Anna Nordström

Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden

Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P < 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6 kg) and had more total (+2.4 kg), gynoid (+191 g) and abdominal (+136 g) adipose tissue than those in the lowest quintile (all P < 0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n = 193/594 cases/controls) being at 1.55-fold (95% CI 1.21–1.99; P < 0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n = 130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.

Bone Loss and Fracture Risk After Reduced Physical Activity

Former male young athletes partially lost benefits in BMD (g/cm2) with cessation of exercise, but, despite this, had a higher BMD 4 years after cessation of career than a control group. A higher BMD might contribute to the lower incidence of fragility fractures found in former older athletes ⩾60 years of age compared with a control group.

Abdominal and Gynoid Fat Mass Are Associated with Cardiovascular Risk Factors in Men and Women

CONTEXT Abdominal obesity is an established risk factor for cardiovascular disease (CVD). However, the correlation of dual-energy x-ray absorptiometry (DEXA) measurements of regional fat mass with CVD risk factors has not been completely investigated. OBJECTIVE The aim of this study was to investigate the association of estimated regional fat mass, measured with DEXA and CVD risk factors. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study of 175 men and 417 women. DEXA measurements of regional fat mass were performed on all subjects, who subsequently participated in a community intervention program. MAIN OUTCOME MEASURES Outcome measures included impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, and hypertension. RESULTS We began by assessing the associations of the adipose measures with the cardiovascular outcomes. After adjustment for confounders, a sd unit increase in abdominal fat mass was the strongest predictor of most cardiovascular variables in men [odds ratio (OR)=2.63-3.37; P<0.05], whereas the ratio of abdominal to gynoid fat mass was the strongest predictor in women (OR=1.48-2.19; P<0.05). Gynoid fat mass was positively associated with impaired glucose tolerance, hypertriglyceridemia, and hypertension in men (OR=2.07-2.15; P<0.05), whereas the ratio of gynoid to total fat mass showed a negative association with hypertriglyceridemia and hypertension (OR=0.42-0.62; P<0.005). CONCLUSIONS Abdominal fat mass is strongly independently associated with CVD risk factors in the present study. In contrast, gynoid fat mass was positively associated, whereas the ratio of gynoid to total fat mass was negatively associated with risk factors for CVD.

Traumatic brain injury and young onset dementia: A nationwide cohort study

To investigate the association between traumatic brain injuries (TBIs) and the risk of young onset dementia (YOD), that is, dementia before 65 years of age.

Length of hospital stay after hip fracture and short term risk of death after discharge: a total cohort study in Sweden

Objective To investigate relation between inpatient length of stay after hip fracture and risk of death after hospital discharge. Setting Population ≥50 years old living in Sweden as of 31 December 2005 with a first hip fracture the years 2006-12. Participants 116 111 patients with an incident hip fracture from a closed nationwide cohort. Main outcome measure Death within 30 days of hospital discharge in relation to hospital length of stay after adjustment for multiple covariates. Results Mean inpatient length of stay after a hip fracture decreased from 14.2 days in 2006 to 11.6 days in 2012 (P<0.001). The association between length of stay and risk of death after discharge was non-linear (P<0.001), with a threshold for this non-linear effect of about 10 days. Thus, for patients with length of stay of ≤10 days (n=59 154), each 1-day reduction in length of stay increased the odds of death within 30 days of discharge by 8% in 2006 (odds ratio 1.08 (95% confidence interval 1.04 to 1.12)), which increased to16% in 2012 (odds ratio 1.16 (1.12 to 1.20)). In contrast, for patients with a length of stay of ≥11 days (n=56 957), a 1-day reduction in length of stay was not associated with an increased risk of death after discharge during any of the years of follow up. Limitations No accurate evaluation of the underlying cause of death could be performed. Conclusion Shorter length of stay in hospital after hip fracture is associated with increased risk of death after hospital discharge, but only among patients with length of stay of 10 days or less. This association remained robust over consecutive years.

Sports-related concussion increases the risk of subsequent injury by about 50% in elite male football players

Background Little is known about the short-term and long-term sequelae of concussion, and about when athletes who have sustained such injuries can safely return to play. Purpose To examine whether sports-related concussion increases the risk of subsequent injury in elite male football players. Study design Prospective cohort study. Methods Injuries were registered for 46 male elite football teams in 10 European countries in the 2001/2002–2011/2102 seasons. Two survival models were used to analyse whether concussion increased the subsequent risk of an injury in the first year. Results During the follow-up period, 66 players sustained concussions and 1599 players sustained other injuries. Compared with the risk following other injuries, concussion was associated with a progressively increased risk of a subsequent injury in the first year (0 to <3 months, HR=1.56, 95% CI 1.09 to 2.23; 3 to <6 months, HR=2.78, 95% CI 1.58 to 4.89; 6–12 months, HR=4.07, 95% CI 2.14 to 7.76). In the second model, after adjustment for the number of injuries in the year preceding the concussion, this injury remained significantly associated with the risk of subsequent injury in the first year (HR=1.47, 95% CI 1.05 to 2.05). Conclusions Concussion was a risk factor for sustaining subsequent injury within the following year. In-depth medical evaluation, which includes neurological and cognitive assessment, is warranted within the concussion management and return-to- play process.

