Sex-biased expression of the TLR7 gene in severe COVID-19 patients: Insights from transcriptomics and epigenomics.

There is abundant epidemiological data indicating that the incidence of severe cases of coronavirus disease (COVID-19) is significantly higher in males than females worldwide. Moreover, genetic variation at the X-chromosome linked TLR7 gene has been associated with COVID-19 severity. It has been suggested that the sex-biased incidence of COVID-19 might be related to the fact that TLR7 escapes X-chromosome inactivation during early embryogenesis in females, thus encoding a doble dose of its gene product compared to males. We analyzed TLR7 expression in two acute phase cohorts of COVID-19 patients that used two different technological platforms, one of them in a multi-tissue context including saliva, nasal, and blood samples, and a third cohort that included different post-infection timepoints of long-COVID-19 patients. We additionally explored methylation patterns of TLR7 using epigenomic data from an independent cohort of COVID-19 patients stratified by severity and sex. In line with genome-wide association studies, we provide supportive evidence indicating that TLR7 has altered CpG methylation patterns and it is consistently downregulated in males compared to females in the most severe cases of COVID-19.

Elevated body mass index is associated with an increased risk of infectious disease admissions and mortality: a mendelian randomization study.

OBJECTIVE: The effect of body mass index (BMI) on the risk of infectious diseases admissions and mortality is unclear and is difficult to study given the risks of confounding variables. METHODS: We used genome-wide association studies (GWASs) with mendelian randomization (MR) to obtain causal inference of BMI on the following infectious diseases outcomes: hospital admissions for pneumonia, sepsis, urinary tract infections, skin and soft tissue infections (SSTIs) or all-cause infections. For patients with pneumonia and sepsis, we also analysed their 28-day and 90-day mortalities. The UK Biobank (UKB) cohort (n > 500 000) provided data for GWASs on infectious diseases. The GIANT consortium (n = 681 265) GWAS was used to identify single-nucleotide polymorphisms (SNPs) associated with BMI. RESULTS: Genetically increased BMI, by one standard deviation, was associated with higher rates of admission due to all infectious disease. The effect was most important for SSTIs (OR: 1.11, 95%CI: 1.09, 1.12). Increasing BMI by one standard deviation was associated with higher pneumonia mortality, especially at 28 days (OR: 1.03, 95%CI: 1.01, 1.05). BMI was not clearly associated with sepsis mortality, although interpretation of the results was limited by a small sample size. There were consistent findings in sensitivity analysis performed by removing highly pleiotropic SNPs and multivariate MR including type-2 diabetes mellitus, estimated glomerular filtration rate, high-density lipoprotein, educational attainment, and a history of smoking. CONCLUSIONS: Increased BMI was associated with increased risk of admission for infectious disease and mortality. While the pathophysiology behind this phenomenon remains unknown, increasing BMI may influence immune dysregulation.

Mutation in the vasopressin gene eliminates the sex difference in social reinforcement in adolescent rats.

The neuropeptide, arginine vasopressin (AVP), is thought to contribute to sex differences in normative and pathological social development by regulating social motivation. Recent studies using Brattleboro rats that have a mutation in the Avp gene, however, have suggested that AVP impacts adolescent social behaviors of males and females in a similar manner through actions on behavioral state (i.e., arousal). In the present study, we made use of a recently developed operant conditioning paradigm to test whether the chronic, lifelong AVP deficiency caused by the Brattleboro mutation impacts the reinforcement value of social stimuli during adolescence. Operant responding for access to a familiar conspecific was assessed in male and female adolescent wild type (WT; normal AVP), heterozygous Brattleboro (HET), and homozygous Brattleboro (HOM) rats. Following the social reinforcement test, rats were tested in the same operant paradigm except that the social reinforcer was replaced with a light reinforcer to determine whether effects of the Brattleboro mutation were specific to social stimuli or a general characteristic of operant conditioning. WT males directed a greater proportion of their responding toward the social and light stimuli than WT females; only males exhibited a preference for these reinforcers over unreinforced ports. The sex difference in social reinforcement was absent in HOM rats, whereas the sex difference in light reinforcement was present in all genotypes. These data indicate that adolescent males are more sensitive to the reinforcing properties of social and light stimuli, and that the sex difference in social, but not light, reinforcement depends upon normal levels of AVP. These findings support the hypothesis that AVP plays a critical role in sex differences in social development by acting on factors that influence social motivation.

Cdh13 and AdipoQ gene knockout alter instrumental and Pavlovian drug conditioning.

