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.

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.

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.

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.

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.

Quantitative genetics of circulating molecules associated with bone metabolism: a review.

This paper reviews recent advances in the studies of various biochemical factors (biomarkers) involved in bone metabolism and remodeling. The collected data in this area suggest the existence of complex and multilevel relationships between calciotropic hormones, various cytokines and growth factors. The paper summarizes the data on the magnitude of the familial and genetic effects on the interindividual variation in circulating levels of many of these biomarkers. The majority of the cited heritability estimates are well above 20%, reaching up to 80% for some cytokines (e.g., TNFalpha and VEGF). These estimates point to potential targets for the identification of novel quantitative trait loci involved in the control of the respective molecules variation. This information is of particular importance, because the available data on the association between specific genes/polymorphisms and the respective circulating molecules variation is still very limited. The paper also provides recent findings on the genetics of co-variation between the circulating levels of various biomarkers. It shows that only in a few instances, such as for example, between IGF-I and IGFBP-3, and IGFBP-1 and leptin, significant and substantial genetic (and environmental) correlations were found. It appears that despite the prominent strong genetic effects on variation of each of the numerous biomarkers, the pleiotropic effects are rather limited. We consider briefly some important new data obtained using the gene expression approach and microarray technique. The data, for instance, indicate that the genetic effects on bone metabolism appear to be an open system, which can be activated or modulated by external factors such as drugs, e.g., PTH. Extensive molecular genetic studies in this area are both timely and imperative to detect the specific genes affecting variation (and co-variation) of the circulating factors associated with bone metabolism.

Quantitative genetic study of radiographic hand bone size and geometry.

Despite the obvious epidemiological significance of bone size (BS) and geometry (BG) traits as risk factors for osteoporotic fracture, very little is still known concerning the extent of their genetic determination. In the present paper we report the results of quantitative genetic analysis of a number of BG and BS indices, as well as of BMD measurements, obtained on a large pedigree-based sample (296 nuclear families, 1208 individuals) of plain hand radiographs. The families studied were all ethnically Caucasians (Chuvasha) living in small villages along the Volga River (Russia). The sample consisted of 636 men and 572 women, aged 18-91 years. To assess hand bone size we used the outcome of principal component analysis conducted on 48 measurements of metacarpal bones and proximal phalanges (PC-BS). Two BG indices, average metacarpal cortical index and breaking bending resistance index (BBRI), also measured on metacarpal and proximal phalanges were used. Again the outcome of the principal component PC-BBRI was examined in the genetic analysis. PC-BS measurements strongly correlated with body length (r = 0.75, P < 0.001) and weight (r = 0.39, P < 0.001), suggesting that they indeed reflected hand skeleton size. Familial correlations for all studied traits, adjusted for covariates (sex, age, etc.), were all highly significant statistically. For example, parent/offspring correlations ranged between 0.248 (P < 0.001) for phalangeal BMD and 0.385 (P < 0.001) for PC-BBRI. Maximum likelihood estimates of the variance component analysis confirmed these results, indicating that approximately 58 to 66% of the residual variance of the studied traits was attributable to genetic effects. Bivariate analysis clearly revealed that while genetic variation of the phalangeal BMD was independent of the genetic effects influencing hand BS and BG, the latter two were strongly interrelated. A substantial proportion of PC-BS and PC-BBRI variation was due to shared genetic (r(G) = 0.468 +/- 0.063) and environmental (r(E) = 0.704 +/- 0.052) factors.

Multivariate analysis of the twenty-year follow-up of the Donolo-Tel Aviv Prospective Coronary Artery Disease Study and the usefulness of high density lipoprotein cholesterol percentage.