High aerobic fitness in late adolescence is associated with a reduced risk of myocardial infarction later in life: a nationwide cohort study in men

AIMS Cardiovascular disease is the leading cause of morbidity and mortality worldwide, and signs of atherosclerosis are present in all large arteries already in adolescence. We investigated the association between high physical fitness in late adolescence and myocardial infarction (MI) later in life. METHODS AND RESULTS The study cohort comprised 743 498 Swedish men examined at the age of 18 years during conscription 1969-84. Aerobic fitness (Wmax) and muscle strength at conscription were measured using standardized methods. Myocardial infarctions occurring in the cohort were tracked through national registers. During a median follow-up period of 34 years, 11 526 MIs were registered in the cohort. After adjusting for age, body mass index (BMI), diseases, education, blood pressure, and socio-economic factors, one standard deviation increase in the level of physical fitness (Wmax) was associated with an 18% decreased risk of later MI [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.80-0.85]. The beneficial effects of Wmax were significant across all recognized BMI groups, ranging from lean (BMI < 18.5) to obese (BMI > 30) (P < 0.05 for all). However, obese men (BMI > 30) in the highest fourth of Wmax had a higher risk of MI than did lean men (BMI < 18.5) in the highest (HR 4.6, 95% CI 1.9-11.2), and lowest (HR 1.7, 95% CI 1.2-2.6) fourth of Wmax. CONCLUSIONS We report a significant graded association between aerobic fitness in late adolescence and MI later in life in men. However, obese men with a high aerobic fitness had a higher risk of MI than lean men with a low aerobic fitness.

Risk Factors in Late Adolescence for Young-Onset Dementia in Men: A Nationwide Cohort Study

IMPORTANCE Young-onset dementia (YOD), that is, dementia diagnosed before 65 years of age, has been related to genetic mutations in affected families. The identification of other risk factors could improve the understanding of this heterogeneous group of syndromes. OBJECTIVE To evaluate risk factors in late adolescence for the development of YOD later in life. DESIGN We identified the study cohort from the Swedish Military Service Conscription Register from January 1, 1969, through December 31, 1979. Potential risk factors, such as cognitive function and different physical characteristics, were assessed at conscription. We collected other risk factors, including dementia in parents, through national register linkage. PARTICIPANTS All Swedish men conscripted for mandatory military service (n=488,484) with a mean age of 18 years. SETTING Predominantly Swedish men born from January 1, 1950, through December 31, 1960. EXPOSURE Potential risk factors for dementia based on those found in previous studies, data available, and quality of register data. MAIN OUTCOMES AND MEASURE All forms of YOD. RESULTS During a median follow-up of 37 years, 487 men were diagnosed as having YOD at a median age of 54 years. In multivariate Cox regression analysis, significant risk factors (all P< .05) for YOD included alcohol intoxication (hazard ratio, 4.82 [95% CI, 3.83-6.05]); population-attributable risk, 0.28), stroke (2.96 [2.02-4.35]; 0.04), use of antipsychotics (2.75 [2.09-3.60]; 0.12), depression (1.89 [1.53-2.34]; 0.28), fathers dementia (1.65 [1.22-2.24]; 0.04), drug intoxication other than alcohol (1.54 [1.06-2.24]; 0.03), low cognitive function at conscription (1.26 per 1-SD decrease [1.14-1.40]; 0.29), low height at conscription (1.16 per 1-SD decrease [1.04-1.29]; 0.16), and high systolic blood pressure at conscription (0.90 per 1-SD decrease [0.82-0.99]; 0.06). The population-attributable risk associated with all 9 risk factors was 68%. Men with at least 2 of these risk factors and in the lowest third of overall cognitive function were found to have a 20-fold increased risk of YOD during follow-up (hazard ratio, 20.38 [95% CI, 13.64-30.44]). CONCLUSIONS AND RELEVANCE In this nationwide cohort, 9 independent risk factors were identified that accounted for most cases of YOD in men. These risk factors were multiplicative, most were potentially modifiable, and most could be traced to adolescence, suggesting excellent opportunities for early prevention.

Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women

Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (−174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (β=−0.07; P=0.03) and BUA (β=−0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08–1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004–1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14–2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05–2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position –174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.

Low Bone Mineral Density Is an Independent Risk Factor for Stroke and Death

Background: Recent studies suggest a relationship between atherosclerotic disease and osteoporosis. The aim of the study was to investigate whether bone mineral density (BMD) was prospectively related to stroke and death. Methods: BMD (g/cm2) was measured in 4,302 men and women (mean age 59 years, range 40–75) at baseline. The main outcome measures included validated strokes and death. Results: After a mean follow-up time of 5.6 years (range 0–15.8 years), 139 strokes were registered and 224 subjects had died. After adjustment for age, sex and body mass index, decreased femoral neck BMD and osteoporosis were found to be independent predictors of stroke (hazard ratio, HR, for each standard deviation decrease in BMD = 1.23, 95% CI = 1.01–1.49, and HR for osteoporosis = 1.92, 95% CI = 1.11–3.30). After adjustment for the same variables, the risk of death during follow-up was related to femoral neck BMD (HR = 1.41, 95% CI = 1.21–1.64) and osteoporosis at baseline (HR = 2.05, 95% CI = 1.28–3.29). Adjustment also for smoking, hypertension, hyperlipidemia and diabetes did not change any of these results. Conclusions: We found that decreased BMD as well as osteoporosis of the femoral neck are independently associated with stroke and death. Given the impact of osteoporosis and stroke on morbidity and mortality, this relationship is of high interest for further studies.