Plasma proteome and incident myocardial infarction: sex-specific differences.

BACKGROUND AND AIMS: Few population-based cohort studies, including both men and women, have explored circulating proteins associated with incident myocardial infarction (MI). This study investigated the relationships between circulating cardiometabolic-related proteins and MI risk using cohort-based and Mendelian randomization (MR) analyses and explored potential sex-specific differences. METHODS: The discovery cohort included 11 751 Swedish adults (55-93 years). Data on 259 proteins assessed with Olink proximity extension assays, biochemical, and questionnaire-based information were used. Participants were followed up for incident MI and death over 8 years through linkage to Swedish registers. Replication analyses were conducted on the UK Biobank sample (n = 51 613). In MR analyses, index cis-genetic variants strongly related to the proteins were used as instrumental variables. Genetic association summary statistic data for MI were obtained from the CARDIoGRAMplusC4D consortium and FinnGen. RESULTS: Forty-five proteins were associated with incident MI in discovery and replication samples following adjustment for potential confounders and multiple testing. In the secondary analysis, 13 of the protein associations were sex-specific, with most associations identified among women. In MR analysis, genetically predicted higher levels of renin, follistatin, and retinoic acid receptor responder protein 2 were linked to an increased risk of MI. Tissue factor pathway inhibitor, tumor necrosis factor receptors 1 and 2, placenta growth factor had an inverse association with MI. CONCLUSIONS: This study identified both new and confirmed previously established associations between circulating proteins and incident MI and, for the first time, suggested sex-specific patterns in multiple protein-MI associations.

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries.

BACKGROUND: Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. METHODS: This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. FINDINGS: Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I2=61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I2=59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I2=68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. INTERPRETATION: The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. FUNDING: The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre.

Major cardiovascular events and death in parents of children with type 1 diabetes: a register-based matched cohort study in Sweden.

AIMS/HYPOTHESIS: Parenting a child with type 1 diabetes has been associated with stress-related symptoms. This study aimed to elucidate the potential impact on parental risk of major cardiovascular events (MCE) and death. METHODS: In this register-based study, we included the parents of 18,871 children, born 1987-2020 and diagnosed with type 1 diabetes in Sweden at <18 years. The median parental age at the child's diagnosis was 39.0 and 41.0 years for mothers and fathers, respectively. The cohort also encompassed 714,970 population-based matched parental control participants and 12,497 parental siblings. Cox proportional hazard regression models were employed to investigate the associations between having a child with type 1 diabetes and incident MCE and all-cause death, and, as secondary outcomes, acute coronary syndrome and ischaemic heart disease (IHD). We adjusted for potential confounders including parental type 1 diabetes and country of birth. RESULTS: During follow-up (median 12 years, range 0-35), we detected no associations between parenting a child with type 1 diabetes and MCE in mothers (adjusted HR [aHR] 1.02; 95% CI 0.90, 1.15) or in fathers (aHR 1.01; 95% CI 0.94, 1.08). We noted an increased hazard of IHD in exposed mothers (aHR 1.21; 95% CI 1.05, 1.41) with no corresponding signal in fathers (aHR 0.97; 95% CI 0.89, 1.05). Parental sibling analysis did not confirm the association in exposed mothers (aHR 1.01; 95% CI 0.73, 1.41). We further observed a slightly increased hazard of all-cause death in exposed fathers (aHR 1.09; 95% CI 1.01, 1.18), with a similar but non-significant estimate noted in exposed mothers (aHR 1.07; 95% CI 0.96, 1.20). The estimates from the sibling analyses of all-cause death in fathers and mothers were 1.12 (95% CI 0.90, 1.38) and 0.73 (95% CI 0.55, 0.96), respectively. CONCLUSIONS/INTERPRETATION: Having a child diagnosed with type 1 diabetes in Sweden was not associated with MCE, but possibly with all-cause mortality. Further studies are needed to disentangle potential underlying mechanisms, and to investigate parental health outcomes across the full lifespan.

Dietary fatty acids and incident hip fractures in cohorts of women and men. A relative validation and follow-up study.

