Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium.

OBJECTIVE: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. METHODS: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. RESULTS: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3×10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. CONCLUSION: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.

OBJECTIVES: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. METHODS: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. RESULTS: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. CONCLUSIONS: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Sex differences in the association between body mass index and total hip or knee joint replacement resulting from osteoarthritis.

OBJECTIVE: To examine the association between body mass index (BMI) and osteoarthritis (OA) leading to total hip (THR) or knee (TKR) joint replacement. METHODS: Case-control study design. All patients still living in Iceland who had had a THR or TKR resulting from OA before the end of 2002 were invited to participate. First-degree relatives of participating patients served as controls. A total of 1473 patients (872 women) and 1103 controls (599 women), all born between 1910 and 1939 and who had answered a questionnaire including questions about height and weight, were analysed. A randomly selected sample, representative of the Icelandic population, was used as a secondary control group. RESULTS: The OR, adjusted for age, occupation and presence of hand OA, for having a THR was 1.1 (95% CI 0.9 to 1.5) for overweight men and 1.7 (95% CI 1.0 to 2.9) for obese men. The OR for having a TKR was 1.7 (95% CI 1.1 to 2.6) for overweight men and 5.3 (95% CI 2.8 to 10.1) for obese men. The OR for having a THR was 1.0 (95% CI 0.8 to 1.3) for overweight women and 1.0 (95% CI 0.6 to 1.5) for obese women. The OR for having a TKR was 1.6 (95% CI 1.1 to 2.2) for overweight women and 4.0 (95% CI 2.6 to 6.1) for obese women. CONCLUSION: This study supports a positive association between high BMI and TKR in both sexes, but for THR the association with BMI seems to be weaker, and possibly negligible for women.

Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: the AGES Reykjavik study.

OBJECTIVE: There is evidence that atherosclerosis may contribute to the initiation or progression of osteoarthritis. To test this hypothesis, the presence and severity of hand osteoarthritis (HOA) was compared with markers of atherosclerotic vascular disease in an elderly population. PATIENTS AND METHODS: The AGES Reykjavik Study is a population-based multidisciplinary study of ageing in the elderly population of Reykjavik. In a study of 2264 men (mean age 76 years; SD 6) and 3078 women (mean age 76 years; SD 6) the severity of HOA, scored from photographs, was compared with measures of atherosclerosis. These included carotid intimal thickness and plaque severity, coronary calcifications (CAC) and aortic calcifications and reported cardiac and cerebrovascular events. RESULTS: After adjustment for confounders, both carotid plaque severity and CAC were significantly associated with HOA in women, with an odds ratio of 1.42 (95% CI 1.14 to 1.76, p = 0.002) for having CAC and 1.25 (95% CI 1.04 to 1.49, p = 0.016) for having moderate or severe carotid plaques. Both carotid plaques and CAC also exhibited significant linear trends in relation to HOA severity in women in the whole AGES Reykjavik cohort (p<0.001 and p = 0.027, respectively, for trend). No significant associations were seen in men. Despite this evidence of increased atherosclerosis, women with HOA did not report proportionally more previous cardiovascular or cerebrovascular events. CONCLUSIONS: The results indicate a linear association between the severity of HOA and atherosclerosis in older women. The pathological process of HOA seems to have some components in common with atherosclerosis. Prospective studies may help elucidate the possible mechanisms of this relationship.

Hand radiology characteristics of patients carrying the T(303)M mutation in the gene for matrilin-3.

OBJECTIVE: To determine whether the recently described hand osteoarthritis (HOA)-associated T(303)M mutation in the gene for matrilin-3 (MATN3) is associated with specific radiological changes on hand radiographs. METHOD: Standard hand radiographs from 26 HOA patients carrying the T(303)M missense mutation in the MATN3 gene (T(303)M patients) were compared with those from 52 HOA controls matched for sex, age, and clinical disease severity. Two blinded readers scored the radiographs, using the Verbruggen-Veys anatomical scoring system for the interphalangeal and metacarpophalangeal joints and the OARSI atlas scoring system for the first carpometacarpal (CMC1) joints. A scoring system based on the latter was used for the scaphoid-trapezoid-trapezoideum (STT) joints. RESULTS: No particular distinguishing features were found in the T(303)M patients and the prevalence of erosive and cystic changes was similar to the control group. As a group, however, the T(303)M patients had more severe thumb-base affection, particularly in the STT joint. Thus, definite radiological OA in both CMC1 and STT joints and higher STT scores compared with CMC1 were significantly more common in patients carrying the T(303)M mutation. Radiological scores for joint-space narrowing (CMC1 and STT) and osteophytes (STT) were also significantly higher in the T(303)M patients. CONCLUSION: Patients carrying the T(303)M mutation in the gene for matrilin-3 express a form of HOA that is radiologically indistinguishable from idiopathic HOA in individual patients but they have more severe thumb-base involvement, particularly in the STT joint. This is the first described genetic mutation that is associated with a common form of osteoarthritis.