Genome-wide association studies in humans have suggested that variants of the cadherin-13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction-related behaviors, we assessed Cdh13 knockout (KO) rats and AdipoQ KO mice using intravenous cocaine self-administration and conditioned place preference (CPP) paradigms. During intravenous cocaine self-administration, male Cdh13 heterozygous (+/-) and KO (-/-) rats showed increased cue-induced reinstatement compared with wild-type (WT) rats when presented with a cocaine-paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 -/- rats showed higher responding for a saccharin reinforcer and learned the choice reaction time (RT) task more slowly than WTs. However, we found no differences between Cdh13 -/- and +/+ rats in responding for sensory reinforcement, number of premature responses in the RT task, tendency to approach a Pavlovian food cue, CPP and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ -/- mice, there was a significant increase in CPP to methamphetamine (1 mg/kg) but not to a range of d-amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse.

Strong genetic influences on measures of behavioral-regulation among inbred rat strains.

A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral-regulation were tested in a panel of eight inbred rat strains. These measures were: (1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, (2) attention and impulsivity, as measured by a choice reaction time task and (3) impulsivity as measured by a delay discounting task. Deficient behavioral-regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n = 9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the eight inbred rat strains on the choice reaction time task was compared to the performance of outbred Sprague Dawley (n = 28) and Heterogeneous strain rats (n = 48). The results indicate a strong genetic influence on complex tasks related to behavioral-regulation and indicate that some of the measures tap common genetically driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral-regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders.

Common variants in genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1/2), adiponectin concentrations, and diabetes incidence in the Diabetes Prevention Program.

AIMS: Baseline adiponectin concentrations predict incident Type 2 diabetes mellitus in the Diabetes Prevention Program. We tested the hypothesis that common variants in the genes encoding adiponectin (ADIPOQ) and its receptors (ADIPOR1, ADIPOR2) would associate with circulating adiponectin concentrations and/or with diabetes incidence in the Diabetes Prevention Program population. METHODS: Seventy-seven tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ (24), ADIPOR1 (22) and ADIPOR2 (31) were genotyped. Associations of SNPs with baseline adiponectin concentrations were evaluated using linear modelling. Associations of SNPs with diabetes incidence were evaluated using Cox proportional hazards modelling. RESULTS: Thirteen of 24 ADIPOQ SNPs were significantly associated with baseline adiponectin concentrations. Multivariable analysis including these 13 SNPs revealed strong independent contributions of rs17366568, rs1648707, rs17373414 and rs1403696 with adiponectin concentrations. However, no ADIPOQ SNPs were directly associated with diabetes incidence. Two ADIPOR1 SNPs (rs1342387 and rs12733285) were associated with ∼18% increased diabetes incidence for carriers of the minor allele without differences across treatment groups, and without any relationship with adiponectin concentrations. CONCLUSIONS: ADIPOQ SNPs are significantly associated with adiponectin concentrations in the Diabetes Prevention Program cohort. This observation extends prior observations from unselected populations of European descent into a broader multi-ethnic population, and confirms the relevance of these variants in an obese/dysglycaemic population. Despite the robust relationship between adiponectin concentrations and diabetes risk in this cohort, variants in ADIPOQ that relate to adiponectin concentrations do not relate to diabetes risk in this population. ADIPOR1 variants exerted significant effects on diabetes risk distinct from any effect of adiponectin concentrations.

25-Hydroxyvitamin D in Canadian adults: biological, environmental, and behavioral correlates.

SUMMARY: We assessed vitamin D status and its correlates in the population-based Canadian Multicentre Osteoporosis Study (CaMos). Results showed that serum 25-hydroxyvitamin D levels <75 nmol/L were common. Given Canada's high latitude, attention should be given to strategies for enhancing vitamin D status in the population. INTRODUCTION: Inadequate vitamin D has been implicated as a risk factor for several clinical disorders. We assessed, in a Canadian cohort, vitamin D status and its correlates, based on serum 25-hydroxyvitamin D [25(OH)D], the best functional indicator of vitamin D status. METHODS: We studied 577 men and 1,335 women 35+ years from seven cities across Canada in the randomly selected, population-based Canadian Multicentre Osteoporosis Study (CaMos). Participants completed a comprehensive questionnaire. Serum 25(OH)D was measured by immunoassay. Multivariate linear regression modeling assessed the association between 25(OH)D and determinants of vitamin D status. RESULTS: Participants (2.3%) were deficient in 25(OH)D (<27.5 nmol/L); a further 18.1% exhibited 25(OH)D insufficiency (27.5-50 nmol/L). Levels <75 nmol/L were evident in 57.5% of men and 60.7% of women and rose to 73.5% in spring (men) and 77.5% in winter (women); 25(OH)D <50 nmol/L was ≤10% year round for those supplementing with ≥400 IU vitamin D/day but was 43.9% among those not supplementing in winter and spring. The strongest predictors of reduced 25(OH)D for both men and women were winter and spring season, BMI ≥30, non-white ethnicity, and lower vitamin D supplementation and its modification by fall and winter. CONCLUSIONS: In this national Canadian cohort, vitamin D levels <75 nmol/L were common, particularly among non-white and obese individuals, and in winter and spring. Vitamin D intake through diet and supplementation and maintenance of normal weight are key modifiable factors for enhancing vitamin D status and thus potentially influencing susceptibility to common chronic diseases.