OBJECTIVES: Hip fractures are associated with a high burden of morbidity and mortality. Diet is essential for preventing fragility fractures, but the role of dietary fatty acids on the risk of hip fracture is uncertain. The aim was to investigate how intake of different dietary fatty acids relates to the risk of hip fracture. A relative validation of the long-term intake of dietary fatty acids estimated from food frequency questionnaires (FFQs) was also performed. DESIGN, SETTINGS AND PARTICIPANTS: We used data collected in two population-based cohorts, the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men, aged 45-82 years). Data from the repeated investigations in the cohorts and cross-sectional data from their clinical sub-cohorts were used. MEASUREMENTS: Diet data was collected in FFQs. Incident hip fractures were gathered by individual linkage to national registers. We performed Cox regression analysis to investigate associations between dietary fatty acids and hip fracture. Follow-up time was between January 1st, 1998 and December 31st, 2020. The validation was performed using correlation analyses, comparing fatty acids measured in adipose tissue with estimated fatty acid intakes from FFQs. RESULTS: During up to 23 years of follow-up (mean 18 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. A low linoleic acid (LA) and high intakes of long-chain n-3 fatty acids were associated with higher hip fracture risk in a non-linear way. In quartile 4 compared to quartile 1 of LA, the multivariable-adjusted hazard ratio of hip fracture was 0.89 (95% Confidence Interval: 0.81, 0.97). The study confirmed the validity of FFQs to capture the intake of the specific dietary long-chain n-3 fatty acids. The estimated intake of LA, α-linolenic acid, and myristic acid were also adequately captured by the FFQs. Validity was confirmed in both women and men. CONCLUSION: A low to moderate intake of linoleic acid and a higher intake of long-chain n-3 fatty acids were associated with a higher risk of hip fractures. The results indicate that attention should be paid to dietary fatty acid composition for the optimal prevention of fragility fractures.

Meat consumption and the risk of hip fracture in women and men: two prospective Swedish cohort studies.

PURPOSE: To study the association between meat intake (predominantly red and processed meats) and the risk of hip fracture, as well as the association between meat intake and biomarkers of inflammation, oxidative stress, bone turnover, body composition, and bone mineral density (BMD). METHODS: Data from the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men) with repeated investigations and their respective clinical sub-cohorts was utilised. Incident hip fractures were ascertained through individual linkage to registers. Associations were investigated using multivariable Cox and linear regression analyses. RESULTS: During up to 23 years of follow-up (mean 18.2 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. Each daily serving of meat intake conferred a hazard ratio (HR) of 1.03 (95% confidence interval [CI] 1.00; 1.06) for hip fracture. In quintile 5, compared to quintile 2, the HR was 1.11 (95% CI 1.01; 1.21) among all participants. In the sub-cohorts, meat intake was directly associated with circulating levels of interleukin-6, C-reactive protein, leptin, ferritin, parathyroid hormone, and calcium. CONCLUSION: A modest linear association was found between a higher meat intake and the risk of hip fractures. Our results from the sub-cohorts further suggest that possible mechanisms linking meat intake and hip fracture risk may be related to the regulation of bone turnover, subclinical inflammation, and oxidative stress. Although estimates are modest, limiting red and processed meat intake in a healthy diet is advisable to prevent hip fractures.

Declining hip fracture burden in Sweden 1998-2019 and consequences for projections through 2050.

We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1-30.2%) in women and 29.3% (95% CI 27.5-30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (≥ 80 years). Without an algorithm, a naïve estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections.

Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass.

BACKGROUND: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. METHODS: We used data from a population-based cohort of 4950 Swedish women (55-85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. RESULTS: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. CONCLUSIONS: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis.

Self-reported physical activity and different cardiovascular diseases-Results from updated measurements over 40 years.