A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p.

OBJECTIVE: To describe a large kinship with inherited hip osteoarthritis (OA) and its associated susceptibility locus. METHODS: Four generations of a kinship with familial hip OA were identified and characterized by family history and by clinical, radiographic, and histopathologic examination. In the genome-wide search for a susceptibility locus, OA cases were defined as those who had undergone total hip replacement associated with a clinical and radiographic diagnosis of hip OA. A genome-wide scan was performed using a framework set of microsatellite markers with an average spacing of 10 cM. RESULTS: The hip OA of this family was indistinguishable from that of idiopathic, nonfamilial hip OA. There was no apparent evidence of spondyloepiphyseal dysplasia or other dysplasias usually associated with mutations in collagen genes. The genome-wide scan revealed a locus on chromosome 16p between 28 cM and 47 cM from the telomere, and this locus met the criteria for suggestive linkage (multipoint allele-sharing logarithm of odds [LOD] score 2.58, P = 1.6 x 10(-4)). Two additional regions with LOD scores of >1.5 were obtained. CONCLUSION: We have identified and described the largest kinship with familial hip OA reported to date. Evidence for linkage in this family suggests that a gene for susceptibility to hip OA exists on chromosome 16p. This represents an independent identification of a susceptibility locus previously reported for hip OA in this geographic region.

Assessment of primary hip osteoarthritis: comparison of radiographic methods using colon radiographs.

OBJECTIVE: To compare the reliability of quantitative measurement of minimum hip joint space with a qualitative global assessment of radiological features for estimating the prevalence of primary osteoarthritis (OA) of the hip in colon radiographs. METHODS: All colon radiographs from patients aged 35 or older, taken at three different radiographic departments in Iceland during the years 1990-96, were examined. A total of 3002 hips in 638 men and 863 women were analysed. Intraobserver and interobserver reliability was assessed by measuring 147 randomly selected radiographs (294 hips) twice by the same observer, and 87 and 98 randomly selected radiographs (174 and 196 hips) by two additional independent observers. Minimum hip joint space was measured with a millimetre ruler, and global assessment of radiological features by a published atlas. RESULTS: With a minimum joint space of 2.5 mm or less as definition for OA, 212 hips were defined as having OA. When the global Kellgren and Lawrence assessment with grade 2 (definite narrowing in the presence of definite osteophytes) or higher as definition for OA was used, 202 hips showed OA. However, only 166 hips were diagnosed as OA with both systems. With 2.0 or 3.0 mm minimum joint space as cut off point, the difference between the two methods increased. Both intrarater and interrater reliability was significantly higher with joint space measurement than with global assessment. CONCLUSIONS: Overall prevalence of radiological OA was similar with the two methods. However, the quantitative measurement of minimum hip joint space had a better within-observer and between-observer reliability than qualitative global assessment of radiographic features of hip OA. It is thus suggested that minimum joint space measurement is a preferable method in epidemiological studies of radiological hip OA.

The inheritance of hip osteoarthritis in Iceland.

OBJECTIVE: To assess, in a population-wide study in Iceland, the genetic contribution to hip osteoarthritis (OA) leading to total hip replacement (THR). METHODS: Information from 2 population-based databases in Iceland was combined: a national registry of all THRs performed between 1972 and 1996, and a genealogy database of all available Icelandic genealogy records for the last 11 centuries. A genetic contribution to THR for OA was assessed by 1) identifying familial clusters of OA patients with THR, 2) applying the minimum founder test (MFT) to estimate the minimum number of ancestors ("founders") that would account for the genealogy of all 2,713 patients with THR for OA, compared with the average number of founders for control lists, 3) calculating an average pairwise kinship coefficient (KC) for the patient list and control lists, and 4) estimating the relative risk (RR) for THR among relatives of OA patients who have undergone the procedure. One thousand matched control lists, each the same size as the patient list, were created using the genealogy database. RESULTS: A large number of familial clusters of patients with THR for OA were identified. The MFT showed that OA patients descended from fewer founders than did subjects in the control groups (P < 0.001). The average pairwise KC among patients with OA was greater than in the control population (P < 0.001). The RR for THR among siblings of OA patients was 3.05 (95% confidence interval 2.52-3.10). CONCLUSION: This population-based study shows that Icelandic patients with hip replacement for OA are significantly more related to each other than are matched controls drawn from the Icelandic population. These findings support a significant genetic contribution to a common form of OA and encourage the search for genes conferring an increased susceptibility to OA.

