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

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.     

Genetic linkage studies

Linkage analysis is used to map genetic loci by use of observations of related individuals. We provide an introduction to methods commonly used to map loci that predispose to disease. Linkage analysis methods can be applied to both major gene disorders (parametric linkage) and complex diseases (model-free or non-parametric linkage). Evidence for linkage is most commonly expressed as a logarithm of the odds score. We provide a framework for interpretation of these scores and discuss the role of simulation in assessment of statistical significance and estimation of power. Genetic and phenotypic heterogeneity can also affect the success of a study, and several methods exist to address such problems.     

Sleep and morning pain in primary osteoarthritis

Sleep physiology, pain and mood symptoms of 8 patients with idiopathic osteoarthritis of the hands who complained of morning symptoms were compared to 7 age and sex matched subjects with similar joint pathology, but who did not complain of morning symptoms. The "AM Symptoms" group had sleep related (nocturnal) myoclonus, associated with increased morning peripheral joint tenderness and decreased grip strength, whereas the "No Complaint" group had improved mood in the morning.     

Early-onset primary osteoarthritis and mild chondrodysplasia

Three generations of a nonconsanguineous family with premature onset of primary (idiopathic) osteoarthritis (OA) were studied for clues to the etiopathogenesis of their disorder. Articular symptoms began in their second and third decades of life and involved multiple joints, both typical and atypical for primary OA. Radiographs of the majority of involved peripheral joints showed abnormalities typical of primary OA. Evidence of chondrodysplasia was found in the spines. Pathologic examination of femoral heads obtained at total hip arthroplasty from 3 affected family members showed moderate to severe OA. Articular cartilage proteoglycans from these specimens were evaluated for aggregatability with hyaluronic acid, levels of chondroitin sulfate and keratan sulfate, and core protein structure. The results from each patient's specimen differed from the results of the other specimens. We conclude that this family's disorder, primary OA associated with a mild chondrodysplasia, was a late-onset overlap form of an epiphyseal dysplasia, that a defect common to hyaline articular and physeal cartilage was primary, and that a single structural proteoglycan abnormality was not likely to be the underlying cause.     

Finer linkage mapping of primary hip osteoarthritis susceptibility on chromosome 11q in a cohort of affected female sibling pairs

OBJECTIVE: To finer linkage-map a primary osteoarthritis (OA) susceptibility locus as a prerequisite to linkage disequilibrium/association analysis. METHODS: A 50-cM interval of chromosome 11q that we had previously identified as harboring susceptibility to hip OA in a female sibling-pair cohort was subjected to finer linkage mapping. Thirty-five microsatellite markers with a mean marker interval of 1.4 cM were genotyped in 146 families containing female sibling pairs who were concordant for hip OA, as ascertained by total hip replacement. RESULTS: Two-point and multipoint linkage analysis revealed 2 distinct regions of linkage within the 50-cM interval. The first locus had a linkage interval of 11.9 cM and was centered at 81.5 cM from the 11p telomere, with a maximum multipoint logarithm of odds (LOD) score of 2.4. The second region had a linkage interval of 6.5 cM and was centered at 93.1 cM from the 11p telomere, with a maximum multipoint LOD score of 1.8. CONCLUSION: Dense linkage mapping has highlighted the presence of 2 loci on chromosome 11q, each conferring susceptibility to hip OA. Both loci are sufficiently narrow for association analysis to be undertaken.     

Genetic epidemiology of primary osteoarthritis

Primary osteoarthritis (OA) is a late onset disease that fits most accurately into the oligogenic, multifactorial class of genetic diseases. Twin pair and family risk studies have highlighted a surprisingly large genetic component to OA and have prompted the search for predisposing genes. These searches have taken three forms: (1) parametric linkage analysis of rare families in which OA segregates as a Mendelian trait, (2) model-free linkage analysis of affected sibling pairs, and (3) association analysis of known candidate genes. Within the past year linkage analysis studies have highlighted that chromosomes 2, 4, 6, 7, 11, 16, and the X may each harbor an OA susceptibility gene. Chromosomes 2, 4, and 16 were identified in multiple genome scans and are therefore the most likely to encode susceptibility. Association analysis of candidates suggests that the syntenic genes for type II collagen and the vitamin D receptor (12q12--q13.1) may also encode for OA susceptibility.     