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.

A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length.

BACKGROUND: Telomere length is a predictor for a number of common age related diseases and is a heritable trait. METHODS AND RESULTS: To identify new loci associated with mean leukocyte telomere length we conducted a genome wide association study of 314,075 single nucleotide polymorphisms (SNPs) and validated the results in a second cohort (n for both cohorts combined = 2790). We identified two novel associated variants (rs2162440, p = 2.6 x 10(-6); and rs7235755, p = 5.5 x 10(-6)) on chromosome 18q12.2 in the same region as the VPS34/PIKC3C gene, which has been directly implicated in the pathway controlling telomere length variation in yeast. CONCLUSION: These results provide new insights into the pathways regulating telomere homeostasis in humans.

Plasma adiponectin concentrations are associated with body composition and plant-based dietary factors in female twins.

Circulating adiponectin is emerging as an important link between obesity, type 2 diabetes, and cardiovascular disease (CVD). However, the spectrum of lifestyle factors that modulate the adiponectin concentration remains to be elucidated, particularly among women. We conducted a cross-sectional study of 877 female twin pairs from the TwinsUK adult twin registry. Using a co-twin design, we examined dietary and body composition influences on adiponectin by conducting matched, within-pair analyses to eliminate confounding. Following multivariable adjustment within-twin pairs, significant influences on adiponectin (log-transformed, percent change per SD of the dietary/body composition variable) were observed for nonstarch polysaccharides (3.25%; 95% CI: 0.06, 6.54; P < 0.05) and magnesium intake (3.80%; 95%CI: 0.17, 7.57; P < 0.05), with a trend toward an association for fruit and vegetable (F&V) intakes (2.55%; 95% CI: -0.26, 5.45; P = 0.08). These modest positive associations cannot be explained by confounding through other lifestyle factors shared by the twins. A significant relationship between adiponectin and 3 derived dietary patterns (F&V, dieting, traditional English), carbohydrate, protein, trans fat, and alcohol intake was also observed. Strong inverse associations with adiponectin were observed for BMI (-10.72%; 95% CI: -13.78, -7.55), total (-6.89%: 95% CI: -10.34, -3.30; P < 0.05), and central fat mass (-12.50%; 95% CI: -15.82, -9.05; P < 0.05); these relationships were significant both when twins were analyzed as individuals and when characteristics were contrasted within-twin pairs, suggesting a direct effect. We observed modest associations between dietary factors and adiponectin in female twins, independent of adiposity, and report strong inverse associations with body composition. These data reinforce the importance of weight maintenance and increasing consumption of diets rich in plant-based foods to prevent CVD and type 2 diabetes.

Effectiveness of antiresorptives for the prevention of nonvertebral low-trauma fractures in a population-based cohort of women.

UNLABELLED: Observational studies are needed to quantify real-life effectiveness of antiresorptive therapy in the prevention of clinical fractures. Antiresorptive therapies were associated with an overall 32% reduction in low-trauma nonvertebral fracture risk among women 50 and older. Effectiveness may be lower among older women and those without risk factors. INTRODUCTION: Randomized controlled trials have shown that antiresorptive therapies reduce the risk of fracture in selected populations, but further study is needed to quantify their real-life effectiveness. The study objective was to determine the association between antiresorptive use and low-trauma nonvertebral fracture in women 50 and older. METHODS: The design was a retrospective nested case-control study (density-based sampling) within the Canadian Multicentre Osteoporosis Study. There were 5,979 eligible women with 453 cases and 1,304 matched controls. RESULTS: The current use of antiresorptives was associated with a decreased risk of fracture with OR = 0.68, 95% CI: 0.52-0.91; where OR is the adjusted odds ratio and CI is the confidence interval. Subgroup analysis yielded OR = 0.61, 95% CI: 0.42-0.89 for ages 50-74; OR = 0.76, 95% CI: 0.50-1.17 for ages 75+; OR = 0.58, 95% CI: 0.40-0.83 for those with a major risk factor; and OR = 0.92; 95% CI: 0.59-1.42 for those without a major risk factor. Major risk factors were prevalent low-trauma fracture, vertebral deformity (grade 2+), and BMD T-score < or = -2.5. CONCLUSIONS: Antiresorptive therapy is associated with a clinically important reduction in low-trauma nonvertebral fracture risk among community-dwelling women aged 50 and older. Antiresorptive therapy may be less effective for women 75 and older and women without major risk factors.

Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study.

BACKGROUND: Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. METHODS: In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. FINDINGS: We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5x10(-8)). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6.3x10(-12) for lumbar spine and p=1.9x10(-4) for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1.3, 95% CI 1.09-1.52, p=0.002) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7.6x10(-10) for lumbar spine and p=3.3x10(-8) for femoral neck) and increased risk of osteoporosis (OR 1.2, 95% CI 1.01-1.42, p=0.038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3.0x10(-6)). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2.3x10(-17)). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1.3, 1.08-1.63, p=0.006) and this effect was independent of bone mineral density. INTERPRETATION: Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.

Natural history and risk factors for bone loss in postmenopausal Caucasian women: a 15-year follow-up population-based study.

UNLABELLED: In this 15-year follow-up study, we found that the estimated rate of bone loss at the femoral neck (FN) for women aged 45-68 was linear at a rate of 1.67% per year, but quadratic for lumbar spine (LS) at a rate of 3.12% initially, and slowing down with age. We also confirmed the protective role of HRT, increasing weight, and lean mass in long-term bone loss. INTRODUCTION: The objective was to describe the natural history of bone loss and explore the role of environmental factors in postmenopausal women over a 15-year period. METHODS: Bone mineral density (BMD) at the FN and the LS were measured in postmenopausal women from the Chingford Study. Height, weight, HRT status, and calcium/vitamin D supplement were assessed at each visit. Osteoarthritis of hip and spine was assessed by X-ray at baseline and at year 8. RESULTS: A total of 955 postmenopausal women with an average age of 54.7 at baseline were included. Both FN and LS BMD decreased significantly with age (p<0.0001). The decline was larger in the LS (-3.12% per year), which showed a quadratic relationship, than in the FN (-1.67% per year) with a linear relationship. The rate of bone loss was reduced by one third annually for the FN and LS respectively in current HRT users. Change in weight was positively associated with both DeltaFN and DeltaLS BMD (beta=0.16% and 0.09% change in DeltaFN and DeltaLS BMD per kilogramme change in weight respectively, p<0.0001 for both sites). Spine OA and progression were positively associated with DeltaLS BMD (beta=1.22% change in DeltaLS BMD per grade in spine OA and 0.45% change in DeltaLS BMD for patients who progressed, p<0.0001 for spine OA and p=0.002 for spine OA progression). Spine OA (beta=0.54% change in DeltaFN BMD per grade, p<0.0001), but not progression, and hip OA were positively associated with DeltaFN BMD. Furthermore, both age and body weight at baseline were positively associated with both DeltaFN and DeltaLS BMD (beta=0.02-0.04% change in DeltaFN and DeltaLS BMD per year increase in age at baseline and 0.004-0.007% change in DeltaFN and DeltaLS BMD per kilogramme increase in weight at baseline, all p<0.0001). CONCLUSION: This large population-based longitudinal study demonstrated that the decline of BMD over 15 years is linear with age for the FN, but quadratic for the LS. The study confirmed the protective role of HRT, increased weight and lean mass in long-term bone loss.

Homocysteine levels and leukocyte telomere length.