Prevalence and inheritance of hip osteoarthritis in Iceland.

The purpose of this study was to: (I) assess the prevalence of hip osteoarthritis (OA) in Iceland and compare it with that in Southern Scandinavia, (II) determine the incidence of total hip replacement (THR) for primary OA in Iceland, (III) compare two different methods for defining radiographic hip OA, (IV) assess in a population-wide study in Iceland the genetic contribution t hip OA leading to THR, and (V) perform a genome-wide scan of a large Icelandic family to identify a chromosomal susceptibility locus for hip OA leading to THR. many Icelandic patients with hip OA have been well aware that this disease "goes in the family". by examining a large proportion of all Icelandic colon radiographs taken 1990-1996 the prevalence of radiographic hip OA in Iceland was found to be at least five-fold higher compared to Swedish and Danish studies that have used the same methods. A comparison of two methods for estimating hip OA from colon radiographs showed that a simple quantitative method of measuring joint space was more reliable than a qualitative method. The age-standardized incidence of THR for primary hip OA in Iceland between 1982 and 1996 was estimated and found to be about 50 percent higher than for Sweden. The higher Icelandic prevalence of hip OA may explain most of this difference. To investigate the contribution of heritability to hip OA leading to THR, information from two population-wide database in Iceland was combined: A national registry of THR between 1972 and 1996, and a genealogy database of all Icelandic genealogy records for the last 11 centuries made available by deCode Genetics. The genetic contribution to THR for OA was assessed by (a) identifying familial clusters of THR for OA, (b) applying the minimum founder test (MFT) to estimate the minimum number of ancestors to account for all patients with THR for OA, compared to the average number of founders for control lists, (c) calculating an average pairwise kinship coefficient (KC) for the patient and control lists, (d) estimating the relative risk (RR) for relatives of patients with THR for OA. A large number of familial clusters of patients with THR for OA were identified. MFT showed that OA patients descended from fewer founders than the control groups. The average pairwise KC among patients with OA was greater than in the population. RR for siblings of THR for OA patients was 3.05 (2.52, 3.10). Icelandic patients with THR for OA are thus significantly more related to each other than are matched controls. These findings support a significant genetic contribution to a common form of OA and encourages the search for genes conferring an increased susceptibility to OA. New techniques now make it possible to search the whole human genome for chromosomal susceptibility loci associating with OA. A genome wide scan was done to identify susceptibility loci for hip OA leading to THR, using DNA from a large Icelandic family with a very high prevalence of primary hip OA. A genome locus with a lod score of 2.58 was identified on chromosome 16p. A similar locus has been reported on from England. This is the first instance where what may be the same susceptibility locus for OA is independently described in two different populations with hip OA. We have identified other families with hip OA which link to the studied family and are continuing an expanded genome-wide scan. Continued studies of the kind outlined here will clarify the complex genetic background of OA and identify genetic variation associated with the disease. In addition to improving our understanding of the pathogenesis of OA and identifying new molecular targets for treatment, this will allow a better insight into the interactions between genetic background and environmental factors that initiate and drive OA.

Incidence of total hip replacement for primary osteoarthrosis in Iceland 1982-1996.

We report the incidence of total hip replacements performed in Iceland between 1982 and 1996. During this period, 3,403 hip arthroplasties were done. The annual number of procedures increased from 94 hips in 1982 to 323 hips in 1996. Annual rates of total hip replacements due to primary osteoarthrosis per 10(5) inhabitants were 68 in 1982-1986, 90 in 1987-1991, and 114 in 1992-1996. In the years 1992-1996, the age-standardized incidence of total hip replacements for primary osteoarthrosis was 3/10(5) among patients younger than 39 years of age, while it was 621/10(5) among those 70-79 years of age. The mean age at surgery for primary osteoarthrosis was 69 years in both men and women. Incidence rates in various countries are difficult to compare, but by using age-standardized data and correction for differences in population structures between Iceland and Sweden, we find that the incidence of total hip replacement for primary osteoarthrosis of the hip is at least 50% higher in Iceland than in Sweden. This difference is consistent with the higher prevalence of hip osteoarthrosis observed in Iceland than in Sweden.

