Unveiling potential therapeutic targets for diabetes-induced frozen shoulder through Mendelian randomization analysis of the human plasma proteome

Abstract

IntroductionThis study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms.Research design and methodsWe employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein–protein interaction network.ResultsOur MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p<3.03E-5). According to colocalization analysis, parathyroid hormone-related protein (PTHLH) was moderately correlated with the genetic variance of frozen shoulder (posterior probability=0.68), while secreted frizzled-related protein 4 was highly correlated with the genetic variance of frozen shoulder (posterior probability=0.97). Additionally, nine plasma proteins were activated during diabetes-associated pathologies. Subsequent MR analysis of nine diabetic target proteins with four frozen shoulder causal proteins indicated that insulin receptor subunit alpha, interleukin-6 receptor subunit alpha, interleukin-1 receptor accessory protein, glutathione peroxidase 7, and PTHLH might contribute to the onset and progression of frozen shoulder induced by diabetes.ConclusionsOur study identified a causal relationship between diabetes and frozen shoulder, highlighting the pathological pathways through which diabetes influences frozen shoulder.

Genetic analysis and characterization of reproductive control genes in Belgian and Qinchuan cattle population structure

“…PTHLH also plays a key regulatory role in mammary gland and bone development, contributing to its in uence on the reproductive function of the cow. In beef cattle, PTHLH in uences bone formation and homeostasis by regulating endochondral osteogenesis and epithelial-mesenchymal interactions [23]. UGT2B10 (Uridine 5'-diphospho-glucuronosyltransferase 2B10) is a UDP-glucuronosyltransferase primarily involved in the N-glycosylation of drugs and xenobiotics.UGT2B10 in uences reproductive function of female animals by regulating the metabolism and clearance of estrogens during the reproductive cycle [24].…”