BACKGROUND: Self-reported leisure-time physical activity (PA) has previously been linked to risk of cardiovascular disease (CVD). We now aim to investigate the strength of associations between PA and different CVDs and how the risk varies with age. METHODS: PA and traditional CV risk factors assessed by a questionnaire on a four-level scale in 2,175 men at age 50 years in the ULSAM study. Examinations were thereafter repeated at ages 60, 70, and 77. RESULTS: During 40 years follow-up, 883 individuals experienced a CVD (myocardial infarction, stroke, or heart failure). Using data from all four examinations, a graded reduction in risk of incident CVD was seen with increasing PA (HR 0.84, 95%CI; 0.77-0.93, p = 0.001 for trend test). PA was related to myocardial infarction (HR 0.84, 95%CI; 0.74-0.95, 490 cases), heart failure (HR 0.79, 95%CI; 0.68-0.91, 356 cases), but only of borderline significance vs ischemic stroke (HR 0.85, 95%CI; 0.73-1.00, 315 cases) when the CVDs were analyzed separately. Adjusting for traditional CV risk factors attenuated all relationships between PA and incident CVD, and PA did not improve discrimination of CVD when added on top of risk factors. When 10-year risk was calculated from each examination, age 70 was the time-point when PA was most closely related to incident CVD. CONCLUSION: Leisure-time physical activity is related to future CVD. This was most evident at 70 years of age. If a causal relationship between self-reported PA and CVD exists, this relationship might to a major degree be mediated by traditional risk factors.

Associations between exploratory dietary patterns and incident type 2 diabetes: a federated meta-analysis of individual participant data from 25 cohort studies.

PURPOSE: In several studies, exploratory dietary patterns (DP), derived by principal component analysis, were inversely or positively associated with incident type 2 diabetes (T2D). However, findings remained study-specific, inconsistent and rarely replicated. This study aimed to investigate the associations between DPs and T2D in multiple cohorts across the world. METHODS: This federated meta-analysis of individual participant data was based on 25 prospective cohort studies from 5 continents including a total of 390,664 participants with a follow-up for T2D (3.8-25.0 years). After data harmonization across cohorts we evaluated 15 previously identified T2D-related DPs for association with incident T2D estimating pooled incidence rate ratios (IRR) and confidence intervals (CI) by Piecewise Poisson regression and random-effects meta-analysis. RESULTS: 29,386 participants developed T2D during follow-up. Five DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, were associated with higher incidence of T2D. The strongest association was observed for a DP comprising these food groups besides others (IRRpooled per 1 SD = 1.104, 95% CI 1.059-1.151). Although heterogeneity was present (I2 = 85%), IRR exceeded 1 in 18 of the 20 meta-analyzed studies. Original DPs associated with lower T2D risk were not confirmed. Instead, a healthy DP (HDP1) was associated with higher T2D risk (IRRpooled per 1 SD = 1.057, 95% CI 1.027-1.088). CONCLUSION: Our findings from various cohorts revealed positive associations for several DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, adding to the evidence-base that links DPs to higher T2D risk. However, no inverse DP-T2D associations were confirmed.

The impact and causal directions for the associations between diagnosis of ADHD, socioeconomic status, and intelligence by use of a bi-directional two-sample Mendelian randomization design.

BACKGROUND: Previous studies have reported associations between attention-deficit/hyperactivity disorder (ADHD) and lower socioeconomic status and intelligence. We aimed to evaluate the causal directions and strengths for these associations by use of a bi-directional two-sample Mendelian randomization (MR) design. METHODS: We used summary-level data from the largest available genome-wide association studies (GWAS) to identify genetic instruments for ADHD, intelligence, and markers of socioeconomic status including the Townsend deprivation index, household income, and educational attainment. Effect estimates from individual genetic variants were combined using inverse-variance weighted regression. RESULTS: A genetically predicted one standard deviation (SD) increment in the Townsend deprivation index conferred an odds ratio (OR) of 5.29 (95% confidence interval (CI) 1.89-14.76) for an ADHD diagnosis (p<0.001). A genetically predicted one SD higher education level conferred an OR of 0.30 (95% CI 0.25-0.37) (p<0.001), and a genetically predicted one SD higher family income provided an OR of 0.35 (95% CI 0.25-0.49; p<0.001). The associations remained after adjustment for intelligence whereas the lower odds of an ADHD diagnosis with higher intelligence did not persist after adjustment for liability to greater educational attainment (adjusted OR 1.03, 95% CI 0.68-1.56; p=0.87). The MR analysis of the effect of ADHD on socioeconomic markers found that genetic liability to ADHD was statistically associated with each of them (p<0.001) but not intelligence. However, the average change in the socioeconomic markers per doubling of the prevalence of ADHD corresponded only to 0.05-0.06 SD changes. CONCLUSIONS: Our results indicate that an ADHD diagnosis may be a direct and strong intelligence-independent consequence of socioeconomic related factors, whereas ADHD appears to lead only to modestly lowered socioeconomic status. Low intelligence seems not to be a major independent cause or consequence of ADHD.

