Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women

Forster, Tracy; Chapman, Kay; Marcelline, Lucy; Mustafa, Zehra; Southam, Lorraine; Loughlin, John

doi:10.1002/art.11427

Cited by 31 publications

(17 citation statements)

References 13 publications

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“…It was not long before IL-1b was being used frequently with in vivo and ex vivo cartilage as a model of arthritis for the testing of pharmacotherapeutics and investigations of arthritis signaling (50). Genetic evidence for a role of IL-1b in OA came much more recently with the discovery of polymorphisms in the IL-1 gene cluster that act as risk factors for OA (51)(52)(53). In arthritis imaging research, IL-1b is now used to simulate osteoarthritis in animal models in order to track progression of mild disease by emerging techniques (54).…”

Section: Models Of Osteoarthritis In Articular Cartilagementioning

confidence: 99%

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

et al. 2006

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In this article, both sodium magnetic resonance (MR) and T 1r relaxation mapping aimed at measuring molecular changes in cartilage for the diagnostic imaging of osteoarthritis are reviewed. First, an introduction to structure of cartilage, its degeneration in osteoarthritis (OA) and an outline of diagnostic imaging methods in quantifying molecular changes and early diagnostic aspects of cartilage degeneration are described. The sodium MRI section begins with a brief overview of the theory of sodium NMR of biological tissues and is followed by a section on multiple quantum filters that can be used to quantify both bi-exponential relaxation and residual quadrupolar interaction. Specifically, (i) the rationale behind the use of sodium MRI in quantifying proteoglycan (PG) changes, (ii) validation studies using biochemical assays, (iii) studies on human OA specimens, (iv) results on animal models and (v) clinical imaging protocols are reviewed. Results demonstrating the feasibility of quantifying PG in OA patients and comparison with that in healthy subjects are also presented. The section concludes with the discussion of advantages and potential issues with sodium MRI and the impact of new technological advancements (e.g. ultra-high field scanners and parallel imaging methods). In the theory section on T 1r , a brief description of (i) principles of measuring T 1r relaxation, (ii) pulse sequences for computing T 1r relaxation maps, (iii) issues regarding radio frequency power deposition, (iv) mechanisms that contribute to T 1r in biological tissues and (v) effects of exchange and dipolar interaction on T 1r dispersion are discussed. Correlation of T 1r relaxation rate with macromolecular content and biomechanical properties in cartilage specimens subjected to trypsin and cytokineinduced glycosaminoglycan depletion and validation against biochemical assay and histopathology are presented. Experimental T 1r data from osteoarthritic specimens, animal models, healthy human subjects and as well from osteoarthritic patients are provided. The current status of T 1r relaxation mapping of cartilage and future directions is also discussed. Copyright # 2006 John Wiley & Sons, Ltd. KEYWORDS: cartilage; arthritis; spin-lock; T1rho; sodium; MRI OSTEOARTHRITIS Osteoarthritis (OA) affects more than half of the population above the age of 65 (1,2) and has a significant negative impact on the quality of life of elderly individuals (3). The economic costs in the USA from OA have been estimated to be more than 1% of the gross domestic product (4). OA is now increasingly viewed as a metabolically active joint disorder of diverse etiologies. The biochemistry of the disease is characterized by the following changes in cartilage: reduced proteoglycan (PG) concentration, possible changes in the size of collagen fibril and aggregation of PG, increased water content and increased rate of synthesis and degradation of matrix macromolecules. The earliest changes in the cartilage due to OA result in a partial breakdown in the proteoglyc...

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Section: Models Of Osteoarthritis In Articular Cartilagementioning

confidence: 99%

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

et al. 2006

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“…4 Association was also tested in a second cohort comprising 244 female patients with hip OA. The probands and cases were ascertained through the Nuffield Orthopaedic Centre and had undergone total joint replacement of the hip only (mono-or bilateral) for primary OA.…”

Section: Patients For Association Analysismentioning

confidence: 99%

“…Finer linkage mapping of our chromosome 4 linkage generated a maximum multipoint LOD score of 3.1 at 4q13.1-q13.2 in 146 families, each with two or women concordant for primary OA ascertained by total hip replacement (THR). 4 Using public databases, we searched the chromosome 4q linkage interval for plausible functional candidate genes. These were selected based upon a reported or suspected role in skeletal joint tissue biology.…”

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confidence: 99%

Genetic association analysis of the IGFBP7, ADAMTS3, and IL8 genes as the potential osteoarthritis susceptibility that maps to chromosome 4q

Kawahara

Forster²,

Chapman³

et al. 2005

Annals of the Rheumatic Diseases

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“…A number of linkage studies of OA at different sites have been performed in single large pedigrees and in multiple families (6)(7)(8)(9)(10)(11)(12)(13)(14). The genes responsible for the observed linkage peaks have not yet been clearly determined or validated, and results from different linkage studies show little overlap.…”

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confidence: 99%

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

Spector¹,

Reneland²,

Mah³

et al. 2006

Arthritis & Rheumatism

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Objective. To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee.Methods. We examined >25,000 SNPs located within ϳ14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression.Results. The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in casecontrol samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role.Conclusion. A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.Osteoarthritis (OA) is a degenerative joint disease that primarily affects the knees, hips, hands, and spine (1). The biology and epidemiology of OA seem to differ between sites, with a different balance of risk factors and age at onset for different sites. For genetic purposes, site-specific classification is likely to be important, with differential linkage and association results for the hip and the spine (2).

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Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women

Cited by 31 publications

References 13 publications

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

Genetic association analysis of the IGFBP7, ADAMTS3, and IL8 genes as the potential osteoarthritis susceptibility that maps to chromosome 4q

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

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Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women

Cited by 31 publications

References 13 publications

Sodium and T1ρ MRI for molecular and diagnostic imaging of articular cartilage

Sodium and T1ρ MRI for molecular and diagnostic imaging of articular cartilage

Genetic association analysis of the IGFBP7, ADAMTS3, and IL8 genes as the potential osteoarthritis susceptibility that maps to chromosome 4q

Association between a variation in LRCH1 and knee osteoarthritis: A genome‐wide single‐nucleotide polymorphism association study using DNA pooling

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Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage

Sodium and T_1ρ MRI for molecular and diagnostic imaging of articular cartilage