Prevalence of hip osteoarthritis in Iceland.

OBJECTIVE: To assess the prevalence of primary hip osteoarthritis (OA) in Iceland. To compare the prevalence of primary hip OA in Iceland with published rates of primary hip OA for related Scandinavian populations. METHODS: Roentgenographs were examined of 1530 Icelandic people 35 years or older (653 males, 877 females) subjected to colon radiography during the years 1990-1996. The radiographs examined represent approximately 40% of all colon radiographs taken in Iceland during this period. After exclusion of non-primary hip OA cases, the minimum hip joint space was measured with a mm ruler. Presence of hip OA was defined as a minimum joint space of 2.5 mm or less on an anteroposterior radiograph. Intraclass correlation coefficients for inter and intraobserver variability of assessment of mm joint space were 0.91 and 0.95, respectively. RESULTS: Of the 1517 people included, 227 hips in 165 patients (77 men, 88 women) were diagnosed as having radiological primary hip OA. The mean age at colon examination for these patients was 68 (35-89) years. The overall prevalence of coxarthrosis among all examined patients 35 years and older was 10.8% (12% for men, 10% for women), rising from 2% at 35-39 years to 35.4% for those 85 years or older. If the population structure (age and sex distribution) for those older than 35 years in Iceland was used to standardise prevalence for both Iceland and south Sweden (using previously published data for south Sweden), the age and sex standardised prevalence of hip OA for those older than 35 years in Iceland was 8%, compared with 1.2% for south Sweden. CONCLUSIONS: The prevalence of radiological primary hip OA is very high in Iceland, and in excess of fivefold higher than the prevalence found by using similar techniques in studies on related populations in southern Scandinavia. The rate difference is particularly notable for those younger than 70 years.

Long-term results after infantile Blount's disease.

A long-term follow-up of 49 patients with an average age of 38 years (range: 25-67 years) who had experienced infantile Blount's disease was done. Thirty-seven patients had bilateral disease, giving a total of 86 affected knees. Thirty-eight knees had conservative or no treatment during childhood; 13 were treated by epiphysiodesis, and 35 by osteotomy. At follow-up, 11 knees showed arthrosis, and 9 were graded as mild. Ten knees had been surgically treated by medial meniscectomy at an average age of 29 years (range: 19-45 years), after the diagnosis of Blount's disease. Four of the knees showed arthrosis. Most of the patients had a straight leg and mild or no pain from their knee. It is concluded that most children with infantile Blount's disease will, at the age of 40 years, have a straight leg without arthrosis and that one third can reach this result without any treatment.

Long-term results after adolescent Blount's disease.

A long-term follow-up study was made of 23 patients with an average age of 47 years (range 38-68 years) who had adolescent Blount's disease. Four patients had bilateral disease (27 affected knees). Nine knees had no treatment during childhood, 11 were treated by physiodesis, and seven were treated by osteotomy of the proximal tibia. At follow-up, most of the patients had no pain or mild pain from their knee. Nine knees showed arthrosis. We conclude that most children with adolescent Blount's disease will have a straight leg at middle age without arthrosis and that this result can be obtained in one of four patients without treatment.

Metaphyseal-diaphyseal angle in Blount's disease. A 30-year follow-up of 13 unoperated children.

We analyzed the metaphyseal-diaphyseal angle in 13 patients with infantile Blount's disease, who had been followed without treatment during the entire growth period and without any form of realignment procedure in adulthood. On diagnosis at 23 (17-35) months of age, the metaphyseal-diaphyseal angle varied between 7 degrees and 25 degrees. At follow-up, most of the legs were almost straight. We found that the diagnosis of Blount's disease cannot be based solely on the metaphyseal-diaphyseal angle and that a bowed knee must be followed with repeated examinations before it can be decided whether treatment is needed.

Anterior acromioplasty. A comparison of two techniques.

A prospective randomised study was made of 20 patients who underwent acromioplasty for the chronic impingement syndrome. Ten were operated on by Neer's technique and 10 with a modification where the deltoid origin was spared. Rehabilitation was more rapid with a better range of movement in the latter group. Acromioplasty with this modification offers benefits compared with the standard procedure.