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BACKGROUND: Observational studies have suggested that the gut hormone ghrelin is an early marker of future risk of developing gastrointestinal cancer. However, whether ghrelin is a causal risk factor remains unclear. We conducted a genome-wide association study (GWAS) of plasma ghrelin and used Mendelian randomization (MR) to investigate the possible causal association between ghrelin and gastrointestinal cancer risk. METHODS: Genetic variants associated with plasma ghrelin were identified in a GWAS comprising 10 742 Swedish adults in the discovery (N=6259) and replication (N=4483) cohorts. The association between ghrelin and gastrointestinal cancer was examined through a two-sample MR analysis using the identified genetic variants as instruments and GWAS data from the UK Biobank, FinnGen, and a colorectal cancer consortium. RESULTS: GWAS found associations between multiple genetic variants within ±200 kb of the GHRL gene and plasma ghrelin. A two-sample MR analysis revealed that genetically predicted higher plasma ghrelin levels were associated with a lower risk of gastrointestinal cancer in UK Biobank and in a meta-analysis of the two studies. The combined odds ratio per approximate doubling of genetically predicted plasma ghrelin was 0.91 (95% confidence interval, 0.85-0.99; P=0.02). Colocalization analysis revealed limited evidence of shared causal variants for plasma ghrelin and gastrointestinal cancer at the GHRL locus (posterior probability H4=24.5%); however, this analysis was likely underpowered. CONCLUSIONS: Our study provides evidence in support of a possible causal association between higher plasma ghrelin levels and a reduced risk of gastrointestinal cancer. IMPACT: Elevated plasma ghrelin levels might reduce the risk of gastrointestinal cancer.

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.

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 beha

Background It is unclear whether the effect on mortality of a higher body mass index (BMI) can be compensated for by adherence to a healthy diet and whether the effect on mortality by a low adherence to a healthy diet can be compensated for by a normal weight. We aimed to evaluate the associations of BMI combined with adherence to a Mediterranean-like diet on all-cause and cardiovascular disease (CVD) mortality. Methods and findings Our longitudinal cohort design included the Swedish Mammography Cohort (SMC) and the Cohort of Swedish Men (COSM) (1997–2017), with a total of 79,003 women (44%) and men (56%) and a mean baseline age of 61 years. BMI was categorized into normal weight (20–24.9 kg/m2), overweight (25–29.9 kg/m2), and obesity (30+ kg/m2). Adherence to a Mediterranean-like diet was assessed by means of the modified Mediterranean-like diet (mMED) score, ranging from 0 to 8; mMED was classified into 3 categories (0 to <4, 4 to <6, and 6–8 score points), forming a total of 9 BMI × mMED combinations. We identified mortality by use of national Swedish registers. Cox proportional hazard models with time-updated information on exposure and covariates were used to calculate the adjusted hazard ratios (HRs) of mortality with their 95% confidence intervals (CIs). Our HRs were adjusted for age, baseline educational level, marital status, leisure time physical exercise, walking/cycling, height, energy intake, smoking habits, baseline Charlson’s weighted comorbidity index, and baseline diabetes mellitus. During up to 21 years of follow-up, 30,389 (38%) participants died, corresponding to 22 deaths per 1,000 person-years. We found the lowest HR of all-cause mortality among overweight individuals with high mMED (HR 0.94; 95% CI 0.90, 0.98) compared with those with normal weight and high mMED. Using the same reference, obese individuals with high mMED did not experience significantly higher all-cause mortality (HR 1.03; 95% CI 0.96–1.11). In contrast, compared with t

Atypical femoral fractures are burdened with a high rate of reoperation. In our nationwide analysis, the increased rate of reoperation was related to patient background characteristics, such as age and health status, rather than fracture type. Introduction Patients with atypical fractures are complex to treat and burdened with a high risk of reoperation. We hypothesized that patients with surgically treated, complete atypical fractures have a higher risk of any reoperation and reoperation related to healing complications than patients with common femoral shaft fractures but that this increase would become insignificant when adjusted for predefined characteristics. Methods A cohort of 163 patients with atypical fractures and 862 patients with common femoral shaft or subtrochanteric fractures treated from 2008 to 2010 and who had follow-up radiographs and register data available until 31 December 2014 was included. Reoperations were identified by a complementary review of radiographs and register data and were used to calculate risks for any reoperation and reoperations related to healing complications. Results Patients with atypical fractures were more likely to be reoperated for any reason, age-adjusted OR 1.76 (95% CI, 1.08 to 2.86). However, patients with common fractures had a shorter follow-up due to a threefold higher death rate. Accordingly, in a multivariable-adjusted time-to-event model, the increased risk lost statistical significance for any reoperations, cause-specific HR 1.34 (95% CI, 0.85 to 2.13), and for reoperations related to healing complications, HR 1.32 (95% CI, 0.58 to 3.0). Continued use of bisphosphonate in the first year after the fracture did not affect the reoperation rate. Conclusions Our findings suggest that the increased risk of reoperation after an atypical femur fracture is largely explained by patient characteristics and not fracture type.

Objective: Co-aggregation of autoimmune diseases is common, suggesting pa rtly shared etiologies. Genetic factors are believed to be important, but objective measures of environ mental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at esti mating heritability and genetic overlap in seven organspecific autoimmune diseases. Design: Prospective twin cohort study. Methods: We used a cohort of 110 814 twins to examine co-aggregation an d heritability of Hashimoto's thyroiditis, atrophic gastritis, celiac disease, Graves' disease, type 1 dia betes, vitiligo and Addison's disease. Hazard ratios (HR) were calculated for twins developing the same or different disea se as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estim ate the genetic influence on co- aggregation. Heritability for individual disorders was calculated using stru ctural equational modeling adjusting for censoring and truncation of data. Results: Co-aggregation was more pronounced in monozygotic twins (media n HR: 3.2, range: 2.2-9.2) than in dizygotic twins (median HR: 2.4, range: 1.1-10.0). Heritability was moder ate for atrophic gastritis (0.38, 95% CI: 0.23-0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49-0. 71) for Graves' disease to 0.97 (95% CI: 0.91- 1.00) for Addison's disease. Conclusions: Overall, co-aggregation was more pronounced in monozygotic tha n in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co- aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our r esults validate and refine previous heritability estimates based on smaller twin cohorts.