Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5×10−8), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28×103) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.
Introduction:It is known that laboratorial tests (urinary albumin excretion and glomerular filtration rate), routinely used for nephropathy diagnosis in type 1 diabetes (T1DM), have limitations that justify the evaluation of new renal biomarkers. This study assessed the performance of cystatin C, Study Protocol Articlealkaline phosphatase (AP) and gamma-glutamyl transferase (GGT) for nephropathy diagnosis in T1DM patients. The reduction of economic cost and increase in sensibility and specificity from correct biochemical diagnosis of diabetic nephropathy is an important objective of this work. Methods: Cystatin C, AP and GGT were determined in plasma and urine of healthy individuals (N=35) and T1DM patients with (N=45) and without nephropathy (N=80). Results: The plasma levels of cystatin C, AP and GGT, as well as urinary levels of cystatin C and AP were able to differentiate diabetic patients with and without nephropathy. Plasma cystatin C better followed the progression of albuminuria. Cystatin C and AP discriminated the onset of nephropathy in T1DM patients better than creatinine. AP plasma/urine ratio progressively increased from the controls to the diabetic patients without and with nephropathy. Conclusion:The plasma levels of cystatin C and AP may be useful, with the classical markers of renal function, for nephropathy diagnosis and monitoring in T1DM patients.
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