FOLLOW-UP RESEARCH IN FAMILIAL SYMPTOMATIC OA (FOA) AT MULTIPLE JOINT LOCATIONS

The osteoarthritis (OA) research of Molecular Epidemiology aims to identify
determinants conferring OA susceptibility by applying molecular epidemiological
approaches to familial OA patients in the GARP study and in early onset OA
families (FOA). Up to now little is known about the early molecular processes
commencing OA onset, however, such insights are considered crucial for the
development of effective disease modifying treatments. Genome wide genetic
association studies have identified common DNA variants that associate to OA
susceptibility with small effect sizes on disease risk and little biologically
relevant information. We then initiated exome sequencing in order to discover
rare deleterious mutations with larger effect sizes and more biological
meaning. This was performed in a selection of 50 patients with familial OA.
These OA patients originated from the GARP study and from early onset OA
families (FOA) collected 20 years ago when the OA research of the Slagboom
group started at TNO-Prevention and Health in collaboration with the
Rheumatology department of the LUMC. Identification of such mutations may
provide important insights into the underlying mechanisms and pathways driving
the onset of OA in these families and possibly in the general OA patient
population. Once the mutations are identified we perform functional follow up
research which provides insights in causal OA pathways in these families,
enabling us to make cellular models as a tool to discover agents to prevent
and/or cure OA.

In one FOA family we have detected a deleterious mutation in a compelling gene
which co-segregates with the FOA phenotype in the family. This mutation is,
therefore, is likely to be causal to the early onset OA. The objective of the
study is:


a) To perform a clinical evaluation (x-rays and physical examination) of family
members to assess the penetrance of the mutation in this family.

b)To collect biological speciment (blood urine and a skin biopsy and possibly
cartilage) to investigate the mechanism by which the mutation causes OA. The
cartilage will be collected in case family members need to undergo a joint
replacement surgery as result of their OA

We will sent the FOA family a newsletter which informs them about; the recent
advances in our research, what type of information has now become available in
their family and an invitation to participate in follow up research. Family
members can express their interest in any of these topics by telephone, regular
mail or e-mail. In earlier correspondence, family members indicated their
appreciation to be informed on the research progress and were asked permission
to be approached again. Only persons who gave permission will be informed and
approached.
When FOA family members have responded positively to the newsletter, we will
approach the person by telephone to give information about the new results and
if applicable refer the patient and/or family members to the clinical
geneticist (Prof. Dr. M. Breuning, who has been consulted and informed on the
situation). When the patient is willing to participate to the additional follow
up research a questionnaire, considering current symptoms, signs and risk
factors of OA will be send by post. In this mail correspondence the
participants are asked to give informed consent also for a hospital visit.
During the hospital visit familymembers will undergo a clinical evaluation and
blood, urine and a skin biopsy will be taken.

Participants will be subjected to rontgen radiation (0.9 mSV, category IIa)
this means that the research needs to be at least aiming to acquire clinical
applied knowledge.

Participants will be asked to give a skin biopsy which may result in a small
skar.