Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

Objective. To more finely linkage-map primary osteoarthritis (OA) susceptibility loci on chromosomes 4 and 16.Methods. Two hundred eighteen families, each with 2 or more women concordant for primary OA (ascertained by total hip replacement [THR] or total knee replacement), were genotyped using highly polymorphic microsatellite markers from chromosomes 4 and 16, at an average density of 1 marker every 4 cM. Two-point and multipoint linkage analyses were performed for all 218 families and for the 146 families from the 218 that included women concordant for THR (female-THR families).Results. A single region of linkage was identified on chromosome 4q, with a maximum multipoint logarithm of odds (LOD) score (MLS) of 3.1 in the 146 female-THR families. This locus was centered 79 cM from the 4p telomere and had a 1-LOD support interval of 4 cM. Two regions of linkage were identified on chromosome 16, the first on 16p with an MLS of 1.7 in the female-THR families and the second on 16q with an MLS of 1.9 in all 218 families. The first locus was centered 46 cM and the second 89 cM from the p-telomere. The 1-LOD support intervals were 12 cM and 10 cM, respectively. Conclusion.Finer linkage mapping using a high density of microsatellite markers has narrowed female OA susceptibility loci on chromosomes 4 and 16. The regions have been narrowed sufficiently for association analysis.

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Introduction The Bone and Joint Monitor Project was developed to quantify the global burden of musculoskeletal conditions and develop strategies for their prevention. Experts within the Monitor Project have worked previously with officers at the World Health Organization (WHO) to estimate morbidity and mortality associated with rheumatic conditions. The present collaboration seeks means of providing additional and more current burden data. Objective To develop recommendations for performing epidemiological studies in sample populations with musculoskeletal conditions and problems, accounting for determinants and consequences to the individual and society. Methods Recommendations have been developed identifying the most relevant domains for measuring and monitoring the various musculoskeletal conditions by review of epidemiological data on occurrence, determinants and outcomes, and by expert opinion. Instruments that measure these domains were reviewed. Results The domains recommended follow the principles of the WHO International Classification of Functioning, Disability and Health [1,2], and consider: health condition; body function and structure; activity limitation; participation restriction; personal and environmental contextual factors; and, in addition, the resource utilisation and social consequences. The musculoskeletal conditions and problems considered were osteoarthitis, inflammatory arthritis, osteoporosis, spinal problems, musculoskeletal trauma and injuries, and musculoskeletal pain with restricted activity. The selection of indicators for each domain considered the feasibility of their use in a health interview survey (HIS), a health examination survey (HES), a register or a clinical study. Consensus on case definition was reached depending on the study methodology. For example, osteoporosis defined by bone densitometry cannot be ascertained in an HIS, whereas the outcome of osteoporosis (i.e. fragility fracture) can be. Osteoarthitis can be identified as joint pain in an HIS but the preferred definition is pain with X-ray changes and can only be ascertained in an HES. Previously validated generic and disease-specific instruments have been identified that include indicators for all or most of the recommended domains for the consequences of the different conditions and problems. The indicators of the domains for resource utilisation and social consequences and feasibility for collection will vary in different socioeconomic and geographic areas. Guidance on sampling methods is also being developed. Conclusions The comparability of data collected across the globe will improve by the application of agreed upon indicators that consider key domains for the different musculoskeletal conditions and problems in epidemiological studies conducted in different populations.