An in-depth study of the associations between osteoarthritis- and osteoporosis-related phenotypes at different skeletal locations.

The relationship between OA and osteoporosis characteristics remains controversial. This study revealed that age-adjusted hand OA is associated with lower hand/arm BMD levels. Wrist fracture occurrence is associated with increased OA hand scores and low arm BMD. Conversely, age-adjusted knee and spine OA is associated with high spine, hip, and total BMDs. INTRODUCTION: Osteoarthritis (OA) and osteoporosis are two common musculoskeletal diseases which contribute a high burden of disability, yet assessments of their relationship remains controversial. The aim of this study was to clarify the association between bone mineral densities (BMD) of the hand, arm, spine, hip, and total body, and OA of the hand and knee and lumbar disc degeneration in two different ethnic groups. METHODS: Radiographic assessments of the hand, knee, and spine were collected and coded for joint space narrowing, osteophytes, and the Kellgren-Lawrence score from Chuvashian (n = 1504) and British (n = 2280) individuals. BMD measurements of standard skeletal sites were estimated by dual X-ray absorptiometry. Age- and familial-adjusted regression analyses were conducted to determine associations. RESULTS: Knee OA affection was positively associated with elevated hip, spine, and total body BMD levels (p < 0.001). Additionally, disc degeneration phenotypes showed significant positive associations with the hip, spine, and total BMD (p < 0.001). However, increased hand OA scores was significantly negatively correlated with arm and hand BMD measurements in males and females in both samples (p < 0.001). Additionally, higher hand OA scores were significantly associated with wrist fracture. CONCLUSIONS: We discovered a clear pattern of association between hand OA and low hand and arm BMD, with increased risk of wrist fracture, as well as reproducing previous associations between knee and spine OA and elevated spine, hip, and total body BMD. It appears that hand OA manifests differently in comparison to hip and knee OA.

Hierarchical, imbalanced pro-inflammatory cytokine networks govern the pathogenesis of chronic arthropathies.

BACKGROUND: Chronic inflammatory arthropathies, such as rheumatoid arthritis (RA), spondyloarthritis, including psoriatic arthritis (PsA), ankylosing spondyloarthritis (AS), osteoarthritis (OA), and intervertebral disc degenerative disease (DDD) constitute major public health problems that are anticipated to grow significantly as the human population ages. However, many aspects concerning the molecular mechanisms underlying their onset and progression remain unclear. DESIGN: This narrative review critically analyzes the molecular mechanisms underlying the inflammation-associated pathogenesis of the aforementioned joint diseases. This includes, in particular, the major role played by several key soluble factors (such as cytokines and the associated signaling pathways, designated as "fragile nodes") produced by local cells and recruited to the joints' immune cells, whose elimination by specific drugs has dramatically improved the diseases' symptomatology and outcome in human clinical trials or in rodent arthritis models. HYPOTHESIS AND THE AIM OF THIS REVIEW: We hypothesize that the pathogenesis of chronic inflammatory arthropathies is governed by hierarchical, imbalanced pro-inflammatory cytokine networks (HIPICNs) (comprising a combination of fragile nodes) that are created during the development of both autoimmune (RA, PsA, and AS) and non-autoimmune (OA and DDD) disorders. The main aim of this review is to provide evidence that despite substantial pathobiological differences between these arthropathies, the HIPICNs created are quite common, thus justifying the merging of these disorders mechanistically and suggesting that these common mechanisms exist in the onset and progression of different joint diseases.

Quantitative genetics of circulating Dickkopf-related protein 1 (DKK1) in community-based sample of UK twins.