OBJECTIVE: Elevated plasma homocysteine is a risk factor for vascular diseases, possibly due to homocysteine-mediated increase in oxidative stress and inflammation. As leukocyte telomere length (LTL) registers the cumulative oxidative stress and inflammation, we examined the relationship between homocysteine and LTL. METHODS: LTL was measured using the Southern blot method. The relationship between LTL and homocysteine levels was considered for confounding with the following covariates: age, sex, smoking, obesity, physical activity, menopause, hormone replacement therapy use and creatinine clearance. RESULTS: 1,319 healthy subjects were recruited from a population-based cohort. LTL was negatively correlated with plasma homocysteine levels, after adjustment for smoking, obesity, physical activity, menopause, hormone replacement therapy use and creatinine clearance. The difference in multiply-adjusted LTL between the highest and lowest tertile of homocysteine levels was 111 base pairs (p=0.004), corresponding to 6.0 years of telomeric aging. This relationship was further accentuated by decreased concentrations of serum folate and increased levels of C-reactive protein. CONCLUSIONS: Increased homocysteine levels are associated with shortened LTL, further supporting the tenet that LTL is an index of cardiovascular risk.

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice.

RATIONALE: Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT2A receptors, with serotonergic receptors of the 5-HT1A and 5-HT2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter. OBJECTIVE: Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice. METHODS: SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle. RESULTS: The visual stimulus exerted control in both genotypes. LSD-induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital-induced stimulus control in 80% of WT mice and 54% of knockout mice. CONCLUSIONS: Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT1A and/or 5-HT2A receptors underlies the absence of stimulus control by LSD.

Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort.

OBJECTIVE: Thyroid hormone action influences many metabolic and synthetic processes, but the degree of regulation attributed to genes and environmental factors affecting normal variation remains controversial. DESIGN: We investigated the magnitude of the genetic and environmental determination of serum concentrations of free (f) T3, fT4, TSH and the fT4 x TSH product and their variation, in a large cohort of twin pairs. Female dizygous and monozygous twins (849 and 213 pairs, respectively) from the TwinsUK registry (mean age 45.5, range 18-80 years) were studied. RESULTS: Comparison of thyroid parameters within various groups showed no differences between smoking categories, and higher serum TSH and lower fT3 in subjects with positive thyroid antibodies. Using structural equation modelling, we estimated the heritable contribution to serum thyroid parameters (with 95% confidence intervals) to be 65% (58%-71%) for TSH, 65% (58%-71%) for the fT4 x TSH product, 39% (20%-55%) for fT4 and 23% (3%-41%) for fT3. CONCLUSIONS: We conclude that genetic regulation is a particularly important determinant of TSH and the fT4 x TSH product, and is a less important determinant of fT4 and fT3 concentrations in Caucasian women. These data from a large well-characterized cohort suggest that while there is a strong heritable contribution to serum TSH, variation in fT4 and fT3 concentrations may be less explained by genetic factors and more driven by environmental effects than previously thought.

Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis.

UNLABELLED: Telomere length decreases with age and is associated with osteoblast senescence. In 2,150 unselected women, leukocyte telomere length was significantly correlated with bone mineral density. Clinical osteoporosis was associated with shorter telomeres, suggesting that telomere length can be used as a marker of bone aging. INTRODUCTION: The length of telomeres in proliferative cells diminishes with age. Telomere shortening and telomerase activity have been linked to in vitro osteoblast senescence and to increased secretion of pro-inflammatory cytokines. We explored whether bone mineral density correlates with telomere length in leukocytes. MATERIALS AND METHODS: The relationship between leukocyte telomere length, bone mineral density (BMD) and osteoporosis (as defined by the World Health Organization) was examined in a cohort of 2,150 women from a population-based twin cohort aged 18-79. RESULTS: After adjusting for age, body mass index, menopausal status, smoking, hormone replacement therapy status, telomere length was positively correlated with BMD of the spine (p < 0.005), forearm (p < 0.013), but not the femoral neck (p < 0.06). Longer telomeres were associated with reduced the risk of clinical OP at two or more sites (odds ratio = 0.594 95% CI 0.42-0.84 p < 0.003) and in women over the age of 50, clinical osteoporosis was associated with 117 bp shorter telomere length (p < 0.02) equivalent to 5.2 years of telomeric aging. CONCLUSIONS: Shortened leukocyte telomere length is independently associated with a decrease in BMD and the presence of osteoporosis in women. Our data provide evidence that leukocyte telomere length could be a marker of biological aging of bone.

Serum adiponectin and bone mineral density in women.

