Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

OBJECTIVE: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. DESIGN: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. RESULTS: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. CONCLUSION: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Developmental hemostasis: A lifespan from neonates and pregnancy to the young and elderly adult in a European white population.

Absolute values of reference ranges for coagulation assays in humans vary within the entire lifespan and confirm the concept of developmental hemostasis. It is known that physiologic concentrations of coagulation factors (F) gradually increase over age: they are lower in premature infants as compared to full-term babies, healthy children or adults. Here we demonstrate in a cohort of 1011 blood donors and in a group of 193 healthy pregnant women, that the process of developmental hemostasis proceeds in adults. During the course of pregnancy F and activation markers steadily increase until delivery with a parallel decrease noticed for protein S. From adolescents, young adults to the elderly there is a further increase of F, reaching significance starting between 35 and 50years of age compared to younger subjects. Covering the entire lifespan FVIII and von-Willebrand-factor showed the lowest values in carriers of blood group "O". Apart from pregnancy differences related to gender, pill users, smoking habits or the presence of thrombophilic variants were reported. Laboratory test results should be compared to age-related reference intervals when hemostatic defects are suspected to avoid misclassifications as being "healthy", prone to "bleeding" or vice versa to "thrombosis".

End-stage renal disease and thrombophilia.

Chronic kidney disease is an established risk factor for arterial and venous thromboembolism (TE). Whereas the overall risk of TE in moderately decreased kidney function is approximately 2.5-fold higher compared to patients with normal renal function, the risk increase is 5.5-fold in patients with severe renal dysfunction. In patients with renal dysfunction and arterial thrombosis (OR: 4.9), malignancy (OR: 5.8) surgery (OR: 14.0) or thrombophilia (OR: 4.3) the risk to suffer from venous TE is higher compared to the risk associated to the baseline renal dysfunction alone. The treatment options for end-stage renal diseases include hemodialysis, peritoneal dialysis and kidney transplantation. During all treatment modalities thrombotic complications have been described, namely catheter malfunction and shunt thrombosis in patients undergoing hemodialysis in up to 25% of patients, and TE, pulmonary embolism or graft vessel thrombosis in approximately 8% of patients. The reported incidence of reno-vascular thrombosis following renal transplantation leading to hemorrhagic infarction with organ rejection or organ loss varied between 2-12%. Keeping in mind the multifactorial etiology of TE in patients with kidney dysfunction a general screening for thrombophilia in this patient group is not indicated. Selected screening on an individual patient basis should be discussed if the family history for TE is positive or the patient itself had suffered one thrombosis before the onset of the renal disease or multiple TEs during hemodialysis or post kidney transplantation in patients waiting for living donor kidney transplantation.