UNLABELLED: Dickkopf-related protein 1 (DKK1) is a major inhibitor of Wnt signalling pathway but also plays an important role in bone formation. Its circulating levels appear to correlate significantly with plasma levels of inflammatory factors, fractalkine and IL-6. This study, using a large sample of UK twins, showed that the variation of each of these factors and correlation between them was explained by the genetic factors, and indicated possible association with DKK1 gene variants. INTRODUCTION: DKK1 is involved in the development of several inflammatory conditions related to bone and joint degradation. Our objectives were to explore the genetic contribution (heritability) to circulating DKK1 variation and its correlation with other inflammatory cytokines, interleukin 6 (IL-6) and fractalkine, and to test whether the DKK1 heritability could be attributable to single nucleotide polymorphisms (SNPs) mapped to DKK1, IL-6 and FRCT genes. METHODS: The study included a large community-based sample of 4939 women drawn from the general UK population. Plasma samples were analysed for circulating levels of DKK1, IL-6 and fractalkine (FRCT); 65 SNPs of DKK1, IL-6 and FRCT candidate genes, with MAF >0.1, were examined. We applied variance component analysis to evaluate contribution of putative genetic (including above SNPs) and environmental factors to variation of DKK1, and its correlation with IL-6 and FRCT. RESULTS: Putative genetic factors explained 42.2 ± 2 % of the total variation of circulating DKK1 levels, and were also significant for fractalkine and IL-6 variations. Most importantly, we report significant phenotypic (0.208 ± 0.006-0.459 ± 0.007) and genetic (0.338 ± 0.069-0.617 ± 0.033) correlations between these molecules. We found evidence suggestive of association between the DKK1 and its structural genes variants. CONCLUSIONS: Circulating DKK1 levels correlated significantly with levels of IL-6 and FRCT, known risk factors for several inflammatory processes suggesting a potential role of DKK1 in inflammation and tissue injury. Our results suggest the contribution of genetic factors in inter-individual variation of DKK1 levels in human population. However, further studies are required to determine genetic polymorphisms affecting DKK1 variation and its correlation with IL-6 and FRCT.

Late successful weight reduction and maintenance among overweight and obese adults--a two-year retrospective study.

AIMS: Our purpose was to identify those factors associated with successful late weight reduction and maintenance among overweight and obese adults who failed to achieve initial weight reduction success. METHODS: Medical computerized files of 5254 participants, who failed to achieve ≥ 5% weight reduction after an initial 6-month period, were retrospectively analyzed to identify predictors associated with late successful weight reduction and maintenance (≥ 5% during the first and second years, respectively). Over 40 independent variables were analyzed. The main outcome was the percentage of weight change. RESULTS: Significant predictors of late success in weight reduction were as follows: more visits to a dietitian, higher baseline BMI, and any initial weight reduction (0-5%) (OR=3.69, compared with participants who initially gained weight). The use of insulin (OR=0.499) and the presence of hypertension (OR=0.75) were significantly correlated with failure to reduce weight. Predictors of late maintenance were as follows: more visits to a dietitian, higher baseline BMI, any initial weight reduction, a younger age, not being treated with insulin (OR=0.316), and more weighings (OR=1.68). CONCLUSIONS: A substantial sub-group of obese and overweight patients was able to reduce their weight at a slower rate than the defined successful time of 6 months. Significant specific predictors were identified. Diabetic and hypertensive patients are at a significantly higher risk of failure to reduce and maintain weight. Using regression models, we calculated the probability of successful late weight reduction. This calculation could serve as a clinical tool for a professional team.

Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles?

Osteocytes, entrapped within a newly mineralized bone matrix, possess a unique cellular identity due to a specialized morphology and a molecular signature. These features endow them to serve as a bone response mechanism for mechanical stress in their microenvironment. Sclerostin, a primarily osteocyte product, is widely considered as a mechanotranduction key molecule whose expression is suppressed by mechanical loading, or it is induced by unloading. This review presents a model suggesting that sclerostin is major mediator for integrating mechanical, local, and hormonal signals, sensed by the osteocytes, in controlling the remodeling apparatus. This central role is achieved through interplay between two opposing mechanisms: (1) unloading-induced high sclerostin levels, which antagonize Wnt-canonical-ß-catenin signaling in osteocytes and osteoblasts, permitting simultaneously Wnt-noncanonical and/or other pathways in osteocytes and osteoclasts, directed at bone resorption; (2) mechanical loading results in low sclerostin levels, activation of Wnt-canonical signaling, and bone formation. Therefore, adaptive bone remodeling occurring at a distinct bone compartment is orchestrated by altered sclerostin levels, which regulate the expression of the other osteocyte-specific proteins, such as RANKL, OPG, and proteins encoded by "mineralization-related genes" (DMP1, PHEX, and probably FGF23). For example, under specific terms, sclerostin regulates differential RANKL and OPG production, and creates a dynamic RANKL/OPG ratio, leading either to bone formation or resorption. It also controls the expression of PHEX, DMP1, and most likely FGF23, leading to either bone matrix mineralization or its inhibition. Such opposing up- or down-regulation of remodeling phases allows osteocytes to function as an "external unit", ensuring transition from bone resorption to bone formation.Mini Abstract: The osteocyte network plays a central role in directing bone response either to mechanical loading, or to unloading, leading correspondingly to bone formation or resorption. This review shows a key role of the osteocyte-produced sclerostin as a major mediator of the molecular mechanisms involved in the process of adaptive bone remodeling.

Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.

OBJECTIVE: There is a need to find biochemical markers that would identify people with increased risk of developing radiographic knee osteoarthritis (RKOA). The aim of this study was to evaluate the ability of cartilage and bone biomarkers (cartilage oligomeric matrix protein (COMP), aggrecan, cellular inhibitor of apoptosis protein (cIAP), N-telopeptide-to-helix (NTx)) to predict RKOA incidence in a 10-year follow-up of UK females from the Chingford community study. METHOD: Joint space narrowing (JSN), osteophytes (OSP) and Kellgren-Lawrence (K/L) grades were scored from radiographs of both knees at study baseline and 10 years later in 1,003 women aged 45-64. Circulating levels of biomarkers and demographic variables were measured at baseline. Statistical association analysis was conducted between the potential predictor factors measured at baseline and documentation of RKOA at 10-year follow-up. RESULTS: Age and body mass index (BMI), were significant predictors of incidence of RKOA as assessed by K/L and OSP. Considering biomarkers, independent significant association was found between COMP circulating levels and K/L scores (Odd Ratio (OR) = 2.87, 95% Confidence Interval (CI) = 1.19-6.89, P = 0.018). Significant negative association was detected between aggrecan plasma concentrations and JSN, with OR = 0.37 (95% CI 0.15-0.89), P = 0.026. CONCLUSIONS: Aggrecan and COMP circulating levels contribute to identification of phenotype-specific RKOA incidence. These data suggest potentially protective role of aggrecan in cartilage loss, as measured by JSN. High COMP levels are risk factors for development of RKOA, as assessed by K/L scores.

Is interaction between age-dependent decline in mechanical stimulation and osteocyte-estrogen receptor levels the culprit for postmenopausal-impaired bone formation?

Declining estrogen levels during menopause are widely considered to be a major cause of age-dependent bone loss, which is primarily manifested by increased bone resorption by osteoclasts. We present accumulating evidence supporting another aspect of metabolic bone loss, suggesting that the combined interaction between age-dependent factors, namely, estrogen deficiency and reduced day-by-day activity/mechanical stimulation, directly leads to a reduction in anabolic processes. Such decreased bone formation results in diminished bone strength and failure to maintain the load-bearing competence of a healthy skeleton and to postmenopausal osteoporosis disorder. Estrogen receptors (ERs), as mediators of estrogenic actions, are essential components of bone osteocyte and osteoblast mechano-adaptive responses. ER expression appears to be upregulated by adequate circulating estrogen levels. ERα signaling pathways participate in the mechanotransduction response through obligatory "non-genomic" actions that occur independently of estrogen binding to ER and by a potentially "genomic", estrogen-dependent mode. The experimental data indicate that cross talk between the ERα-"non-genomic" and Wnt/ß-catenin signaling pathways constitutes the major regulatory mechanism. This interaction uses mechanically and ER-induced prostaglandin E2 as a mediator for the downregulation of osteocyte production of sclerostin. Sclerostin suppression, in turn, is a central prerequisite for load-induced formation and mineralization of the bone matrix. It is therefore plausible that future strategies for preventing and treating postmenopausal osteoporosis may use estrogenic compounds (such as selective estrogen receptor modulators or phytoestrogens) with physical activity, to complement antiresorptive therapy, aimed at stopping further bone loss and possibly even reversing it by stimulation of bone gain.

A significant association exists between receptor tyrosine kinase-like orphan receptor 2 gene variants and the OPG/RANKL ratio in human plasma.