CONTEXT: Bone mineral density (BMD) is positively associated with body weight. This association persists even at non-load bearing sites, suggesting that a nonmechanical factor such as an adipocyte-derived hormone may modulate BMD. OBJECTIVE: The objective of the study was to evaluate the relationship between adiponectin, an adipocyte-derived hormone, and BMD. DESIGN, SETTING, PARTICIPANTS: A total of 1735 nondiabetic women were recruited from a large, population-based cohort (mean age, 50.0 yr). We employed linear regression methods to estimate the relationship between adiponectin and BMD. MAIN OUTCOME MEASURES: Percentage change in BMD (as measured at total hip, spine, femoral neck, and forearm) and markers of bone turnover associated with a doubling of fasting serum adiponectin levels were measured. RESULTS: Employing age-adjusted analysis, each doubling of serum adiponectin was associated with a mean 2.7% decrease in BMD [total hip, -3.2% (95% confidence interval, -4.1, -2.3); femoral neck, -3.1% (-4.0, -2.1); forearm, -2.0 (-2.6, -1.4); spine, -2.6 (-3.5, -1.7)]. After adjustment for potential confounding factors, including BMI, serum leptin, central fat mass, hormone replacement therapy, smoking, and exercise, this relationship persisted, although decreased in magnitude. When stratified by menopausal status, the relationship between serum adiponectin and BMD strengthened in postmenopausal women but disappeared in premenopausal women. Serum adiponectin was positively associated with serum osteocalcin but not with urine deoxypyridinoline. CONCLUSIONS: After adjustment of measures of body fat, increasing levels of adiponectin were associated with a decrease in BMD, even at non-load bearing sites. These data suggest that adiponectin, an adipocyte-derived hormone, may play a role in bone metabolism through nonmechanical mechanisms and that this effect may be mediated by menopausal status.

An analysis of which anti-osteoporosis therapeutic regimen would improve compliance in a population of elderly adults.

OBJECTIVE: Although medications to prevent osteoporotic fractures have been proven to be effective, compliance to these therapies is generally poor. Therapeutic regimens for different anti-osteoporotic medications differ widely and it is currently unknown which regimen would be most preferred by patients. RESEARCH DESIGN AND METHODS: We conducted a large, population-based study to discern which therapeutic attributes would be most preferable to a population representative of the age and sex distribution of patients with osteoporosis. RESULTS: Our study sample was restricted to persons aged 55 years and over and comprised 2485 individuals (mean age of 64.5 years). The study population was predominantly female (90.3%) and two-thirds of the respondents reported current daily medication use. Nearly half (45%) of the study population preferred to take medications daily, while one in five preferred weekly therapy and 30% preferred monthly therapy (p < 0.0001 for between proportion comparisons). When given the option of choosing between three different medication regimen scenarios, those subjects not currently using anti-osteoporotic medications preferred a theoretical regimen which was daily and did not involve subsequent fasting and maintaining an upright posture. CONCLUSIONS: Our data suggest that compliance with osteoporotic medications could be improved if patients are able to choose a therapeutic regimen best suited to their particular needs. The majority of subjects preferred a drug which was taken daily and with minimal inconvenience, rather than a weekly drug with slightly more inconvenience. Given that most physicians currently prescribe anti-osteoporotic therapy as a weekly regimen, at the time of diagnosis physicians should ascertain which regimen would be most preferable to patients prior to initiating therapy.

The effect of cyclooxygenase-2 inhibitors on bone mineral density: results from the Canadian Multicentre Osteoporosis Study.

INTRODUCTION: The use of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated to not only impair load-induced bone formation but also prevent menopause-associated bone loss. We hypothesized that COX-2 inhibitor use would be associated with increased bone mineral density (BMD) in postmenopausal women not using estrogen therapy and, conversely, with decreased BMD in men. METHODS: The Canadian Multicentre Osteoporosis Study is a longitudinal, randomly selected, population-based community cohort. We present data from men (n=2,004) and postmenopausal women age 65 and older (n=2,776) who underwent a BMD measurement and structured interview in the 5th year of the study. The outcome measure was percent difference in BMD (g/cm(2)). RESULTS: Daily COX-2 inhibitor use was reported by 394 subjects. In men, daily use of COX-2 inhibitors was associated with a lower BMD at all hip sites, with a percent difference of -3.1% [95% confidence interval (CI), -6.0, -0.3] between users and nonusers at total hip. In postmenopausal women not using estrogen replacement therapy, daily COX-2 inhibitor use was associated with higher BMD at most sites [percent difference at total hip: +3.0% (95% CI, 0.3, 5.8)]. These effects appeared to be dose-dependent. CONCLUSION: COX-2 inhibitor use was associated with a lower BMD in men and, on the other hand, with a higher BMD in postmenopausal women not using estrogen replacement therapy. Men who have used COX-2 inhibitors may wish to seek BMD measurement to assess their fracture risk. However, COX-2 inhibitors may have utility in postmenopausal women if bone-selective analogs can be developed.