Does the risk of chronic low back pain depend on age at menarche or menopause? A population-based cross-sectional and cohort study: the Trøndelag Health Study

Objective In most population-based studies of low back pain (LBP), women have a higher risk than men, possibly reflecting hormonal influences. The aim of this study was to explore associations between age at menarche and menopause and risk of chronic LBP. Design Population-based cross-sectional and cohort study designs. Setting The HUNT2 and HUNT3 medical surveys of the entire population of Nord-Trøndelag County in Norway. Main outcome measure Prevalence or risk of chronic LBP, defined as LBP persisting at least 3 months continuously during last year. Participants Associations between age at menarche and prevalence of chronic LBP were examined in cross-sectional data from HUNT2, comprising 27 697 women aged 20–69 years, with 7300 women reporting LBP. The corresponding cohort data included 11 659 women without LBP at baseline in HUNT2, with 2353 women reporting LBP at follow-up 11 years later in HUNT3. Cross-sectional data on age at menopause or premenopausal status included 11 332 women aged 40–69 years, with 3439 women reporting chronic LBP. Corresponding cohort data included 7893 women without LBP at baseline, of whom 1100 developed LBP. Methods Associations between age at menarche or menopause and risk of chronic LBP were examined by generalised linear modelling. Results A U-shaped association was indicated between age at menarche and risk of chronic LBP, both in the cross-sectional and cohort studies. Age at menarche ≤11 years was associated with an increased risk of chronic LBP, with a relative risk of 1.32 (95% CI 1.15 to 1.52), compared with age 14 years at menarche, after relevant adjustments. Corresponding cross-sectional crude absolute risks were 32% and 25%, respectively. No association was established between age at menopause and risk of LBP. Being premenopausal had no influence on risk. Conclusions In contrast to results for age at menopause, the association with age at menarche suggests that hormonal factors affect the risk of LBP.publishedVersio

Genetic Risk Score for Intracranial Aneurysms:Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10(-3) per year [95% CI, -6.49×10(-3) to -3.14×10(-3)]; P=1.82×10(-8)), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

A Comparison of Anthropometric Measures for Assessing the Association between Body Size and Risk of Chronic Low Back Pain: TheHUNT Study

Background: Previous work indicates that overweight and obese individuals carry an increased risk of experiencing chronic low back pain (LBP). It is not known, however, how the association with body size depends on the choice of anthropometric measure used. Objective: This work compares relationships with LBP for several measures of body size. Different results may indicate underlying mechanisms for the association between body size and risk of LBP. Methods: In a cohort study, baseline information was collected in the community-based HUNT2 (1995&ndash;1997) and HUNT3 (2006&ndash;2008) surveys in Norway. Participants were 10,059 women and 8725 men aged 30&ndash;69 years without LBP, and 3883 women and 2662 men with LBP at baseline. Associations with LBP at end of follow-up were assessed by generalized linear modeling, with adjustment for potential confounders. Results: Relationships between waist-hip-ratio and occurrence of LBP at end of follow-up were weak and non-significant after adjustment for age, education, work status, physical activity, smoking, lipid levels and blood pressure. Positive associations with LBP at end of follow-up were all significant for body weight, BMI, waist circumference and hip circumference after similar adjustment, both in women without and with LBP at baseline, and in men without LBP at baseline. After additional mutual adjustment for anthropometric measures, the magnitude of the association with body weight increased in women without LBP at baseline (RR: 1.130 per standard deviation, 95% CI: 0.995&ndash;1.284) and in men (RR: 1.124, 95% CI 0.976&ndash;1.294), with other measures showing weak associations only. Conclusion: Central adiposity is unlikely to play a major role in the etiology of LBP. Total fat mass may be one common factor underlying the associations observed. The association with body weight remaining after mutual adjustment may reflect mechanical or structural components behind the relationship between overweight or obesity and LBP

Is there a U-shaped relationship between physical activity in leisure time and risk of chronic low back pain? A follow-up in the HUNT Study