SUMMARY: There is a paucity of studies investigating association between ROR2 gene variants and osteoporosis and osteoarthritis-related phenotypes. The published literature suggests that osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL) are essential for bone metabolism and correlate with osteoarthritis manifestation and progression. The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma. The present results also suggest significant association between ROR2 polymorphisms and severity of radiographic hand osteoarthritis. INTRODUCTION: Despite the importance of the ROR-2 in skeletal physiology, there is a paucity of studies investigating the potential association of ROR2 gene variants with phenotypes relevant to osteoporosis and osteoarthritis. On the other hand, there is a considerable body of literature suggesting that OPG and RANKL and their ratio (OPG/RANKL) are essential for regulating bone resorption. This is also correlated with osteoarthritis manifestation and progression. The present study therefore examines whether ROR2 polymorphisms may be associated with the OPG/RANKL ratio and hand osteoarthritis (HOA). METHODS: The study was conducted in a family-based sample of 1,515 Caucasian individuals, assessed for radiographic hand osteoarthritis, using the Kellgren/Lawrence score. Of these, 865 individuals were genotyped for 19 SNPs, relatively equally covering the ROR2 locus, and their plasma levels of OPG and RANKL were assayed. The association between the selected SNPs and OPG, along with the OPG/RANKL ratio and HOA, was explored using the pedigree disequilibrium test. RESULTS: Of the total of 57 tests, 16 nominally significant results (p < 0.05) were obtained, which is considerably more than the three normally expected for type I error. The significant association signals for all three phenotypes were mapped to the intron 1 region. The most significant results were detected between OPG/RANKL and rs7048756 (p < 0.0005) and between adjacent rs4744107 and Kellgren/Lawrence score (p = 0.006). CONCLUSIONS: The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma and also suggests ROR2 association with HOA.

Quantitative genetic study of amphiregulin and fractalkine circulating levels--potential markers of arthropathies.

OBJECTIVE: Amphiregulin (AREG) and Fractalkine (FRACT), are involved in a variety of normal and pathological processes, and are both suggested to be relevant to joint degeneration. The aims of the present study included (1) testing association between circulating levels of these biomarkers and joint pathologies, (2) evaluation of the putative genetic and familial factors' effect on AREG and FRACT variability. DESIGN: The study was conducted in the family-based sample of 923 Caucasian individuals. Variance component analysis was used to assess contribution of genetic and environmental factors to variability of AREG and FRACT concentration. RESULTS: The mean levels of FRACT were significantly higher in the affected group with arthropathies (synovial joints osteoarthritis (OA) and disc degenerative disease, DDD) then in the control group (P<0.0004). Circulating AREG levels were higher in DDD (P=0.0272). Genetic factors constituted the main source of the interindividual differences of the AREG and FRACT levels in our sample, and explained 29.68% and 41.68% of the total variation, respectively. The phenotypic correlation between AREG and FRACT was substantial (r=0.55, P=0.0001) and was associated with both common genetic and environmental factors. Specifically, 30% of the phenotypic correlation between AREG and FRACT was due to common genetic effects. CONCLUSIONS: Further studies are required to assess relevancy of FRACT to clinical diagnosis and prognosis of arthropathies, to investigate the mechanisms behind the observed phenotypic and genetic covariation among the studied biomarkers, and to explore specific genetic polymorphisms affecting AREG and FRACT variation.

Quantitative genetic study of the circulating osteopontin in community-selected families.

