SMAD3 is associated with the total burden of radiographic osteoarthritis: the Chingford study.
BACKGROUND
A newly-described syndrome called Aneurysm-Osteoarthritis Syndrome (AOS) was recently reported. AOS presents with early onset osteoarthritis (OA) in multiple joints, together with aneurysms in major arteries, and is caused by rare mutations in SMAD3. Because of the similarity of AOS to idiopathic generalized OA (GOA), we hypothesized that SMAD3 is also associated with GOA and tested the hypothesis in a population-based cohort.


METHODS
Study participants were derived from the Chingford study. Kellgren-Lawrence (KL) grades and the individual features of osteophytes and joint space narrowing (JSN) were scored from radiographs of hands, knees, hips, and lumbar spines. The total KL score, osteophyte score, and JSN score were calculated and used as indicators of the total burden of radiographic OA. Forty-one common SNPs within SMAD3 were genotyped using the Illumina HumanHap610Q array. Linear regression modelling was used to test the association between the total KL score, osteophyte score, and JSN score and each of the 41 SNPs, with adjustment for patient age and BMI. Permutation testing was used to control the false positive rate.


RESULTS
A total of 609 individuals were included in the analysis. All were Caucasian females with a mean age of 60.9±5.8. We found that rs3825977, with a minor allele (T) frequency of 20%, in the last intron of SMAD3, was significantly associated with total KL score (β = 0.14, Ppermutation = 0.002). This association was stronger for the total JSN score (β = 0.19, Ppermutation = 0.002) than for total osteophyte score (β = 0.11, Ppermutation = 0.02). The T allele is associated with a 1.47-fold increased odds for people with 5 or more joints to be affected by radiographic OA (Ppermutation = 0.046).


CONCLUSIONS
We found that SMAD3 is significantly associated with the total burden of radiographic OA. Further studies are required to reveal the mechanism of the association.
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Erfan
E
Aref-Eshghi
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Yuhua
Y
Zhang
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
Deborah
D
Hart
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
Ana M
AM
Valdes
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Andrew
A
Furey
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Glynn
G
Martin
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Guang
G
Sun
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Proton
P
Rahman
Musculoskeletal Epidemiology and Biobank, University of Oxford, Oxford, United Kingdom.
Nigel
N
Arden
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
Tim D
TD
Spector
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada; Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
Guangju
G
Zhai
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008875:Middle Aged; D010003:Osteoarthritis / Q000000981:diagnostic imaging*; D011859:Radiography; D051900:Smad3 Protein / Q000502:physiology*
C497790:SMAD3 protein, human; D051900:Smad3 Protein