Milk and Fermented Milk Consumption and Risk of Stroke: Longitudinal Study.

The role of milk and fermented milk consumption in stroke risk is unclear. We investigated associations of time-updated information on milk and fermented milk consumption (1997 and 2009) with total stroke, cerebral infarction, and hemorrhagic stroke risk among 79,618 Swedish women and men (mean age 61.3 years). During a mean follow-up of 17.7 years, we identified 9735 incident cases of total stroke, of which 7573 were cerebral infarctions, 1470 hemorrhagic strokes, and 692 unspecified strokes. Compared with an intake of 100 g/day of milk, the multivariable-adjusted hazard ratios (95% confidence interval) of cerebral infarction were 1.05 (1.02-1.08) for 0 g/day, 0.97 (0.95-0.99) for 200 g/day, 0.96 (0.92-1.00) for 400 g/day, 0.98 (0.94-1.03) for 600 g/day, and 1.01 (0.94-1.07) for 800 g/day. Corresponding estimates for hemorrhagic stroke were 0.98 (0.91-1.05) for 0 g/day, 1.02 (0.97-1.07) for 200 g/day, 1.07 (0.98-1.17) for 400 g/day, 1.13 (1.02-1.25) for 600 g/day, and 1.19 (1.03-1.36) for 800 g/day. No associations were observed between milk consumption and total stroke or for fermented milk consumption and any of the stroke outcomes. Higher long-term milk consumption based on repeated measures of intake was weakly and non-linearly associated with cerebral infarction, and was directly associated with hemorrhagic stroke.

What CVD risk factors predict self-perceived risk of having a myocardial infarction? A cross-sectional study.

BACKGROUND: This study aims to identify predictors of self-perceived risk of myocardial infarction (MI). METHODS: Among 564 men and women (50-65 years; randomly selected from the Swedish population), we assessed risk perception as relative self-perceived risk compared to others (lower, same, higher) and percentage ten-year absolute risk. Predictors (added blockwise) were identified using multinomial or linear regression, providing odds ratios (ORs) or ß coefficients with their 95% confidence intervals (CI). RESULTS: The mean of self-perceived 10-year MI risk was 12%. Lower BMI (AOR 0.57, 95% CI: 0.44-0.75), low stress (AOR 2.51, 95% CI: 1.39-4.52), high level of physical activity (AOR 1.66, 95% CI:1.01-2.74), hypertension (AOR 0.42, 95% CI: 0.23-0.76), family history (AOR 0.38, 95% CI: 0.21-0.69), and poor general health (AOR 0.41, 95% CI: 0.19-0.89) predicted if respondents perceived their MI risk as lower. Poor general health (AOR 1.94, 95% CI: 1.01-3.73), family history (AOR 2.72, 95% CI: 1.57-4.72), and high cholesterol (AOR 2.45, 95% CI: 1.18-5.09) predicted if respondents perceived their MI risk as higher. Low level of self-perceived CVD knowledge and low numeracy predicted if respondents perceived their MI risk as the same as others. High cholesterol (B 6.85, 95% CI: 2.47-11.32) and poor general health (B 8.75, 95% CI: 4.58-13.00) predicted a higher percentage of perceived ten-year risk. CONCLUSION: General health was a common predictor of self-perceived MI risk. Lifestyle factors (BMI, physical activity) and stress dominated the predictors for perceiving MI risk as lower than others, while high cholesterol predicted perception of high risk.

A posteriori dietary patterns in 71-year-old Swedish men and the prevalence of sarcopenia 16 years later.