UNLABELLED: The study assessed contribution of genetic factors to variability of osteopontin (OPN) levels. Evidence of association of OPN levels with polymorphisms in its structural gene and integrin-binding sialoprotein gene loci was obtained. The results motivate research of OPN-related proteins and genes with respect to biomineralization and other biological processes. INTRODUCTION: OPN is a major phosphoprotein in bone, which plays key role in regulation of bone mineralization process. It is considered as a promising biomarker for osteoarthritis and osteoporosis, and various other pathological conditions. However, the contribution of genetics and other confounding factors to OPN circulating levels variation in general population has never been specifically determined. The main aims of the present study included (1) evaluation of the putative genetic and familial factors' effect on OPN variability and (2) testing the hypothesis that OPN plasma levels are associated with the genetic polymorphisms in its structural gene locus (SPP1) and in integrin-binding sialoprotein gene locus (IBSP). METHODS: To address these questions, we used a family-based sample of 925 apparently healthy Caucasian individuals. Association of OPN levels with three SNPs in each of the two selected gene loci was explored using pedigree disequilibrium tests. RESULTS: Some 58% and 13% of the OPN levels variability were attributable to genetic factors and common spouse environment, respectively. Three SNPs showed nominally significant association with OPN (p < 0.05). Of these, rs2616262 linked to IBSP promoter region remained significant after correction for multiple testing (p = 0.003). Significant association of this SNP and rs10516799 (distal segment of SPP1) with OPN was confirmed in several statistical tests. Using a special modification of variance component analysis, we examined gene-gene and gene-sex interaction effects, but found non-significant confirmation for these hypotheses. CONCLUSIONS: Further studies are required to confirm the observed results and to explore the underlying molecular and physiological mechanisms.

Morphological and biochemical features of obesity are associated with mineralization genes' polymorphisms.

BACKGROUND: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently extensively studied as a candidate gene for obesity phenotypes. As the human homologue of the mouse progressive ankylosis (ANKH) and alkaline phosphatase (ALPL) are known functional partners of ENPP1 in bone mineralization, we hypothesized that these genes may also be jointly involved in determining obesity features. AIM: To examine the effects of the three genes, possible gene-sex and gene-gene interactions on variability of four obesity phenotypes: the body mass index (BMI), the waist-hip ratio (WHR), the epidermal growth factor receptor (EGFR), and leptin. SUBJECTS AND METHODS: In all, 962 healthy individuals from 230 families were genotyped for 45 single nucleotide polymorphisms (SNPs). The association analysis was performed using two family based association tests (family based association test and pedigree disequilibrium test). The combined P-values of the two tests were estimated by Monte-Carlo simulations. Relative magnitude of the genetic and familial effects, gene-sex and gene-gene interactions were assessed using variance component models. RESULTS: Associations were observed between ENPP1 polymorphisms and BMI (P=0.0037) and leptin (P=0.0068). ALPL markers were associated with WHR (P=0.0026) and EGFR (P=0.0001). The ANKH gene was associated with all four studied obesity-related traits (P<0.0184), and its effects were modulated by sex. Gene-gene interactions were not detected. CONCLUSION: The observed pattern of association signals indicates that ANKH may have a generalized effect on adipose tissue physiology, whereas ENPP1 and ALPL affect distinct obesity features. The joint analysis of related genes and integration of the results obtained by different methods used in this research should benefit other studies of similar design.

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium.

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genome-wide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81x10(-5)). The C allele conferred a reduced risk of 33% to 41% using a case-control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA.

Age-related changes and secular trends in hand bone size.

The aim of the present study was to evaluate age- and sex-related changes in the size and shape of long hand bones in a large Chuvashian cohort using cross-sectional and longitudinal study designs. The data were gathered in 1994 (557 individuals) and 2002 (513 individuals). The latter sample included 260 individuals that were studied only during the second expedition, and 253 individuals who were previously investigated in 1994. Statistical analyses included a maximum likelihood-based model-fitting technique and a t-test comparison. We found evidence for secular trend of hand bone size in both males and females within the Chuvashian population. In males, the length and total area of the long hand bones were greater in younger individuals, but mid-shaft bone width remained almost the same in individuals born at different periods of the last century. In females, the length of the hand bones and total bone area remained unchanged in women born after 1937. However, bone mid-shaft width gradually decreased in women born after 1940. Therefore, we argue that, at least within the Chuvashian population, there is a secular trend towards a more gracile appendicular skeleton in both males and females.

Family-based association study of polymorphisms in the RUNX2 locus with hand bone length and hand BMD.

