Evaluation of polygenic risk scores for hormones and receptors levels in patients with vestibulodynia: a case-control study

Background: Vulvodynia is a multifactorial disease affecting 7-16% of reproductive-aged women in general population; however, little is still known about the genetics underlying this complex disease. Aim: To compare polygenic risk scores for hormones and receptors levels in a small case-control study to investigate their role in vulvodynia and their correlation with clinical endophenotypes. Methods: Our case-control study included patients with vestibulodynia and healthy women. All participants underwent a vestibular cotton swab test and the assessment of their: hypertonic pelvic floor, vestibular trophic health, vestibular mucosa thickness, and current perception threshold levels (Neurometer® CPT device). Shallow whole genome sequencing and polygenic risk score calculations were performed. Linear regression models were applied to predict whether genomic predisposition to higher/lower levels of hormones and receptors was significantly different between cases and controls, and to investigate the relationship of polygenic risk scores with clinical endophenotypes. Outcomes: The genomic predisposition to hormones and receptors levels, together with clinical endophenotypes, can support vestibulodynia diagnosis and personalized treatment of related pain condition. Results: Thirty women with vestibulodynia and 30 controls were recruited. Significant differences between cases and controls were observed for body mass index, vestibular mucosa thickness, vestibular trophic health, pelvic floor hypertone and pain sensitivity (P < 0.05). Cases showed a genomic predisposition to higher levels of membrane-associated progesterone receptor component 1 compared to controls (P < 0.05). When considering the clinical endophenotypes, cases showed significant correlations between their polygenic risk scores with several clinical measures: predicted genomic levels of testosterone and estrogen receptor and the vestibular mucosa thickness values (estimates: 9.74E-09 and 9.16E-08, respectively; P < 0.05); predicted genomic levels of prolactin and Neurometer® data at 250 Hz (-2.15E-07; P < 0.05); predicted genomic levels of prolactin, membrane-associated progesterone receptor component 2 and mineralocorticoid receptor and Neurometer® data at 5 Hz (-3.75E-07, -3.43E-07 and -3.06E-07, respectively; P < 0.05). Clinical implications: Introduction of polygenic risk scores evaluation in clinical practice can assist early diagnosis and personalized therapeutic treatment of vestibulodynia. Strengths & Limitations: Polygenic risk scores and clinical data allowed the identification of disease endophenotypes and highlighted the possibility of a personalized therapeutic approach. As limitations, these data should be confirmed on a larger cohort and polygenic risk score calculation should be adapted to ancestries other than European. Conclusion: Cases showed significant differences compared to controls on both clinical and genetic data and specific endophenotypes necessary to classify disease development and treatment were identified.