Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson’s disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

The prevalence of obesity in childhood and adolescence has increased worldwide. Long-term effects of adolescent obesity on cause-specific mortality are not well specified. The authors studied 227,000 adolescents (aged 14-19 years) measured (height and weight) in Norwegian health surveys in 1963-1975. During follow-up (8 million person-years), 9,650 deaths were observed. Cox proportional hazards regression was used to compare cause-specific mortality among individuals whose baseline body mass index (BMI) was below the 25th percentile, between the 75th and 84th percentiles, and above the 85th percentile in a US reference population with that of individuals whose BMI was between the 25th and 75th percentiles. Risk of death from endocrine, nutritional, and metabolic diseases and from circulatory system diseases was increased in the two highest BMI categories for both sexes. Relative risks of ischemic heart disease death were 2.9 (95% confidence interval (CI): 2.3, 3.6) for males and 3.7 (95% CI: 2.3, 5.7) for females in the highest BMI category compared with the reference. There was also an increased risk of death from colon cancer (males: 2.1, 95% CI: 1.1, 4.1; females: 2.0, 95% CI: 1.2, 3.5), respiratory system diseases (males: 2.7, 95% CI: 1.4, 5.2; females: 2.5, 95% CI: 1.4, 4.8), and sudden death (males: 2.2, 95% CI: 1.2, 4.3; females: 2.7, 95% CI: 1.1, 6.6). Adolescent obesity was related to increased mortality in middle age from several important causes.

Summary Background Elevated blood pressure and glucose, serum cholesterol, and body mass index (BMI) are risk factors for cardiovascular diseases (CVDs); some of these factors also increase the risk of chronic kidney disease (CKD) and diabetes. We estimated CVD, CKD, and diabetes mortality attributable to these four cardio-metabolic risk factors for all countries and regions between 1980 and 2010. Methods We used data on risk factor exposure by country, age group, and sex from pooled analysis of population-based health surveys. Relative risks for cause-specific mortality were obtained from pooling of large prospective studies. We calculated the population attributable fractions (PAF) for each risk factor alone, and for the combination of all risk factors, accounting for multi-causality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific PAFs by the number of disease-specific deaths from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all inputs to the final estimates. Findings In 2010, high blood pressure was the leading risk factor for dying from CVDs, CKD, and diabetes in every region, causing over 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths; and cholesterol for 10%. After accounting for multi-causality, 63% (10.8 million deaths; 95% confidence interval 10.1–11.5) of deaths from these diseases were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7.1 million deaths; 6.6–7.6) in 1980. The mortality burden of high BMI and glucose nearly doubled between 1980 and 2010. At the country level, age-standardised death rates attributable to these four risk factors surpassed 925 deaths per 100,000 among men in Belarus, Mongolia, and Kazakhstan, but were below 130 deaths per 100,000 for women and below 200 for men in some high-income countries like Japan, Singapore, South Korea, France, Spain, The Netherlands, Australia, and Canada. Interpretations The salient features of the cardio-metabolic epidemic at the beginning of the twenty-first century are the large role of high blood pressure and an increasing impact of obesity and diabetes. There has been a shift in the mortality burden from high-income to low- and middle-income countries.