Exploring the role of gonadotropins in Down syndrome

PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is a common chromosomal disorder that results from the triplication of chromosome 21. Comorbid medical conditions frequently occur among individuals with DS; however, opthalamic disorders such as keratoconus occurs 6 times more often among this population as compared to the general population. Keratoconus is a known multifactorial, progressive, degenerative disease of the cornea; however, the etiology of the disease remains unclear. Our recent work has found that hormone-regulated Prolactin-Induced Protein (PIP) is a potential biomarker of keratoconus but the link between DS and keratoconus remains unclear. Pathway analysis has further linked comorbid DS and keratoconus through gonadotropins and serum amyloid A1 (SAA), a protein linked in a series of studies to cognitive dysfunction among adults with DS. The proposed study aims to determine and validate the role of gonadotropins in the DS population with the keratoconus co-morbidity with the long-term goal to better understand the underlying mechanisms that result in increased risk for ocular co-morbidities such as keratoconus among this population. This pilot study will include n=90 participants (n=30 DS; n=30 comorbid DS and Keratoconus; n=30 healthy controls). All participants will provide biofluid samples of tears and plasma, which will be assayed on an electrochemiluminescence (ECL) platform. Analyses will be performed using R and SPSS 24 (IBM) in a series of steps. Support Vector Machine (SVM) analyses will be applied to examine the use of biomarkers to detect disease presence (i.e. keratoconus comorbidity). Least absolute shrinkage and selection operator (LASSO) analyses will help with variable selection in order to enhance the prediction accuracy of the models. Biomarkers will include hormone specific (LSH, LH, GNRH, LHR, FSHR, GNRHR) as well as a panel of plasma proteins including biomarkers of inflammation linked with cognitive dysfunction (SAA, CRP, ICAM1, VCAM1, IL-6, IL-10, TNF-?, IL-5, IL-7, Eotaxin-3, TARC, A2M, B2M, FVII, TNC, Adiponectin, FABP-3, IL-18, PPY, TPO and I-309). Diagnosis of keratoconus will be utilized as the dependent variable. If successful, data obtained from this study could help facility the development of a screening tool for detecting individuals with DS who are at risk for development of keratoconus, with the goal of defining potential enrollment into clinical trials.