The role of diet in sarcopenia is unclear, and results from studies using dietary patterns (DP) are inconsistent. We assessed how adherences to a posteriori DP are associated with the prevalence of sarcopenia and its components 16 years later. Four DP were defined in the Uppsala Longitudinal Study of Adult Men at baseline (n 1133, average age 71 years). Among 257 men with information at follow-up, 19 % (n 50) had sarcopenia according to the European Working Group on sarcopenia in Older People 2 definition. Adherence to DP2 (mainly characterised by high intake of vegetables, green salad, fruit, poultry, rice and pasta) was non-linearly associated with sarcopenia; adjusted OR and 95 % CI for medium and high v. low adherence: 0·41 (0·17, 0·98) and 0·40 (0·17, 0·94). The OR per standard deviation (sd) higher adherence to DP2 was 0·70 (0·48, 1·03). Adjusted OR (95 % CI) for 1 sd higher adherence to DP1 (mainly characterised by high consumption of milk and cereals), DP3 (mainly characterised by high consumption of bread, cheese, marmalade, jam and sugar) and DP4 (mainly characterised by high consumption of potatoes, meat and egg and low consumption of fermented milk) were 1·04 (0·74, 1·46), 1·19 (0·71, 2·00) and 1·08 (0·77, 1·53), respectively. There were no clear associations between adherence to the DP and muscle strength, muscle mass, physical performance or sarcopenia using EWGSOP1 (sarcopenia n 54). Our results indicate that diet may be a potentially modifiable risk factor for sarcopenia in old Swedish men.

Changes in leisure-time physical activity during the adult life span and relations to cardiovascular risk factors-Results from multiple Swedish studies.

OBJECTIVE: To evaluate how self-reported leisure-time physical activity (PA) changes during the adult life span, and to study how PA is related to cardiovascular risk factors using longitudinal studies. METHODS: Several Swedish population-based longitudinal studies were used in the present study (PIVUS, ULSAM, SHE, and SHM, ranging from hundreds to 30,000 participants) to represent information across the adult life span in both sexes. Also, two cross-sectional studies were used as comparison (EpiHealth, LifeGene). PA was assessed by questionnaires on a four or five-level scale. RESULTS: Taking results from several samples into account, an increase in PA from middle-age up to 70 years was found in males, but not in females. Following age 70, a decline in PA was seen. Young adults reported both a higher proportion of sedentary behavior and a higher proportion high PA than the elderly. Females generally reported a lower PA at all ages. PA was mainly associated with serum triglycerides and HDL-cholesterol, but also weaker relationships with fasting glucose, blood pressure and BMI were found. These relationships were generally less strong in elderly subjects. CONCLUSION: Using data from multiple longitudinal samples the development of PA over the adult life span could be described in detail and the relationships between PA and cardiovascular risk factors were portrayed. In general, a higher or increased physical activity over time was associated with a more beneficial cardiovascular risk factor profile, especially lipid levels.

Type 2 Diabetes and Change in Total Hip Bone Area and Bone Mineral Density in Swedish Men and Women Older Than 55 Years.

CONTEXT: In a cross-sectional study, we found an association between type 2 diabetes mellitus (T2DM) and smaller bone area together with greater bone mineral density (BMD) at the total hip. OBJECTIVE: This work aims to investigate these associations longitudinally, by studying T2DM status (no T2DM n = 1521, incident T2DM n = 119, or prevalent T2DM n = 106) in relation to changes in total hip bone area and BMD. METHODS: In 3 cohorts, the Swedish Mammography Cohort Clinical (SMCC; n = 1060), Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 483), and Uppsala Longitudinal Study of Adult Men (ULSAM; n = 203), with repeat assessment of T2DM status and dual energy x-ray absorptiometry (DXA) measurements of total hip bone area and BMD on average 8 years apart, a linear regression model was used to assess the effect of T2DM status on change in bone area and BMD at the total hip. RESULTS: After meta-analysis, the change in bone area at the total hip was 0.5% lower among those with incident T2DM compared to those without T2DM (-0.18 cm2; 95% CI, -0.30 to -0.06). The change in bone area was similar among those with prevalent T2DM compared to those without (0.00 cm2; 95% CI, -0.13 to 0.13). For BMD, the combined estimate was 0.004 g/cm2 (95% CI, -0.006 to 0.014) among those with incident T2DM and 0.010 g/cm2 (95% CI, -0.000 to 0.020) among those with prevalent T2DM, compared to those without T2DM. CONCLUSION: Those with incident T2DM have a lower expansion in bone area at the total hip compared to those without T2DM.

