Familiality analysis of provoked vestibulodynia treated by vestibulectomy supports genetic predisposition

Background Provoked vestibulodynia is a poorly understood disease that affects 8-15% of women in their lifetime. There is significant inflammation and nerve growth in vestibular biopsies from affected women treated by vestibulectomy compared with matched female population controls without vestibulodynia. The triggers leading to this neurogenic inflammation are unknown, but they are likely multifactorial. Objective Our objective was to determine whether vestibulodynia is more common in close and distantly related female relatives of women diagnosed with the disease and those specifically treated by vestibulectomy. Excess familial clustering would support a potential genetic predisposition for vestibulodynia and warrant further studies to isolate risk alleles. Study Design Using population-based genealogy linked to University of Utah Hospital CPT coded data, we estimated the relative risk of vestibulectomy in female relatives of affected women. We also compared the average pairwise relatedness of cases to the expected relatedness of the population and identified high-disease-burden pedigrees. Results A total of 183 potential vestibulectomy probands were identified using CPT codes. The relative risk of vestibulectomy was elevated in first-degree (20 [6.6-47], P <.00001), second-degree (4.5 [0.5-16], P =.07), and third-degree female relatives (3.4 [1.2-8.8], P =.03). Seventy of these 183 CPT-based probands had available clinical history to confirm a diagnosis of moderate to severe vestibulodynia. Notably, this smaller group of confirmed probands (n = 70) revealed a similar familiality in first-degree (54 [17.5-126], P <.00001), second-degree (19.7 [2.4-71], P =.005), and third-degree relatives (12 [3.3-31], P =.0004), despite less statistical power for analysis. Overall, the average pairwise relatedness of affected women was significantly higher than expected (P <.001) and a number of high-disease-burden Utah families were identified. Conclusion Our data suggest that vestibulodynia treated by vestibulectomy has a genetic predisposition. Future studies will identify candidate genes by linkage analysis in affected families and sequencing of distantly related probands.