Osteonecrosis Clinical Trial
Official title:
Molecular Genetic Study of Avascular Necrosis of the Femoral Head-Revealing ANFH Pathogenesis Mechanism by Cell and Animal Models
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.
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.
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Observational Model: Defined Population, Primary Purpose: Screening, Time Perspective: Cross-Sectional
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