Fracture risk across a wide range of physical activity levels, from sedentary individuals to elite athletes.

OBJECTIVE: To examine how physical activity is associated with risk of different fracture outcomes across the full range of physical activity. METHODS: By combining information from three cohort studies and using generalized structural equation modelling, we estimated a continuous unitless latent variable reflecting physical activity that ranged from sedentary through elite athlete levels. Associations between physical activity and fracture outcomes were assessed with proportional hazards regression using restricted cubic splines with the mean physical activity (corresponding to 20-40 min walking or bicycling/day or 2-3 h exercise/week) as reference. RESULTS: Among 63,980 men and women (49-68 years) and during 13 years of follow-up, 8506 fractures occurred, including 2164 distal forearm, 779 proximal humerus, 346 clinical spine, and 908 hip fractures. Both lower and higher physical activity was associated with higher risk of any fracture compared to the mean. Physical activity at 1 standard deviation (SD) below the mean, corresponding to walking/bicycling <20 min/day or exercising <1-1 h/week, was associated with a lower risk of distal forearm fracture (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.85-0.99) and higher risk of hip fracture (HR: 1.24, 95% CI: 1.13-1.37), but no associations were seen above the mean physical activity level for these fractures. Physical activity was not associated with proximal humerus fracture but had a possible U-shaped association with clinical spine fracture. CONCLUSION: Physical activity was non-linearly associated with fracture risk and the association differed across fracture sites. Up to 2-3 h weekly exercise is beneficial for the prevention of hip fracture but may increase the risk of distal forearm fracture.

Association between Cardiorespiratory Fitness and Circulating Proteins in 50-Year-Old Swedish Men and Women: a Cross-Sectional Study.

BACKGROUND AND AIMS: A strong cardiorespiratory fitness is suggested to have beneficial effects on cardiovascular risk; the exact mechanisms underlying the cardioprotective effects of fitness remain uncertain. Our aim was to investigate associations between cardiorespiratory fitness and multiple plasma proteins, in order to obtain insights about physiological pathways associated with the effects of exercise on cardiovascular health. METHODS: In the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n=444 adults aged 50 years, 50% women), cardiorespiratory fitness was measured by a maximal exercise test on bicycle ergometer with gas exchange (VO2peak) normalized for body lean mass (dual-energy X-ray absorptiometry (DXA)). We measured 82 cardiovascular proteins associated with cardiovascular pathology and inflammation in plasma samples with a proximity extension assay. RESULTS: In sex-adjusted linear regression, VO2peak was associated with 18 proteins after Bonferroni correction for multiple testing (p<0.0006). Following additional adjustment for fat mass (DXA), fasting glucose (mmol/L), low-density lipoprotein (LDL, mmol/L), smoking status, waist/hip ratio, blood pressure (mmHg), education level, and lpnr (lab sequence number), higher VO2peak was significantly associated with lower levels of 6 proteins: fatty-acid binding protein-4 (FABP4), interleukin-6 (IL-6), leptin, cystatin-B (CSTB), interleukin-1 receptor antagonist (IL-1RA), and growth differentiation factor 15 (GDF-15), and higher levels of 3 proteins: galanin, kallikrein-6 (KLK6), and heparin-binding EGF-like growth factor (HB-EGF), at nominal p-values (p<0.05). CONCLUSIONS: We identified multiple novel associations between cardiorespiratory fitness and plasma proteins involved in several atherosclerotic processes and key cellular mechanisms such as inflammation, energy homeostasis, and protease activity, which shed new light on how exercise asserts its beneficial effects on cardiovascular health. Our findings encourage additional studies in order to understand the underlying causal mechanisms for these associations.

Serum 25-hydroxyvitamin D is associated with fracture risk only during periods of seasonally high levels in women with a high body mass index.