Early-onset primary osteoarthritis and mild chondrodysplasia. Radiographic and pathologic studies with an analysis of cartilage proteoglycans

Three generations of a nonconsanguineous family with premature onset of primary (idiopathic) osteoarthritis (OA) were studied for clues to the etiopathogenesis of their disorder. Articular symptoms began in their second and third decades of life and involved multiple joints, both typical and atypical for primary OA. Radiographs of the majority of involved peripheral joints showed abnormalities typical of primary OA. Evidence of chondrodysplasia was found in the spines. Pathologic examination of femoral heads obtained at total hip arthroplasty from 3 affected family members showed moderate to severe OA. Articular cartilage proteoglycans from these specimens were evaluated for aggregatability with hyaluronic acid, levels of chondroitin sulfate and keratan sulfate, and core protein structure. The results from each patient's specimen differed from the results of the other specimens. We conclude that this family's disorder, primary OA associated with a mild chondrodysplasia, was a late-onset overlap form of an epiphyseal dysplasia, that a defect common to hyaline articular and physeal cartilage was primary, and that a single structural proteoglycan abnormality was not likely to be the underlying cause.     

HLA antigens and primary osteoarthritis of the hand

OBJECTIVE: Many studies have examined genetic factors associated with either development or severity of primary osteoarthritis (OA). Analyses of the frequencies of HLA antigens in various OA populations have yielded conflicting results; an increased frequency of HLA-A1, B8, and DR4 alleles has been suggested. We investigated the interrelationship between HLA antigens and primary OA. METHODS: We analyzed the frequency of HLA-A, B, C, DR, and DQ antigens in 95 patients (82 women, 13 men) with primary OA of the hands compared to 200 controls matched for age, sex, and ethnicity. Class I and Class II HLA antigens were evaluated using conventional serologic typing. RESULTS: No statistically significant difference in the distribution of HLA-A1 and B8 antigens was observed in patients with OA compared to controls. By contrast, HLA-B35, B40, DQ1, and CW4 antigens were overrepresented in the OA patients. Haplotype analysis showed an association of B35-DQ1, B40-DQ1, and DR2-DQ1 with increased OA risk. CONCLUSION: Our results suggest a role of the HLA system in the etiopathogenesis of primary OA of the hand.     

Genome scan for quantity of hand osteoarthritis: the Framingham Study

OBJECTIVE: To search for markers linked to quantity of radiographic hand osteoarthritis (OA) in the Framingham Heart Study. METHODS: The sample included 684 original cohort members and 793 offspring in 296 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence (K/L) score, osteophytes, and joint space narrowing (0-3 scale). Four quantitative phenotypes were computed from these measurements: sum of K/L scores across hand joints, sum of osteophyte scores, sum of joint space narrowing scores, and proportion of affected joints. Prior to linkage analysis, these phenotypes were adjusted for age using a linear regression analysis from which standardized residuals were computed. The regression analysis was performed separately for each sex and each generation. The variance component model (SOLAR) was then applied to the normalized scores of the residuals. RESULTS: The average age was 62 years for the original cohort and 54 years for the offspring. Fifty percent of the original cohort and 30% of their offspring had at least 1 affected joint (K/L score >or=2). Heritability ranged from 28% (proportion of joints affected with OA) to 34% (sum of K/L scores). Eight chromosomal regions indicated suggestive linkage (multipoint logarithm of odds [LOD] score >1.5) for at least 1 phenotype; LOD scores were highest for joint space narrowing, with a multipoint LOD score = 2.96 on chromosome 1p at D1S1665. Chromosomes 7, 9, 13, and 19 indicated consistent LOD score elevation for multiple OA phenotypes. CONCLUSION: There are several chromosomes that may harbor OA susceptibility genes. Further investigation of these regions using larger studies and finer maps will be important to confirm linkage.     

Quantitative trait linkage studies of diabetes-related traits

Genetic linkage methods for diseases with complex inheritance are based on assessment of allele sharing between affected relative pairs, but such methods have low power to detect genes with moderate effects. This may explain the difficulty in replication for many of the putative loci for type 2 diabetes. To enhance power to detect diabetes-susceptibility genes, some investigators have performed quantitative-trait linkage studies for diabetes-related traits, including measures of glycemia, insulin sensitivity, insulin secretion, obesity, lipidemia, and blood pressure. These linkage studies have not provided stronger or more consistent evidence for linkage than studies of diabetes affection status, but have identified several loci that may play an important role in the physiologic processes related to the development of type 2 diabetes.     

