[Show abstract][Hide abstract] ABSTRACT: Objective:
The aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families.
Genome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family.
Genome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele.
A potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.
Preview · Article · Nov 2015 · Osteoarthritis and Cartilage
[Show abstract][Hide abstract] ABSTRACT: To examine the association of the interleukin 1 gene (IL1) cluster polymorphisms and their haplotypes with bilateral distal interphalangeal joint osteoarthritis (DIP OA).
Radiographs of both hands of 295 dentists and 248 teachers were examined and classified for the presence of OA using reference images. Bilateral DIP OA was defined by the presence of radiographic findings of grade 2 or more in at least 1 symmetrical pair of the DIP joints. We genotyped 10 single-nucleotide polymorphisms (SNP) in the IL1R1, IL1RL2, IL1A, IL1B, and IL1RN genes using polymerase chain reaction-based methods. Haplotypes were statistically reconstructed using the PHASE program. The association between the genotypes/diplotypes and bilateral DIP OA was examined with logistic regression analysis.
Two IL1B SNP (rs1143634 and rs1143633) were associated with bilateral DIP OA. The carriers of the IL1B rs1143634 minor allele had an increased OA risk [odds ratio (OR) 1.6; 95% confidence interval (CI) 1.08-2.26] compared to the noncarriers. The association was stronger in the dentists. The distribution of the IL1B rs1143633 genotype fit a recessive mode of inheritance (OR 3.03, 95% CI 1.35-6.83, p = 0.006). Two IL1B-IL1RN extended haplotype alleles (211-1 and 121-1) were associated with bilateral DIP OA. An interaction between the IL1B rs1143634 and the IL1R1-IL1RL2 and IL1B-IL1RN extended haplotypes and occupation (increased risk of OA among dentists only) was observed.
Our results provide further evidence for the role of IL1 gene cluster polymorphisms in the etiology of OA and suggest that some of these may predispose DIP joints to the effects of mechanical overload.
No preview · Article · Sep 2009 · The Journal of Rheumatology
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate the relationship of the IL-6 promoter variants G-597A, G-572C and G-174C (rs1800797, rs1800796 and rs1800795, respectively), which have been shown to affect both the transcription and secretion of IL-6, to symptomatic distal interphalangeal (DIP) osteoarthritis (OA).
A total of 535 women aged 45 to 63 years were included. Radiographs of both hands were taken and each DIP joint was evaluated (grade 0 to 4) for the presence of OA. Information on symptoms (pain, tenderness) in each joint was collected by using a self-administered questionnaire. Symptomatic DIP OA was defined by the presence of both radiographic findings of grade 2 or more and symptoms in at least two DIP joints, and symmetrical DIP OA by the presence of radiographic findings of grade 2 or more in at least one symmetrical pair of DIP joints. Common polymorphic loci in the IL-6 gene were amplified and the promoter haplotypes were reconstructed from genotype data with the PHASE program. Logistic regression analysis was used to examine the association between the IL-6 genotypes/diplotypes and the DIP OA outcome.
The G alleles of two promoter single nucleotide polymorphisms (SNPs) G-597A and G-174C were more common among the subjects with symptomatic DIP OA than among those with no disease (P = 0.020 and 0.024, corrected for multiple testing). In addition, the carriage of at least one G allele in these positions increased the risk of disease (P = 0.006 and P = 0.008, respectively). Carrying a haplotype with the G allele in all three promoter SNPs increased the risk of symptomatic DIP OA more than fourfold (odds ratio (OR) 4.45, P = 0.001). Carriage of the G-G diplotype indicated an increased risk of both symmetrical DIP OA (OR 1.52, 95% confidence interval 1.01 to 2.28) and symptomatic DIP OA (OR 3.67, 95% confidence interval 1.50 to 9.00).
The present study showed that the presence of G alleles at common IL-6 polymorphic promoter loci was associated with the more severe DIP OA outcomes, symmetrical and symptomatic.
Full-text · Article · Feb 2008 · Arthritis research & therapy