Association of osteoarthritis susceptibility gene polymorphisms with clinical and radiographic grading

Abstract

Association of osteoarthritis susceptibility gene polymorphisms with clinical and radiographic grading

Saporito Michele1, Minafra Luigi2, Bravatà Valentina2, Forte Giusi I2, Cammarata Francesco P2, D’Arienzo Michele1 and Boniforti Filippo3

1Clinica Ortopedica e Traumatologica, Università degli Studi di Palermo, Palermo;
2IBFM CNR-LATO, Cefalù (PA);
3U.O.C. di Ortopedia e Traumatologia, Ospedale G. Giglio, Cefalù (PA).

Introduction. Osteoarthritis (OA) is polygenic and multifactorial disease. Associations between radiographic and clinical signs are widely described in literature. In order to update the grading of OA, we verified associations between: radiographic grade according to Kellgren and Lawrence (KL), clinical features assessed by the American Knee Society Score (AKSS), age and polymorphisms in the principal osteoarthritis susceptibility (OS) genes.
Methods. We enrolled 66 Sicilian individuals affected by primary knee osteoarthritis. Clinical evaluation was performed using AKSS and radiographic grading using KL scale simplified in three groups. BMI and age were recorded. OMIM and dbSNP Short Genetic Variation databases were used to select gene regions containing the following polymorphisms: FRZB rs288326 (OS1A), rs7775 (OS1B), MATN3 rs77245812 (OS2), ASPN D14 repeats (OS3), PTHR2 rs76758470 (OS4), GDF5 rs143383 (OS5), DVWA rs11718863 (OS6A) and DVWA rs7639618 (OS6B). One undred healthy subjects were enrolled as control samples for genetic analysis. Patient genotypes were obtained using Sanger DNA sequencing analysis.
Results. A significant statistical association between the variables analyzed was reported in all associations tested (KL versus KS, FS and age). A mild to severe OA radiographic grade was related to severe clinical conditions and loss of articular function. Severity of symptoms increased with age. A significant statistical association was found between KL grading and GDF5 rs143383, DVWA rs11718863 and rs7639618 genetic alterations. In addition, our genotyping results suggest that OS6 polymorphisms can be associated with a more severe OA radiographic grade displaying a possible predictive role as markers of OA progression.
Conclusions. A statistically significant association between clinical and radiological grade of OA and OS5 and OS6 SNPs suggests the update of the actual radiographic knee OA classification. Our study shows that OS5 and OS6 SNPs analysis, combined with clinical and radiological signs, could contribute to better define grading and progression of OA and to the development of new therapies.

Full text

Association of osteoarthritis
susceptibility gene polymorphisms
with clinical and radiographic grading
Saporito M1, Minafra L2, Bravatà V2, Cammarata FP2, Forte GI2
D’Arienzo M1 and Boniforti F3
1 Clinica Ortopedica e Traumatologica, Università degli Studi di Palermo (PA)
2 IBFM CNR-LATO, Cefalù (PA)
3 U.O.C di Ortopedia e traumatologia, Ospedale G. Giglio, Cefalù (PA)

OA GENETICS
•United Kingdom, Valdes et al. 2009
•Japan and China, Miyamoto et al. 2008
•Korea, Lee SJ et al. 2013
Different gene mutations are related to
the OA susceptibility, onset and
progression in Caucasian and Asian
populations

METHODS
•61 primary knee OA
affected sicilian patients,
Orthopaedics and Trauma
Unit, Hospital G.Giglio,
Cefalù
•IBFM CNR- LATO
Proteogenomics Lab,
Hospital G.Giglio, Cefalù

MUTATIONAL ANALYSIS
OA susceptibility (OS) gene polymorphisms
from OMIM and dbSNP databases (NCBI)
•OS1 A-B:FRZB rs288326 - rs7775
•OS2: MATN3 rs77245812
•OS3: ASPN D14 repeats
•OS4: PTHR2 rs76758470
•OS5: GDF5 rs143383
•OS6 A-B: DVWA rs1171863 - rs7639618

OA GRADING
Kellgren&Lawrence
scale (KL)
Knee Society Score
(KSS)

RESULTS
OS5
OS6 A-B
KL OA X-rays
grade
Significant statistical association
P=0.02(OS5)
P=0.03 (OS6 A-B)

OS6 - DVWA
•2 double Von Willebrand A
domains protein
•β-tubulin interaction in
cytoskeleton
•Regulation of
chondrocytes
differentiation
•Protect articular joints from
OA onset
•Encode growth
differentiation factor 5
•Bone morphogenic protein
•Involved in development,
homeostasis and repairing
of cartilage.
•OS5 is the only locus
successfully validated in
Asian and European
population
OS5 – GDF5

RESULTS (2)
OS6 A-B
segregate as
haplotype
Severe KL OA
X-rays grade
OS6 A-B are mostly represented
in grade 4 KL (55%: genotype
heterozygote + homozygote)

CONCLUSIONS
•Mutational analysis can be useful to assess
early onset and progression of OA
•OS6 A-B (DVWA SNPs) could be a
predictor of the disease's progression

GRAZIE
michele.saporito01@unipa.it
filippo.boniforti@gmail.com
luigi.minafra@ibfm.cnr.it