The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Post-Transcriptional Nature of Uremia-induced Down-Regulation of hepatic Apolipoprotein A-I production

CKD is associated with premature death from cardiovascular disease which is, in part, driven by HDL deficiency and dysfunction. One of the main causes of HDL deficiency in CKD is diminished plasma apoliprotein A-I level. Plasma ApoA-I is reduced in dialysis patients and hepatic ApoA-I mRNA is decreased in the uremic rats. This study explored the mechanism of uremia-induced down-regulation of ApoA-I. HepG2 cells were incubated in media containing whole plasma or plasma subfractionation from normal subjects and ESRD patients pre- and post-hemodialysis. Cells and culture media were isolated to measure ApoA-I protein and mRNA. ApoA-I promoter activity was measured using transfection with a luciferase promoter construct containing the −2096 to +293 segment of ApoA-I gene. Finally effect of uremic and control plasma was assessed on ApoA-I RNA stability. Exposure to uremic plasma significantly reduced ApoA-I mRNA expression and ApoA-I protein production. These effects were reversed by replacing uremic plasma with normal plasma. While no difference in ApoA-I promoter activity was found between cells exposed to uremic and normal plasma, uremic plasma significantly reduced ApoA-I RNA stability. Experiments using plasma sub-fractions revealed that the inhibitory effect of uremic plasma on ApoA-I mRNA expression resides in fractions containing molecules larger but not smaller than 30kd. The pre- and post-dialysis plasma exerted an equally potent inhibitory effect on ApoA-I mRNA abundance.Uremia lowers ApoA-I production by reducing its RNA stability. The inhibitory effect of uremic milieu on ApoA-I mRNA expression is mediated by non-dialyzable molecule(s) larger than 30 kd

Post-Transcriptional Nature of Uremia-induced Down-Regulation of hepatic Apolipoprotein A-I production

CKD is associated with premature death from cardiovascular disease which is, in part, driven by HDL deficiency and dysfunction. One of the main causes of HDL deficiency in CKD is diminished plasma apoliprotein A-I level. Plasma ApoA-I is reduced in dialysis patients and hepatic ApoA-I mRNA is decreased in the uremic rats. This study explored the mechanism of uremia-induced down-regulation of ApoA-I. HepG2 cells were incubated in media containing whole plasma or plasma subfractionation from normal subjects and ESRD patients pre- and post-hemodialysis. Cells and culture media were isolated to measure ApoA-I protein and mRNA. ApoA-I promoter activity was measured using transfection with a luciferase promoter construct containing the −2096 to +293 segment of ApoA-I gene. Finally effect of uremic and control plasma was assessed on ApoA-I RNA stability. Exposure to uremic plasma significantly reduced ApoA-I mRNA expression and ApoA-I protein production. These effects were reversed by replacing uremic plasma with normal plasma. While no difference in ApoA-I promoter activity was found between cells exposed to uremic and normal plasma, uremic plasma significantly reduced ApoA-I RNA stability. Experiments using plasma sub-fractions revealed that the inhibitory effect of uremic plasma on ApoA-I mRNA expression resides in fractions containing molecules larger but not smaller than 30kd. The pre- and post-dialysis plasma exerted an equally potent inhibitory effect on ApoA-I mRNA abundance.Uremia lowers ApoA-I production by reducing its RNA stability. The inhibitory effect of uremic milieu on ApoA-I mRNA expression is mediated by non-dialyzable molecule(s) larger than 30 kd

Supplementary Material for: Chronic Kidney Disease Results in Deficiency of ABCC6, the Novel Inhibitor of Vascular Calcification

<b><i>Background:</i></b> Chronic kidney disease (CKD) is associated with arterial medial calcification which plays a major role in the pathogenesis of cardiovascular disease in this population. Several factors are known to promote soft tissue and accelerated arterial calcification in CKD including systemic inflammation, altered calcium and phosphate homeostasis, hypertension, and deficiency of endogenous calcification inhibitors. The ABCC6 transporter (ATP-binding cassette subfamily C number 6), also known as multidrug resistance-associated protein 6 (MRP6), is highly expressed in the liver and kidney. Mutation of <i>ABCC6</i> results in pseudoxanthoma elasticum, an inherited disorder characterized by arterial and soft tissue calcification. Given the prevalence of arterial medial calcification in CKD, the present study was undertaken to test the hypothesis that CKD may lead to acquired ABCC6 deficiency. <b><i>Methods:</i></b> CKD was induced via 5/6 nephrectomy in male Sprague-Dawley rats and by adenine-containing diet to cause chronic interstitial nephropathy in female DBA/2J mice. Sham-operated rats and mice fed regular diet served as controls. Liver and kidney tissues were harvested and processed for ABCC6 protein and mRNA analysis. <b><i>Results:</i></b> ABCC6 protein levels were significantly reduced in the liver and kidney tissues from CKD rats and mice. However, ABCC6 mRNA levels were unchanged, pointing to post-transcriptional or post-translational mechanisms for the observed ABCC6 deficiency. Additionally, plasma levels of the calcification inhibitor fetuin-A were significantly decreased in CKD animals compared to controls. <b><i>Conclusions:</i></b> CKD results in acquired ABCC6 transporter deficiency. To our knowledge this abnormality has not been previously reported and may contribute to CKD-associated vascular and soft tissue calcification