Molecular Genetic Study of Avascular Necrosis of the Femoral Head

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Total Enrollment

500 participants

Study Classification

OBSERVATIONAL

Study Start Date

2003-05-31

Study Completion Date

2008-04-30

Brief Summary

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Avascular necrosis of the femoral head (ANFH) is a debilitating disease that commonly leads to destruction of the hip joint in patients at middle age of life and often requires surgical intervention. Previously, we have identified the collagen type II, alpha 1 (COL2A1) gene as the ANFH disease gene. In this grant proposal, we will establish cell ine and animal models to understand the pathophysiology of ANFH, and extend our ongoing study for identifying genes responsible for non-familiar ANFH by looking into other interacting molecules of the pathway.

Detailed Description

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Avascular necrosis of the femoral head (ANFH) is a debilitating disease that usually leads to destruction of the hip joint in the third to fifth decade of life (average age, 36 years). The disease prevalence is unknown, but it has been estimated that 10,000-20,000 new cases per year are diagnosed in the United State. Nearly half of the patients eventually require hip replacement before 40 years of age. The etiology of ANFH is unknown but previous studies indicated that heritable thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi), alcohol intake, and steroid use are risk factors for ANFH.

Although the majority of idiopathic ANFH cases are sporadic, recently we identified three ANFH families showing autosomal dominant inheritance. By genome-wide scan, a significant two-point LOD score of 3.45 at = 0 was obtained between one ANFH pedigree and marker D12S85 on chromosome 12. High-resolution mapping was conducted in a second ANFH family and replicated the linkage to D12S368. When an age-dependent penetrance model was applied, the combined multipoint LOD score achieved 6.43 between D12S1663 and D12S85. Furthermore, by using haplotype analysis and gene-based mutation detection, we have identified the collagen type II, alpha 1 (COL2A1) gene, as the ANFH disease gene. Re-sequencing of the type II collagen (COL2A1) gene demonstrated a glycine with serine mutation in the G-X-Y repeat of type II collagen, in all affected individuals in three pedigrees. In the Pedigree I, a 3665G \>A mutation in exon 50 of the COL2A1 gene (Genbank accession number NM\_001844) and the substitution resulted in a Gly1170Ser codon change (Genbank accession number NP\_001835). A second pedigree was shown to harbor the same mutation but the mutant allele existed in a different haplotype background. In a third pedigree, a 2306G\>A mutation occurred in exon 33 of the gene (Genbank accession number NM\_001844), causing glycine to serine change at codon 717 (Genbank accession number NP\_001835).

On this basis, we propose to study the pathophysiological mechanism(s) of inherited and sporadic ANFH. The main focus of this project includes: (1) Establishing cell line and animal models to investigate the molecular basis of ANFH pathogenesis. (2) Conducting genetic analysis on sporadic ANFH cases, including those who are idiopathic, alcohol consumers or steroid-induced. (3) Using COL2A1 gene as a target, we will design novel therapeutics and prediction procedures to improve the management of the ANFH patients.

Conditions

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Osteonecrosis

Study Design

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Observational Model Type

DEFINED_POPULATION

Study Time Perspective

OTHER

Eligibility Criteria

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Inclusion Criteria

\- avascular necrosis of the femoral head

Exclusion Criteria

\-

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Principal Investigators

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Wei-Ming Chen, M.D.

Role: PRINCIPAL_INVESTIGATOR

Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital

Locations

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Division of Molecular and Genomic Medicine, National Health Research Institutes

Miaoli County, , Taiwan

Site Status RECRUITING

Countries

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Taiwan

Central Contacts

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Shih-Feng Tsai, M.D., Ph.D.

Role: CONTACT

[email protected]

(886)-37-246-166 ext. 35300

Facility Contacts

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Shih-Feng Tsai, M.D, Ph.D

Role: primary