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

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 approximately 14,000 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 case-control 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.

[1]  R. Zimmer,et al.  Comparison of the chondrosarcoma cell line SW1353 with primary human adult articular chondrocytes with regard to their gene expression profile and reactivity to IL-1beta. , 2005, Osteoarthritis and cartilage.

[2]  Yusuke Nakamura,et al.  An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis , 2005, Nature Genetics.

[3]  Nathan J Markward,et al.  Large-Scale Association Study Identifies ICAM Gene Region as Breast and Prostate Cancer Susceptibility Locus , 2004, Cancer Research.

[4]  K. Muir,et al.  Genetic risk of knee osteoarthritis: a sibling study , 2004, Annals of the rheumatic diseases.

[5]  T. Spector,et al.  Association study of candidate genes for the prevalence and progression of knee osteoarthritis. , 2004, Arthritis and rheumatism.

[6]  D. Felson,et al.  A genome scan for joint-specific hand osteoarthritis susceptibility: The Framingham Study. , 2004, Arthritis and rheumatism.

[7]  M. Nelson,et al.  Large-scale validation of single nucleotide polymorphisms in gene regions. , 2004, Genome research.

[8]  A. Grodzinsky,et al.  Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP* , 2004, Journal of Biological Chemistry.

[9]  T. Spector,et al.  Risk factors for osteoarthritis: genetics. , 2004, Osteoarthritis and cartilage.

[10]  L. Southam,et al.  Finer linkage mapping of primary osteoarthritis susceptibility loci on chromosomes 4 and 16 in families with affected women. , 2004, Arthritis and rheumatism.

[11]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[12]  T. Spector,et al.  Evidence of altered bone turnover, vitamin D and calcium regulation with knee osteoarthritis in female twins. , 2003, Rheumatology.

[13]  A. V. van Wijnen,et al.  Inhibitory Effects of Insulin-like Growth Factor-1 and Osteogenic Protein-1 on Fibronectin Fragment- and Interleukin-1β-stimulated Matrix Metalloproteinase-13 Expression in Human Chondrocytes* , 2003, Journal of Biological Chemistry.

[14]  J. Gulcher,et al.  Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. , 2003, American journal of human genetics.

[15]  Susan S. Taylor,et al.  Amino acid variant in the kinase binding domain of dual-specific A kinase-anchoring protein 2: A disease susceptibility polymorphism , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  David A Lee,et al.  Expansion of chondrocytes for tissue engineering in alginate beads enhances chondrocytic phenotype compared to conventional monolayer techniques , 2003, Acta orthopaedica Scandinavica.

[17]  Laura J. Scott,et al.  High-throughput screening for evidence of association by using mass spectrometry genotyping on DNA pools , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Stefan Kammerer,et al.  Association testing by DNA pooling: An effective initial screen , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Daniel Levy,et al.  Genome scan for quantity of hand osteoarthritis: the Framingham Study. , 2002, Arthritis and rheumatism.

[20]  Robert M Nerem,et al.  Mechanical compression alters gene expression and extracellular matrix synthesis by chondrocytes cultured in collagen I gels. , 2002, Biomaterials.

[21]  K. Masuda,et al.  Proliferation of canine intervertebral disk chondrocytes in three-dimensional alginate microsphere culture. , 2002, The Journal of veterinary medical science.

[22]  J. Gulcher,et al.  A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p. , 2001, Arthritis and rheumatism.

[23]  C. Brinckerhoff,et al.  Early response genes induced in chondrocytes stimulated with the inflammatory cytokine interleukin-1beta , 2001, Arthritis research.

[24]  J. Loughlin.  Genetic epidemiology of primary osteoarthritis , 2001, Current opinion in rheumatology.

[25]  R. Strausberg,et al.  High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[27]  L. Peltonen,et al.  Genome scan for predisposing loci for distal interphalangeal joint osteoarthritis: evidence for a locus on 2q. , 1999, American journal of human genetics.

[28]  L. Cardon,et al.  Osteoarthritis-susceptibility locus on chromosome 11q, detected by linkage. , 1999, American Journal of Human Genetics.

[29]  T. Spector,et al.  Twins and the genetic architecture of osteoarthritis. , 1999, Rheumatology.

[30]  F. Breedveld,et al.  Genetic linkage analysis of 14 candidate gene loci in a family with autosomal dominant osteoarthritis without dysplasia. , 1997, Journal of medical genetics.

[31]  J. Kaprio,et al.  Genetic liability to osteoarthritis may be greater in women than men , 1996, BMJ.

[32]  M. Doherty,et al.  Association of two loci on chromosome 2q with nodal osteoarthritis. , 1996, Annals of the rheumatic diseases.

[33]  T. Spector,et al.  Genetic influences on osteoarthritis in women: a twin study , 1996, BMJ.

[34]  K. Kuettner,et al.  Chondrocyte matrix metalloproteinase-8: up-regulation of neutrophil collagenase by interleukin-1 beta in human cartilage from knee and ankle joints. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[35]  T. Spector,et al.  Cigarette smoking and risk of osteoarthritis in women in the general population: the Chingford study. , 1993, Annals of the rheumatic diseases.