Background Physical activity in leisure time is often considered to have favourable effects on the risk of low back pain (LBP), but demonstrating a definite association in epidemiological studies has proven difficult. The purpose of the present study was to explore associations between physical activity and risk of chronic LBP in an adult population and to investigate whether relationships are limited to certain age groups or to females or males. A particular objective was to determine whether support could be found for a U-shaped relationship, with both low and high activity levels carrying greater risk. Methods The relationship between physical activity and risk of chronic LBP was examined in a Norwegian prospective study using data from the community-based HUNT2 and HUNT3 surveys. Participants were 9616 women and 8452 men without LBP at baseline, who reported after 11 years whether they suffered from LBP. Associations between baseline physical activity in leisure time and risk of chronic LBP at end of follow-up were evaluated by generalized linear modelling with adjustment for potential confounders. Results Significant associations between leisure time physical activity and risk were observed in both sexes after age adjustment, mainly suggesting inverse relationships. Women participating in hard physical activity 1–2 h per week had a relative risk (RR) of chronic LBP of 0.81 (95 % CI 0.71–0.93) compared to those with only light physical activity less than 1 h per week. The corresponding RR in men was 0.71 (95 % CI 0.60–0.85). After adjustment for education, employment, occupational activity, body mass index (BMI) and smoking, significant relationships could only be demonstrated in those aged 50 years or more at baseline. The associations differed between female educational groups, with more U-shaped relationships being observed among women with basic education only. Conclusion No strong support was found overall for U-shaped relationships. However, no further general decrease in risk was seen among those with 3 h or more of hard physical activity per week. The contrasts observed between female educational groups may reflect different preferences regarding specific strenuous activities. Men aged 50 years or more seem in particular to benefit from hard physical activities

Do abnormal serum lipid levels increase the risk of chronic low back pain? The Nord-Trøndelag Health Study

Background: Cross-sectional studies suggest associations between abnormal lipid levels and prevalence of low back pain (LBP), but it is not known if there is any causal relationship. Objective: The objective was to determine, in a population-based prospective cohort study, whether there is any relation between levels of total cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides and the probability of experiencing subsequent chronic (LBP), both among individuals with and without LBP at baseline. Methods: Information was collected in the community-based HUNT 2 (1995–1997) and HUNT 3 (2006–2008) surveys of an entire Norwegian county. Participants were 10,151 women and 8731 men aged 30–69 years, not affected by chronic LBP at baseline, and 3902 women and 2666 men with LBP at baseline. Eleven years later the participants indicated whether they currently suffered from chronic LBP. Results: Among women without LBP at baseline, HDL cholesterol levels were inversely associated and triglyceride levels positively associated with the risk of chronic LBP at end of follow-up in analyses adjusted for age only. Adjustment for the baseline factors education, work status, physical activity, smoking, blood pressure and in particular BMI largely removed these associations (RR: 0.96, 95% CI: 0.85–1.07 per mmol/l of HDL cholesterol; RR: 1.16, 95% CI: 0.94–1.42 per unit of lg(triglycerides)). Total cholesterol levels showed no associations. In women with LBP at baseline and men without LBP at baseline weaker relationships were observed. In men with LBP at baseline, an inverse association with HDL cholesterol remained after complete adjustment (RR: 0.83, 95% CI: 0.72–0.95 per mmol/l). Conclusion: Crude associations between lipid levels and risk of subsequent LBP in individuals without current LBP are mainly caused by confounding with body mass. However, an association with low HDL levels may still remain in men who are already affected and possibly experience a higher pain intensity

Do abnormal serum lipid levels increase the risk of chronic low back pain? The Nord-Trøndelag Health Study