Osteoporosis is characterized by reduced bone strength. Bone size and bone mineral density (BMD) are major bone strength determinants. Identification of genes affecting the variability of these traits should improve prognosis and management of osteoporosis. This research was aimed to test the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in the RUNX2 locus. Four SNPs linked to the two RUNX2 promoters were genotyped in 212 nuclear Caucasian families. These SNPs and four pairwise haplotypes were tested for association with eight BL and BMD traits, adjusted for covariates. We observed significant associations between polymorphisms linked to the RUNX2 P1 promoter and BL mean values for three studied bone groups: all 18 bones, proximal and medial bones (p = 0.0118, 0.0085, and 0.0056, respectively). Mean BMD values for all 18 bones, proximal and medial bones were associated with polymorphisms linked to the RUNX2 P2 promoter (p = 0.0032, 0.0077, 0.0007, respectively). Associations with BL and BMD mean values for medial and proximal bones remained significant even after correction for multiple testing. This study provides evidence of the association between polymorphisms linked to the two RUNX2 promoters and variability of hand BL and BMD. The results suggest independent roles for the two RUNX2 promoters in the determination of the traits studied.

Epiphyseal expansion in hand bones: association with age, sex, and hand osteoarthritis.

OBJECTIVES: Previous studies showed increased femoral, neck, and tibial plateau with age in individuals with and without osteoarthritis (OA) at adjacent joints. However, the question whether epiphyseal bone enlargement is a natural phenomenon of aging or associated with OA remains open. The aim of the present study was to evaluate age- and sex-related changes in the relative size of epiphyses of long hand bones and their association with radiographic OA. DESIGN: The data were collected from a population-based European sample in 1994 (557 individuals) and in 2002 (513 individuals). The latter sample included 253 individuals who were previously investigated in 1994. The epiphyseal index (EI), reflecting the relative size of bone epiphyses and hand OA, was evaluated from hand radiographs. Statistical analyses included multiple regression analyses and a maximum likelihood-based model-fitting technique. RESULTS: Hand bone epiphyses increased with age and with OA. In males, the EI gradually increased during their entire life span. In females, the EI remained almost unchanged up to the age of 40, after which, it increased more rapidly than in males. Individuals with OA had higher values of EI at any age. In both sexes, epiphyseal enlargement is a predisposing factor for hand OA progression in adjacent joints. This was clearly seen in males, where old individuals with high EI values had much higher OA scores in comparison with age-matched individuals. CONCLUSIONS: Enlargement of long bone epiphyses with age appears to be a general tendency in the human skeleton. Our study shows that the enlargement of epiphyses may also be related to OA.

Lumbar disc disease shows linkage to chromosome 19 overlapping with a QTL for hand OA.

OBJECTIVE: Cervical and lumbar degenerative disc disease (CDD and LDD, respectively) form part of the spine osteoarthritis (OA) phenotype and are known to be influenced by genetic factors. A genome-wide linkage analysis was performed to identify new chromosomal regions of interest. METHODS: Dizygotic healthy female twin volunteers (n = 348) from the TwinsUK register who had magnetic resonance imaging scans 10 years ago coded for degenerative disease, were identified. Multipoint genome-wide linkage analysis was conducted using 737 highly polymorphic markers of approximate spacing 10 cM. RESULTS: The mean age of the twins was 52 years. Significant linkage peaks (log of the odds (LOD) >3) were identified for LDD at three chromosomal regions. These included chromosome 1 (position 285 cM), chromosome 5 (position 175 cM) and chromosome 19 (position 80 cM). The peak on chromosome 19 had LOD = 4.06, and the empirical p = 6.7x10(-4) confirmed reliability of the linkage signal. It lies close to a linkage peak previously obtained by our group for hand OA. CONCLUSIONS: This genome-wide linkage study of CDD and LDD shows evidence of linkage for LDD on chromosome 19. The region of interest is likely to harbour genes that are common to LDD and hand OA.

Search for hand osteoarthritis susceptibility locus on chromosome 6p12.3-p12.1.

