Objective Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time. Design 1153 Caucasian adults (age range 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥ 2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective. Results Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/ rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression (OR 1.91 (95%CI 1.16-3.15), p = 0.012). Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype. Conclusion A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.
ABSTRACT. Zinc finger protein 191, ZNF24 and Zfp191 in both humans and mice belong to the SCAN domain subfamily of Krüppel-like zinc finger transcription factors. Previous studies have suggested that Zfp191 is a pleiotropic factor involved in embryonic development, hematopoiesis and tumorigenesis. However, little is known about its target genes or its role in other physiological and pathological processes. We have identified the putative target genes of Zfp191, using an in silico genome-wide scan. Three hundred and fifty-five putative target genes were identified, which were enriched into the pathways of immune response according to the pathway analysis. These targets indicated that Zfp191 may function as a mediator of the immune response. This was verified in mice heterozygous for Zfp191 (Zfp191 +/-) using a lipopolysaccharide (LPS)-induced endotoxic shock model. After LPS injection, Zfp191 +/-mice produced significantly less IL-1β and IL-6 compared to wild-type mice and were resistant to LPS-induced endotoxic ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 10 (4): 1712-3721 (2011) Resistance to endotoxic shock in Zfp191 gene-knockout mice 3713shock. The loss of Zfp191 may suppress systemic inflammation by reducing these cytokine levels during LPS-induced endotoxic shock.
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