Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Association of genetic polymorphism in inflammatory cytokines with radiographic knee OA severity and Generalized Osteoarthritis (GOA)

Attur1,  Mukundan, Samuels1,  Jonathan, Krasnokutsky1,  Svetlana, Kornman1,  Ken, Aziz1,  Nazneen, Kraus2,  VB, McDaniel2,  Gary

NYU-Hospital for Joint Diseases, New York, NY
Duke University Medical Center, Durham, NC
New York University School of Medicine, Millburn, NJ
Harvard Med School, Marlborough, MA
Waltham

Purpose:

Osteoarthritis is the most common form of arthritis, and the hereditable component of OA has been estimated to be 50–65%. The IL1 gene cluster region has been repeatedly associated with susceptibility to OA in various joints. This finding is consistent with the notion that inflammatory mediators, particularly IL-1, may be important in the pathogenesis and progression of OA. In these studies we examined the association of SNPs in inflammatory genes with the severity of knee OA and with the presence of generalized OA (GOA, here defined as knee plus hand OA).

Method:

One hundred forty-four OA patients (81 knee OA and 63 GOA) from two separate centers (NYUHJD, N=94 and Duke, N=50) met inclusion criteria: Caucasians of either sex, free of chronic disease other than osteoarthritis, and with a radiographic diagnosis of knee OA. Synovial fluid was available for the 50 Duke patients. Patients were genotyped for single nucleotide polymorphisms (SNPs). These subjects were divided into two groups: knee OA and GOA (knee and hand OA).We performed statistical analysis using Chi square and logistic regression, adjusting for age, gender and BMI to search for associations of radiographic knee OA severity and GOA with individual SNPs and with haplotypes.

Results:

After adjustment for age, gender, and BMI, individual TNF-a, IL1, IL1 receptor antagonist (IL1RN) SNPs were strongly associated with the presence of GOA (Table 1). In three of the four SNPs, alleles associated with increased incidence of GOA have been previously associated with increased cellular production of inflammatory mediators. These alleles are: IL1B (-3737) rs4848306 TT/CT, IL1B (-511) rs16944 CC/CT, and TNF-a (-308) rs1800629 AA/AG. In a separate analysis of knee OA severity based upon JSW, carriage of either one or two copies of a haplotype consisting of IL-1RN rs9005 (A), IL-1RN rs419598 (C), IL-1RN rs315952(T) was associated with lower odds of radiographic severity (OR 0.16; 95% CI 0.06–0.40), greater joint space width (JSW; p=0.0038) compared to those without these haplotypes. Patients with the "protective" haplotype had lower synovial fluid levels of IL-6 (p=0.018) and IL-10 (p=0.038).

Table 1. Association of SNPs with GOA

   Likelihood of GOA
SNPGenotype freq in this OA studypOR (95% CI)
IL1RN rs315952CC/CT44%0.01042.49 (1.24–4.98)
 TT56% 1.0
IL1B (-3737) rs4848306TT/CT67%0.00193.65 (1.62–8.26)
 CC33% 1.0
IL1B (-511) rs16944CC/CT84%0.0223.33 (1.19–9.09)
 TT16% 1.0
TNFa (-308) rs1800629AA/AG59%0.0053.23 (1.43–7.34)
 GG41% 1.0

Conclusion:

Among the cytokines and receptor antagonist studied for genetic association, IL-1RN SNPs (rs9005, rs419598 & rs315952) predicted low risk for knee OA radiographic severity and haplotypes in IL-1B, TNFa ad IL-1RN (rs 315952) strongly associated with increased prevalence of GOA. These genetic markers provide insight into the possible role of inflammatory mediators in knee OA and could prove to be useful biomarkers in DMOAD drug development.

To cite this abstract, please use the following information:
Attur, Mukundan, Samuels, Jonathan, Krasnokutsky, Svetlana, Kornman, Ken, Aziz, Nazneen, Kraus, VB, et al; Association of genetic polymorphism in inflammatory cytokines with radiographic knee OA severity and Generalized Osteoarthritis (GOA) [abstract]. Arthritis Rheum 2009;60 Suppl 10 :767
DOI: 10.1002/art.25847

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