The existence of osteoarthritis susceptibility loci on chromosome 6 for individuals suffering from hip and knee osteoarthritis has been suggested. We determined whether radiographic hand osteoarthritis in a demographically homogeneous population of European origin can be linked to loci on chromosome 6p12.3-p12.1. Nine single nucleotide polymorphisms (SNPs) were genotyped in 764 individuals (members of 189 nuclear and more complex two- or three-generation families). Radiographic hand osteoarthritis was characterized by two traits: (1) the total individual osteoarthritis score (PC1-OA) and (2) the osteophytes score (PC1-OS), obtained from the principal components analysis of sums of the Kellgren and Lawrence grade and of the osteophyte grades, respectively, for 14 joints on each hand. The contribution of genetic and environmental factors and of covariates such as age and body mass index to hand osteoarthritis was evaluated by variance components analysis. The association between the studied traits and selected DNA markers was evaluated by three types of transmission disequilibrium tests. The parent-offspring and sib-sib correlations were statistically significant for all studied traits. The additive genetic effects for PC1-OA and PC1-OS were estimated to be 43% and 37.9%, respectively. Transmission disequilibrium tests consistently revealed a statistically significant association (p values ranged from 0.017 to 0.030) between SNP rs1508632 and PC1-OS. In the tested cohort the putative genetic factors are influential enough to determine interindividual differences regarding the extent of hand osteoarthritis. SNP rs1508632 lies in immediate proximity to the TINAG gene, implicating it as a possible hand osteoarthritis susceptibility gene.

Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes.

UNLABELLED: For the first time the study provides evidence of association of radiographic hand bone length (BL) and bone mineral density (BMD) with polymorphisms in ROR2 gene that plays important role in skeletal development. This contributes to better understanding of bone physiology and may have application in clinical practice. INTRODUCTION AND HYPOTHESIS: Bone size and bone mineral density (BMD) are major determinants of bone strength. Identification of genes affecting these traits' variability is important for better understanding of normal and pathological bone physiology and identification of the individuals at risk for bone fracture. This study tested the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in ROR2 gene that is important in skeletal development. METHODS: Nineteen ROR2 SNPs were genotyped in 705 individuals, belonging to 212 nuclear families. The four tagging SNPs (tSNPs) and the pairwise haplotypes between adjacent tSNPs were tested for association with series of hand BL and BMD measurements, adjusted for covariates, using family-based association tests. RESULTS: We observed significant associations with BL and BMD mean values for all 18 studied hand bones (p = 0.0080, 0.0030), mean BL and BMD for proximal phalanges (p = 0.0218, 0.0060) and metacarpal bones (p = 0.0014, 0.0004). In the latter, the association remained significant after correction for multiple testing. CONCLUSIONS: The region of the first through the second ROR2 introns is most likely to contain the functional polymorphism/s responsible for the observed associations. Further studies are required to identify the ROR2 functional polymorphism/s affecting bone size and BMD variation.

Genetic and environmental determinants of circulating resistin level in a community-based sample.

OBJECTIVE: Resistin is a hormone secreted by adipose tissue, monocytes, bone marrow, and other tissues. It was also proclaimed as an important link between obesity and diabetes. The main objective of this study was to elucidate the contribution of a number of endogenous factors, such as sex, age, obesity characteristics, and genetic effects to the production of resistin in apparently healthy individuals. We also tested the possible relationships between circulating levels of resistin and other adipokines (leptin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)). MEASUREMENTS: The plasma levels of studied adipokines were determined by enzyme-linked immunoassay in pedigree-based sample (n = 616), and subjected to model-based quantitative genetic analysis. RESULTS: Resistin levels were significantly higher in women than in men (3.60 +/- 2.53 vs 3.15 +/- 2.48 ng/ml, P < 0.001), and varied independently of age in either sex. Statistical-genetic analysis revealed significant familial correlations (P < 0.01) for resistin. Adjusted for covariates, 66.38 +/- 10.28% of the resistin variation was attributable to putative genetic factors. A relatively small portion of the resistin variation (11.54 +/- 5.77%) was attributable to sharing a common household environment. The remaining variation, 22.12 +/- 17.69% was due to random environmental (i.e., unmeasured non-additive genetic) effects. The results of our analysis showed modest significant correlation of resistin with TNF-alpha and IL-6, and only in some groups; thus, while resistin was correlated with TNF-alpha in men, the correlation with IL-6 was significant only in the post-menopausal women group. CONCLUSIONS: Our observations indicate that resistin is strongly influenced by genetic factors. The high heritability estimates for resistin concentrations clearly suggest the continuing need for further molecular genetic investigations.