Ida Malkin

Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study

Objective Low back pain (LBP) is a common musculoskeletal disorder, but it is still unclear which individuals develop it. The authors examined the contribution of genetic factors, lumbar disc degeneration (LDD) and other risk factors in a female sample of the general population. Material and Methods A cross-sectional study was conducted among 2256 women (371 and 698 monozygotic and dizygotic twin pairs and 29 sibling pairs and 60 singletons) with a mean age of 50 years (18–84). A self-reported validated questionnaire was used to collect back pain data. Risk factors including body weight, smoking, occupation, physical exercise and MRI assessed LDD were measured. Data analysis included logistic regression and variance decomposition. Results The major factors associated with LBP included genetic background, with OR approximately 6 if the monozygotic co-twin had LBP, or 2.2 if she was a dizygotic co-twin. In addition, LDD and overweight were highly significantly (p<0.001) associated with non-specific LBP. The single most important risk factor was the amount of LDD. After adjustment for other risk factors, the individuals who exhibited advanced LDD (90% vs 10%) had 3.2 higher odds of manifesting LBP. The data also showed a significant (p<0.001) genetic correlation between the LBP and LDD measurements, suggesting that approximately 11–13% of the genetic effects are shared by LDD and LBP. Conclusions The main risk factors for reported episodes of severe and disabling LBP in UK women include the degree of LDD as assessed by MRI, being overweight and genetic heritability.

Modelling of age-related bone loss using cross-sectional data

Background : Current applications of bone mineral density (BMD) data in age studies are not free of certain drawbacks. Since it is well established that age-related patterns of BMD changes involve three distinct periods (bone acquisition in youth, stabilization at maturity, and decrease with ageing), adjusting for age via an inappropriate mathematical function may lead to inconsistencies and wrong conclusions. Hypothesis : The piecewise model, which encompasses the above three periods, will accurately describe the BMD dependence on age. Objective : To examine age-related patterns of BMD changes using a number of possible mathematical functions and to find among them the best-fitting function. Next, to test whether the chosen function is universally applicable or if there are diverse population-specific functions. Material and methods : Thirteen ethnic samples from various regions of Europe and Asia, assigned into five ethnic-geographic groups, were examined. The total sample included 2430 males and 2515 females. Compact BMD of hand phalanges was measured by photodensitometry from plain radiographs of each individual studied. Statistical software was developed for the purposes of the present study; this software gave a maximum likelihood of the parameter estimates for various statistical models (functions). Results : In all samples of sufficient size and representative age range, a two-interval function was found as the best fitting and most parsimonious model to describe the BMD age-related changes. This two-interval function was characterized by age-related bone mass increase, positive slope g 1s in young age or a plateau ( g 1s = 0, i.e. no age-related changes) until a sex-specific age threshold, T 0, after which annual bone loss ensued with a slope coefficient g 2s. Threshold of BMD loss in women of different ethnic groups ranged between 37.85 and 47.77 years, and roughly coincided with perimenopausal age. In males, the age T 0 varied between 27.85 and 49.07 years. The ensuing cortical bone loss appeared to be linear in both sexes, averaging between 0.51% and 1.15% in men and between 0.74% and 1.77% per year of young age BMD value in females. Conclusions : The change of phalangeal BMD with age may be best described by a two-interval function, regardless of sex and ethnic background. However, specific parameter estimates depend both on gender and ethnic affiliation. This study has yielded a well-fitted model of BMD dependence on age suitable for further use in population studies.

The cannabinoid receptor type 2 (CNR2) gene is associated with hand bone strength phenotypes in an ethnically homogeneous family sample

Genetic variants within the CNR2 gene encoding the cannabinoid receptor CB2 have been shown to be associated with osteoporosis and low bone mineral density (BMD) in case-control studies. We now examined the association of polymorphisms in CNR2 with hand bone strength in an ethnically homogeneous healthy family sample of European origin (Chuvashians) living in Russia. We show that non-synonymous CNR2 SNPs are significantly associated with radiographic hand BMD and breaking bending resistance index (BBRI) by two different transmission disequilibrium tests. For both tests highly significant p values (ranging from 0.007 to 0.008 for hand BMD, and from 0.001 to 0.003 for BBRI) were also obtained with additional SNPs at the CNR2 locus. The associations remained significant after correction for multiple testing. In conclusion, in addition to the association of CNR2 polymorphisms with low BMD at selected clinically relevant skeletal sites, we now report their significant association with hand bone strength phenotypes using a family-based study design implying an even broader impact of genetic variation at the CNR2 locus on bone structure and function.

