniExpress BeadChip array (~710, 0000 SNPs); all SNPs passed quality control filters prior to linkage analysis. We eliminated highly correlated SNP markers (i.e., high linkage disequilibrium). Parametric linkage analysis using general dominant and recessive models was performed using the Markov Chain, Monte Carlo linkage analysis method, MCLINK. Results are reported as heterogeneity logarithm of odds scores (HLODs), defined as suggestive (HLOD ≥ 1.86) and significant (HLOD ≥ 3.3) linkage evidence. We also reported the number of individual pedigrees considered &[Prime]linked&[Prime] to a significant genomic peak (i.e., pedigree LOD score ≥ 0.588).

Results

Significant genome-wide linkage evidence was found on chromosome 3p21-3q13 with a maximum HLOD score of 3.56 under a dominant model. There were 4 pedigrees (30.8%) that had at least nominal linkage evidence (LOD ≥ 0.588) in this region. The most informative pedigree for linkage included 12 IC/PBS cases and had an individual LOD score of 2.1 in this region. Other regions with suggestive evidence for linkage included 1p21-1q25, 4q12-13, 9p24-22, and 14q24, all under a dominant model.

Conclusions

While the etiology of IC/PBS is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 likely contributes to IC/PBS predisposition. Further study of the pedigrees underlying this significant linkage evidence and sequence analysis of the affected cases may provide insight into genes contributing to IC/PBS.

Funding

Interstitial Cystitis Association