Serum 25-hydroxyvitamin D (S-25OHD) is used to assess vitamin D status and is known to be affected by season and fat mass. Because these factors are often ignored when interpreting S-25OHD, assessment of vitamin D associations with disease outcomes may be distorted. We aimed to investigate the impact of season of blood draw and fat mass on the association of S25OHD with fracture risk. We enrolled 5000 women, mean ± SD age 68 ± 7 years, with dual-energy x-ray absorptiometry (DXA) scans and blood collection in a population-based cohort. Proportional hazards regression, stratified by season and fat mass, was used to determine hazard ratios (HRs) of fracture according to categories of S-25OHD. Our secondary exposures were serum 1,25-dihydroxycholecalciferol (1,25-(OH)2 D3 ), the most active vitamin D metabolite and plasma parathyroid hormone (P-PTH). During an average of 9.2 years of follow-up, 1080 women had a fracture. Women with S-25OHD <30 nmol/L drawn during sunny months (May-October) had a multivariable-adjusted fracture HR of 2.06 (95% CI, 1.27-3.35) compared with those with S-25OHD >60 nmol/L; those with S-25OHD 30-40 nmol/L had an HR of 1.59 (95% CI, 1.12-2.26). In contrast, S-25OHD drawn during November through April was unrelated to fracture risk. The increased risk with low sunny season S-25OHD was seen only among women with body mass index (BMI) ≥25 kg/m2 or fat mass index (FMI) ≥9.8 kg/m2 . High fat mass and low S-25OHD were independently related to lower S-1,25-dihydroxycholecalciferol, which itself predicted fracture risk with samples collected during the sunny season. Irrespective of season, P-PTH was unrelated to fracture risk. We conclude that S-25OHD is associated with fracture risk only if drawn during periods of seasonally high levels in women with a high BMI. These results have implications for the evaluation of vitamin D status and can explain the lack of effect seen with vitamin D supplementation in many fracture trials. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Prior loss of body mass index, low body mass index, and central obesity independently contribute to higher rates of fractures in elderly women and men.

We aimed to comprehensively evaluate the association of body composition with fracture risk using longitudinal data from a Swedish cohort of 44,366 women and men (mean age of 70 years) and a subcohort of 5022 women. We estimated hazard ratios (HRs) of fracture for baseline body mass index (BMI), BMI change during the prior 12 and 18 years, baseline waist-to-height ratio, total and regional distribution of fat and lean mass, with and without areal bone mineral density (BMD) adjustment. During follow-up (median 8.7 years), 7290 individuals sustained a fracture, including 4279 fragility fractures, of which 1813 were hip fractures. Higher baseline BMI and prior gain in BMI were inversely associated with all types of fracture. Lower fracture rate with higher baseline BMI was seen within every category of prior BMI change, whereas higher prior BMI gain conferred a lower rate of fracture within those with normal baseline BMI. Each standard deviation (SD) higher baseline waist-to-height ratio, after adjustment for BMI, was associated with higher rates of hip fracture in both women and men (HR 1.12; 95% CI, 1.05-1.19). In the subcohort (median follow-up 10 years), higher baseline fat mass index (FMI) and appendicular lean mass index (LMI) showed fracture-protective effects. After BMD adjustment, higher baseline BMI, total LMI, FMI, and higher prior BMI gain were associated with higher fracture rate. Baseline fat distribution also was associated with fracture rate; a 1-SD higher android to gynoid fat mass ratio in prior BMI gainers was associated with BMD-adjusted HRs of 1.16 (95% CI, 1.05-1.28) for any fracture and 1.48 (95% CI, 1.16-1.89) for hip fracture. This pattern was not observed among prior BMI losers. These findings indicate that for optimal fracture prevention, low baseline BMI, prior BMI loss and high baseline central obesity should be avoided in both women and men. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Fasting glucose, bone area and bone mineral density: a Mendelian randomisation study.

AIMS/HYPOTHESIS: Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip. METHODS: We selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10-8) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men. RESULTS: In a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (-0.67 cm2 [95% CI -1.30, -0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm2 [95% CI -0.00, 0.07; p = 0.060]). CONCLUSIONS/INTERPRETATION: Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings.