The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Patients with polycystic ovary syndrome have lower levels of IgM anti-phosphorylcholine antibodies than healthy women.

INTRODUCTION: IgM antibodies against phosphorylcholine (IgM anti-PC) are natural autoantibodies, possibly exerting one of the atheroprotective functions of the immune system. Increased levels of these antibodies reduce the development of atherosclerosis in mice, and low levels of IgM anti-PC have been associated with increased risk for cardiovascular disease (CVD). This study compared levels of IgM anti-PC in women with polycystic ovary syndrome (PCOS, n = 111) and healthy controls (n = 79). METHOD: Levels of IgM anti-PC were measured with ELISA. RESULTS: The median level of IgM anti-PC in patients with PCOS was not significantly different compared to control subjects. However, the proportion of patients with PCOS with low levels of IgM anti-PC, defined as number of individuals below the median level, was significantly higher than among healthy controls, p < 0.05. Patients with PCOS in the oldest age quintile had significantly lower level of IgM anti-PC than control subjects of similar age (p < 0.05) and younger women with PCOS (p < 0.01). CONCLUSION: Our results indicate that women with PCOS more frequently display below-median levels of IgM anti-PC than controls and older women with PCOS have lower median anti-PC levels. Further studies of how this finding translates into actual CVD risk in women with PCOS are needed.

Tissue plasminogen activator and plasminogen activator inhibitor 1 in obese and lean patients with polycystic ovary syndrome.

OBJECTIVE: Disturbances in the fibrinolytic system are predictors of future cardiovascular events. The aim of this study was to compare plasminogen activator inhibitor 1 (PAI-1) activity and tissue plasminogen activator (tPA) mass concentration between patients with polycystic ovary syndrome (PCOS) and control subjects. DESIGN: One hundred thirty-five patients with PCOS (lean and obese) and 81 healthy controls were recruited for the study. Blood samples for PAI-1 activity and tPA mass were collected together with anthropometric measures. RESULTS: Obese patients with PCOS displayed increased tPA mass concentration in comparison with controls (p <0.05), and this finding was consistent regardless of whether patients displayed signs of hyperandrogenism or not. When hyperandrogenism was introduced as a prerequisite for the PCOS diagnosis, obese patients with PCOS displayed increased PAI-1 activity as well, p <0.05. Lean patients with PCOS did not differ in terms of PAI-1 activity or tPA mass concentration in comparison to controls. CONCLUSION: Obese women with PCOS have impaired fibrinolysis, in particular if they also display objective biochemical markers of hyperandrogenism.

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.