Osteoarthritis (OA) is the most common form of arthritis in elderly adults, increasing in incidence with age. Symptomatic OA of the knee and hip is the leading cause of disability among those 65 years of age and older. The relative lack of objective measures of the OA process has been a significant barrier to clinical and therapeutic research. Elucidation of the molecular alterations in osteoarthritic joints, has led to the identification of biomarkers of potential clinical utility. Biomarkers can originate from joint structures such as synovium, cartilage or bone, and can be detected in blood, synovial fluid, urine or joint tissue. Biomarkers with the potential to reflect processes taking place locally in the joint hold great promise as a minimally invasive means to diagnose and monitor arthritis. The purpose of this study is to evaluate the ability of serum biomarkers on invasive means to diagnose and monitor arthritis. The purpose of this study is to evaluate the ability of serum biomarkers on joint pathology to identify OA disease status and genes that predispose to the development of OA.. The markers to be evaluated are cartilage oligomeric matrix protein, hyaluronan and keratan sulfate. The hypothesis is that high levels of the three biomarkers under study, individually or in combination, will identify individuals with joint pathology and can be used as quantitative traits for the purposes of genetic analyses. This will constitute the only large arthritis study of its kind to date. We will establish the reliability of these serum biomarkers as indicators of OA joint pathology and determine threshold values by age, race and gender which are predictive of OA status. Those serum biomarkers indicative of joint pathology will then be quantified in family data sets. We will first establish whether there is a genetic contribution to the traits by estimating trait heritability in a set of 200 small nuclear families which have been phenotyped for the biomarkers. For those traits with a significant genetic component, we will measure the trait values in individuals from large extended pedigrees for which genetic marker genotype data are available and search for genetic linkage between the biomarker trait loci and genetic markers spanning the genome. If our screen identifies a small region(s), both microsatellites as well as single nucleotide polymorphisms (SNPs) will be genotyped. Family-based association techniques to detect linkage disequilibrium will be used. Future studies will include examination of these regions and candidate genes in OA families. These proposed studies will yield very valuable insights into the diagnostic and prognostic capabilities of three serum biomarkers, including age related and racial related differences in value levels. Using this novel approach of identifying OA through the use of serum biomarkers, we ultimately hope to identify genes which contribute to the pathogenesis of OA.
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