Background: Cross-sectional studies suggest associations between abnormal lipid levels and prevalence of low back pain (LBP), but it is not known if there is any causal relationship. Objective: The objective was to determine, in a population-based prospective cohort study, whether there is any relation between levels of total cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides and the probability of experiencing subsequent chronic (LBP), both among individuals with and without LBP at baseline. Methods: Information was collected in the community-based HUNT 2 (1995–1997) and HUNT 3 (2006–2008) surveys of an entire Norwegian county. Participants were 10,151 women and 8731 men aged 30–69 years, not affected by chronic LBP at baseline, and 3902 women and 2666 men with LBP at baseline. Eleven years later the participants indicated whether they currently suffered from chronic LBP. Results: Among women without LBP at baseline, HDL cholesterol levels were inversely associated and triglyceride levels positively associated with the risk of chronic LBP at end of follow-up in analyses adjusted for age only. Adjustment for the baseline factors education, work status, physical activity, smoking, blood pressure and in particular BMI largely removed these associations (RR: 0.96, 95% CI: 0.85–1.07 per mmol/l of HDL cholesterol; RR: 1.16, 95% CI: 0.94–1.42 per unit of lg(triglycerides)). Total cholesterol levels showed no associations. In women with LBP at baseline and men without LBP at baseline weaker relationships were observed. In men with LBP at baseline, an inverse association with HDL cholesterol remained after complete adjustment (RR: 0.83, 95% CI: 0.72–0.95 per mmol/l). Conclusion: Crude associations between lipid levels and risk of subsequent LBP in individuals without current LBP are mainly caused by confounding with body mass. However, an association with low HDL levels may still remain in men who are already affected and possibly experience a higher pain intensity

Physical activity level at work and risk of chronic low back pain: A follow-up in the Nord-Trøndelag Health Study

Background Physical activity in leisure time seems to reduce the risk of low back pain, but it is not known whether occupational activity, as recorded in a representative working population, produces a higher or lower risk. Objective To study associations between physical activity level at work and risk of chronic low back pain. Methods Associations were examined in a Norwegian prospective study using data from the HUNT2 and HUNT3 surveys carried out in the whole county of Nord-Trøndelag. Participants were 7580 women and 7335 men who supplied information about physical activity level at work. Levels considered were sedentary work, work involving walking but no heavy lifting, work involving walking and heavy lifting, and particularly strenuous physical work. Nobody in the cohort was affected by chronic low back pain at baseline. After 11 years, participants reported whether they suffered from chronic low back pain. Generalized linear modelling with adjustment for potential confounders was applied to assess associations with risk factors. Results In age-adjusted analyses both women and men showed statistically significant associations between physical activity at work and risk of chronic low back pain, suggesting positive relationships. For particularly strenuous physical work the relative risk of chronic low back pain was 1.30 (95% CI: 1.00–1.71) in women and 1.36 (95% CI 1.17–1.59) in men, compared to sedentary work. Women still showed a general association with activity level after adjustment for education, leisure time physical activity, BMI, smoking and occupational category. In men, the higher risk was only maintained for particularly strenuous work. Conclusion In this cohort, women had a higher risk of chronic low back pain with work involving walking and heavy lifting or particularly strenuous work, compared to sedentary work. Men participating in particularly strenuous work also experienced a higher risk of chronic low back pain

Physical activity level at work and risk of chronic low back pain: A follow-up in the Nord-Trøndelag Health Study

Background: Physical activity in leisure time seems to reduce the risk of low back pain, but it is not known whether occupational activity, as recorded in a representative working population, produces a higher or lower risk. Objective: To study associations between physical activity level at work and risk of chronic low back pain. Methods: Associations were examined in a Norwegian prospective study using data from the HUNT2 and HUNT3 surveys carried out in the whole county of Nord-Tr&oslash;ndelag. Participants were 7580 women and 7335 men who supplied information about physical activity level at work. Levels considered were sedentary work, work involving walking but no heavy lifting, work involving walking and heavy lifting, and particularly strenuous physical work. Nobody in the cohort was affected by chronic low back pain at baseline. After 11 years, participants reported whether they suffered from chronic low back pain. Generalized linear modelling with adjustment for potential confounders was applied to assess associations with risk factors. Results: In age-adjusted analyses both women and men showed statistically significant associations between physical activity at work and risk of chronic low back pain, suggesting positive relationships. For particularly strenuous physical work the relative risk of chronic low back pain was 1.30 (95% CI: 1.00&ndash;1.71) in women and 1.36 (95% CI 1.17&ndash;1.59) in men, compared to sedentary work. Women still showed a general association with activity level after adjustment for education, leisure time physical activity, BMI, smoking and occupational category. In men, the higher risk was only maintained for particularly strenuous work. Conclusion: In this cohort, women had a higher risk of chronic low back pain with work involving walking and heavy lifting or particularly strenuous work, compared to sedentary work. Men participating in particularly strenuous work also experienced a higher risk of chronic low back pain