An omics investigation into chronic widespread musculoskeletal pain reveals epiandrosterone sulfate as a potential biomarker

Abstract Chronic widespread musculoskeletal pain (CWP) is common, having a population prevalence of 10%. This study aimed to define the biological basis of the CWP/body mass association by using a systems biology approach. Adult female twins (n = 2444) from the TwinsUK registry who had extensive clinical, anthropometric, and “omic” data were included. Nontargeted metabolomics screening including 324 metabolites was carried out for CWP and body composition using dual-energy X-ray absorptiometry. The biological basis of these associations was explored through a genome-wide association study and replicated in an independent population sample (Cooperative Health Research in the Region of Augsburg [KORA] study, n = 2483). A causal role for the genetic variants identified was sought in CWP using a Mendelian randomisation study design. Fat mass/height2 was the body composition variable most strongly associated with CWP (TwinsUK: P = 2.4 × 10−15 and KORA: P = 1.59 × 10−10). Of 324 metabolites examined, epiandrosterone sulfate (EAS) was highly associated with both CWP (P = 1.05 × 10−09 in TwinsUK and P = 3.70 × 10−06 in KORA) and fat mass/height2. Genome-wide association study of EAS identified imputed single nucleotide polymorphism rs1581492 at 7q22.1 to be strikingly associated with EAS levels (P ⩽ 2.49 × 10−78), and this result was replicated in KORA (P = 2.12 × 10−9). Mendelian randomization by rs1581492 genotype showed that EAS is unlikely to be causally related to CWP. Using an agnostic omics approach to focus on the association of CWP with body mass index, we have confirmed a steroid hormone association and identified a genetic variant upstream of the CYP genes, which likely controls this response. This study suggests that steroid hormone abnormalities result from pain rather than causing it, and EAS may provide a biomarker that identifies subgroups at risk of CWP.

Prevalence, pattern and determinants of radiographic hand osteoarthritis in five Russian community-based samples

OBJECTIVE The aim of the study was to evaluate the prevalence and pattern of radiographic hand osteoarthritis (OA) and its association with age, sex, body mass index (BMI), and place of residence in five Russian community-based samples. DESIGN Cross-sectional observational study: The study population comprised ethnic Russians [821 males and 1076 females, aged 18-90 (mean 46.2+/-15.3)], living in five different geographic areas. OA was evaluated for 14 joints of the left hand according to the Kellgren and Lawrence grading scheme. Statistical analyses included prevalence estimation, logistic and generalized model regressions, and chi(2) tests. RESULTS We present extensive data on the prevalence of radiographic hand OA in a total Russian sample. After the age of 65, 98.5% of males and 96.8% of females had at least one affected joint. In individuals younger than 50, OA was most prevalent in the metacarpophalangeal joints, and after age 50, was most prevalent in the distal interphalangeal joints. Prevalence of hand OA was significantly higher in males than in females in ages 35-50. After adjustment for age, age(2) and place of residence, there were no associations between prevalence or severity of hand OA and BMI. CONCLUSIONS Significant differences in prevalence and severity of hand OA were found between the Russian samples living in different geographic areas. Additional studies are needed to discover the mechanism defining the association between places of residence and development of hand OA.

Sampling Correction in Pedigree Analysis

Usually, a pedigree is sampled and included in the sample that is analyzed after following a predefined non-random sampling design comprising several specific procedures. To obtain a pedigree analysis result free from the bias caused by the sampling procedures, a correction is applied to the pedigree likelihood. The sampling procedures usually considered are: the pedigree ascertainment, determining whether a population unit is to be sampled; the intrafamilial pedigree extension, determining what part of the pedigree is to be sampled; and selective censoring of the sampled pedigree, determining whether it should be included in the sample to be analyzed.The probability of pedigree ascertainment is determined by the total set of potential probands in the true pedigree from which the sampled pedigree is obtained and we indicate how the necessary information on this set can be collected. If insufficient information on this set is observed, it is impossible to correct the pedigree likelihood adequately. Here we show that, if only the structure of this set is known, then an ascertainment-model-based pedigree likelihood can be obtained by conditioning on this structure. An ascertainment-model-free (AMF) pedigree likelihood can be correctly constructed by conditioning on all the data in this set, i.e. on both its structure and its phenotypic content. However, if this set has missing data, the AMF likelihood becomes undefined, which limits the utility of this AMF approach originally proposed by Ewens and Shute (1986). We also consider the sampling correction necessary when the pedigrees included in the sample analyzed have been subjected to censoring. The forms of likelihood correction developed here provide asymptotically unbiased estimators of the genetic model only if the formulated model is correct, which means that it must correctly allow for the most important features of the true inheritance of the trait studied. Otherwise, if no special case of the formulated general model is close to the true inheritance model, then the forms of likelihood correction proposed here result in biases, the magnitude and direction of which depend on both the true model and the general analysis model that should subsume it.

Transmission Disequilibrium Test for Hand Bone Mineral Density and 11q12-13 Chromosomal Segment

Abstract:The main aim of the present study was to test the hypothesis that the bone mineral density (BMD) assessed from radiographs of the hand phalanges in a random sample of ethnically homogeneous pedigrees is linked to the 11q12-13 chromosomal segment. The data for the study were gathered from 574 Chuvasha individuals belonging to two- and three-generation pedigrees who live in small villages in the Bashkortostan autonomy, Russia. Preliminary statistical-genetic analysis of the BMD in the pedigrees studied showed that potential genetic effects were highly significant (p<0.001, in comparison with the model assuming no genetic effect), and explained at least 36% of the BMD variation adjusted for sex and age differences. For the transmission/disequilibrium test (TDT) used in our study, a total of 163 nuclear families with two sibs on average were available. Seven DNA microsatellite markers (D11S1313, D11S1765, D11S987, D11S913, D11S983, D11S1314, D11S916) with average spacing of 2 cM on the chromosomal area 11q12-13 were selected for the TDT. The nominal p values (p<0.05–0.0015) obtained from three TDT-type tests used for random and extreme-threshold sampling designs pointed consistently to possible linkage disequilibrium between BMD and some of the DNA markers. There was evidence for possible linkage disequilibrium in the upper part of the chromosomal segment studied (markers D11S1313 and D11S1765), and also in the lower part (markers D11S1983 and D11S1314). The lowest nominal p values (0.0015–0.0067) were obtained from three TDT-type tests for marker D11S1313. However, our findings must still be treated with great caution.

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.

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 hepatocyte growth factor levels and their association with obesity and blood pressure.

Background: Hepatocyte growth factor (HGF) is a member of the adipocytokine family; it is implicated in tissue repair, regeneration, and angiogenesis. Several studies have reported that the HGF plays important role in obesity and cardiovascular disease. Aim: This study examines whether HGF and its phenotypic correlations with obesity and blood pressure (BP), in healthy individuals, are due to shared genetic or common environmental factors. Subjects and methods: Body mass index (BMI), waist-to-hip ratio (WHR), BP, and HGF plasma concentrations were measured in a sample of 733 individuals belonging to 248 pedigrees. Results: The most significant phenotypic correlations were found among HGF, WHR, and systolic BP (p < 0.001). Analysis of the familial aggregation revealed that parent–offspring and sibling correlations in HGF levels, adjusted for age, age2, and sex, were statistically highly significant (p < 0.001). Variance decomposition analysis showed that when adjusted for potential covariates, 48.4% of the HGF variation was due to putative genetic factors. The genetic correlations between all pairs of studied traits (HGF, WHR, and SBP) were statistically significant (p < 0.02) and ranged between 0.23 ± 0.07 and 0.40 ± 0.07. However, correlation between WHR and BP becomes non-significant after adjustment for HGF. Conclusions: The results provide evidence that putative genetic factors involved in regulation of HGF variation contribute also significantly to variation of the obesity and BP. It is possible that the familial resemblance for WHR and the SBP correlation in the studied sample is affected substantially by genetic factors regulating circulating HGF levels.