The aim of this study was to assess the role of high density lipoprotein (HDL)-cholesterol percentage and its relation to other variables assumed to be coronary risk factors. The 20-year follow-up involved 2,633 presumably healthy subjects, 1,308 men and 1,325 women, aged 25 to 69 years at the beginning of the study in 1964. Variables determined at entry examination included total cholesterol, HDL cholesterol, systolic and diastolic blood pressures, body mass index and cigarette smoking. During the 20-year period there were 242 fatal and nonfatal definite coronary events in men, and 108 in women. All variables differed in varying degrees between subjects who did and did not have a definite coronary event. Three multiple logistic regression models revealed that among these variables the most important was HDL-cholesterol percentage, which significantly improved the regression, even after total cholesterol was included with all other risk factors. With the first model, goodness-of-fit tests indicated that predicted values fit the observed values well, even after the first step, if HDL-cholesterol percentage is entered. The second and third models significantly fit the predicted values only after entering the HDL-cholesterol percentages. This means that although all the other variables, including total cholesterol, differed significantly between the affected and nonaffected groups, they were insufficient predictors alone. The results reveal that HDL-cholesterol percentage had the highest predictive value for risk of future coronary disease; it significantly improved the predictive capability of the logistic regression model, even after adjustment for all other mentioned variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Dermatoglyphic traits as possible markers of developmental processes in humans.

Here we provide data on the relationship in variability between common anthropometric characters (stature, interocular diameter, mesosternal chest circumference, bi-trochanteric diameter, and palm length) and dermatoglyphic traits in groups of young healthy individuals. Our working hypothesis was that quantitative variables of fluctuating asymmetry, diversity, and variability involving dermatoglyphic traits, will be higher in more homozygous groups than in heterozygous ones. It was found that individuals who were in the center (average +/- 0.67 SD) of the morphological trait distribution (and therefore perhaps more heterozygous at loci determining the aforementioned morphological traits), have reduced fluctuating asymmetry in their ridge counts (RC). These heterozygous individuals tended to have lower values of the RC-diversity-indices and the Shanon information-measures of discrete digital patterns. On the basis of the present results and a large body of literature data, the use of dermatoglyphic traits as "markers" of developmental processes are discussed.

Quantitative genetic analysis of circulating levels of biochemical markers of bone formation.

Carboxyterminal propeptide of type 1 collagen (PICP) and bone Gla-protein-osteocalcin (BGP) are the most important components of the organic bone matrix and play a key role in bone formation. To investigate whether and to what extent variation of the plasma levels of these indices of bone turnover depends on genetic factors, we studied 355 adults belonging to nuclear pedigrees. Genetic analysis was carried out in 2 steps: 1) variance decomposition analysis was performed using the FISHER statistical package; and 2) complex segregation analysis implemented in the program package MAN. The effect of age and gender differences, gender hormones, as well as PTH and vitamin-D (calcidiol) plasma levels were evaluated simultaneously with the parameters of variance analysis. The results showed that about 50% of PICP variation is attributable to genetic factors. The effect of age was significant among men and postmenopausal women, whereas calcidiol influenced variation of PICP in premenopausal women. The results of variance analysis showed that some 40% of BGP, adjusted for confounding variables, can be explained in genetic factors. Age and PTH were important covariates for osteocalcin in men and premenopausal women. Exploration of the maximum likelihood estimates of the various hypotheses concerning the mode of intergenerational transmission of PICP and BGP demonstrated a good correspondence to the Mendelian mode of inheritance (i.e., major gene effect).

Tel Aviv-Heidelberg three-generation offspring study: genetic determinants of apolipoprotein A1 and apolipoprotein B.

The contribution of major gene and multifactorial effects on variation of plasma apolipoproteins A1 and B has been tested in a large sample of population-based Israeli pedigrees. Our most parsimonious and best fitting model for both apolipoproteins is consistent with Mendelian transmissibility, with significant contribution of major genes (with 2 alleles recessive and dominant within each locus) and polygenes, but neglects effects of common sib environment as well as related intergeneration differences in polygenic effects. Total genetic effects explain 71 and 58% of phenotypic variance of APO-A1 and APO-B levels. The major genes account for about 44 and 32% of the variance in APO-A1 and APO-B, respectively, and the frequency of the recessive alleles determining the high level of apolipoproteins under the study in the Israeli population is in the vicinity of 40% at each locus.