Dissertation committee:
Καναβάκης Ε., Μαλίζος Κ., Τσέζου Α., Κίτσιου - Τζέπη Σ., Ευσταθόπουλος Ν., Χρονόπουλος Ε., Τζέπη Μ.
Summary:
Osteoarthritis (OA) is a common, late-onset disease characterized by the loss
of the articular cartilage of synovial joints. A variety of epidemiological
studies have demonstrated that genetic susceptibility is a key contributor to
OA aetiology.
This is a case-control study in order to investigate the correlation of
polymorphisms in 6 genes with OA. These comprised of : the genes COL1A2 and
COL2A1 coding for the 2 main structural proteins of the cartilage, the genes
ASPN, CALM1, ESR1 involved in the cartilage metabolism, and last the gene ADRB2
implicated in neuroimmune mechanisms of inflammation. These genes were selected
either because of previous association studies with OA (ASPN, CALM1, ESR1,
COL1A2, COL2A1) or on the basis of the hypothesis regarding the contribution of
inflammation in OA (ADRB2).
Our sample consists of 158 patients with idiopathic knee OA and 193
age-matched controls. All participants have answered questionnaires detailing
personal, family history (including menstrual history, smoking, comorbibity,
degree of psysical activity and knee joint use) and their BMI was calculated.
In addition all had knee X-rays and were stratified according to the
Kellgren-Lawrence (K/L) scale.
The variants that were determined and did not show any correlation with OA,
were the GT repeat polymorphism in intron 1 (COL1A2), the R75C, R519C, R789C
mutations (COL2A1) and the Arg16Gly, Glu27Gln polymorphisms (ADRB2).
Our findings regarding the polymorphisms XbaI (A/G) and PvuII (T/C) in intron 1
of the ESR1 were: A significant difference was observed in the frequency
distribution of between OA patients and controls with allele A exerting a
protective role and AG genotype conferring increased risk compared to AA (OR
0.33; 95%CI 0.13-0.84; P>0.02). A significantly increased odds ratio for knee
OA was also observed in individuals having haplotype CG compared to TA (OR
1.86; 95% CI 1.21-2.87; P>0.005) while haplotype TG conferred a six times
increased risk compared to TA (OR 6.03; 95% CI 1.64-24.2; P>0.007).
In asporin, we tested the D repeat polymorphism in exon 2 and found that the
D13 allele has a protective role in relation to OA and the D15 allele (not the
D14, as previously found in the Japanese studies) is a risk factor for OA (OR
1.54).
In CALM1, a single nucleotide polymorphism (SNP) in the promoter region
(-16C/T) had been previously shown to correlate with OA in the Japanese
population. In the Greek patients there was no statistical difference found in
the genotype distribution but the combination of the TT genotype with the
asporin alleles (D14 or D15) confers increased risk for OA, the p value of this
latter finding being borderline (p=0.05).
Finally, our study contributed to the standardization of the DNA microarray
methodology, which can be used for further analysis of polymorphisms/ mutations
in other genes.
Keywords:
Asporin (ASPN), Calmodulin 1 (CALM1), Adrenergic receptor B2 (ADRB2), Collagen 2 Alpha 1 (COL2A1) , Collagen 1 Alpha 2 (COL1A2)