Effects of ginger on primary knee osteoarthritis

IntroductionNonsteroidal anti-inflammatory drugs are effective in relieving osteoarthritis pain, but because of their side effects, search continues for agents that might provide improvement in symptoms with minimal additional risk. Evidence from previous studies suggests that ginger can reduce osteoarthritis pain. The aim of this study is to compare the effects of indomethacin and ginger on relieving osteoarthritis pain.Materials and MethodsA double blind, parallel group clinical trial was designed to evaluate the response of 52 patients with knee osteoarthritis to ginger and indomethacin.ResultsAnalysis of the mean for pain on standing (based on 100 mm visual analogue scale) showed improvement in both groups (22.5 mm in indomethacin group and 23 mm in ginger group, P value = 0.1). Results of improvement in pain after walking 50 feet were similar in both groups (23.5 mm in indomethacin group and 21.4 mm in ginger group, P value = 0.34). Changes in total Western Ontario and MacMaster Universities Osteoarthritis Index score were significant in both groups (4.62 in indomethacin group and 3.39 in ginger group, P value = 0.65).ConclusionGinger is as effective as indomethacin in relieving symptoms of osteoarthritis with negligible side effects. Therefore in patients with intolerance to indomethacin, ginger may be substituted.     

Serum leptin and osteoporosis in postmenopausal women with primary knee osteoarthritis

Aim of the workThe purpose of this study was to evaluate the relationship of serum leptin level and osteoporosis in postmenopausal women with knee osteoarthritis (KOA).Patients and methodsThe study included 40 postmenopausal women with primary KOA and 37 age-matched postmenopausal healthy controls. Plain X-ray knees were performed and assessed using the Kellgren–Lawrence (KL) grading scale. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry (DXA) in lumbar spine, hip and forearm regions. As a bone turn-over marker serum osteocalcin was measured. Serum leptin level was assessed in patients and control.ResultsThe mean age of the KOA patients was 58.05 ± 5.7 years. Osteoporosis was detected among 15% of the KOA patients and 35.1% of the control. The BMD was significantly increased at the spine and wrist in the patients than in the control (p = 0.011 and p = 0.015 respectively). The serum osteocalcin was comparable between patients (19.74 ± 8.05 ng/ml) and control (21.2 ± 8.36 ng/ml) (p = 0.5). Serum leptin was significantly higher in the patient (58.7 ± 27.17 ng/ml) compared to the control (48.75 ± 13.19 ng/ml) (p = 0.048), and significantly correlated with the degree of KOA (p = 0.017). No significant correlation was found between serum osteocalcin level or the BMD and the degree of KOA. There was a significant negative correlation between serum osteocalcin level and forearm BMD in KOA patients (r = −0.33, p = 0.038).ConclusionsAlthough postmenopausal women with KOA had significantly higher BMD, both diseases can coexist. It seemed that osteoarthritis does not prevent the occurrence of osteoporosis. Our study suggested a promising role of leptin as a biomarker of KOA.     

骨关节炎动物模型的生化及磁共振成像研究

目的动态观察豚鼠关节软骨降解的生化及形态学改变，探讨骨关节炎早期病变机制：研究磁共振成像（MRI）检测早期软骨退变的可能性及其表现。方法选用Harfley雌性豚鼠30只，分为出生后1、3、6个月龄，每组各10只。观察豚鼠膝关节软骨降解情况，测定其血清蛋白多糖和雌二醇水平，取胫骨平台软骨测定羟脯氨酸、糖醛酸含量及含水率。取关节软骨组织作蛋白多糖含量测定和组织病理学检查，同时行双侧膝关节矢状面T1WI、PDW和T2WI成像检查。结果3个月组关节软骨即有降解。豚鼠的雌二醇水平和软骨含水率随年龄的增长而升高，而血清蛋白多糖和软骨糖醛酸含量随年龄的增长而下降，各组间差异有统计学意义（P〈0．05）。软骨羟脯氨酸含量各时间段差异无统计学意义，3个月组关节软骨明显变薄，磁共振（MR）信号强度明显降低。6个月组更加明显，与出生后1个月相比，两者差异均有统计学意义（P〈0．05），关节软骨明湿变薄，MR信号强度明显降低；与对照1个月组比较，两者差异均有统计学意义（P〈0．05）。结论原发性骨关节炎血清及软骨生化指标随年龄增高改变明显。雌激素代谢盯能与原发性骨关节炎的发病机制有关。关节软骨的MR信号强度与蛋白多糖含量具有相关性．蛋白多糖的降解在MRI上表现为软骨厚度的变薄和MRI信号强度的降低。这表明通过MRI检查，有可能发现早期的软骨退变。