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Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length
(2020)
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length
(2020)
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
High-energy radiation is used in combination with radiosensitizing therapeutics to treat cancer. The most common radiosensitizers are halogenated nucleosides and cisplatin derivatives, and recently also metal nanoparticles have been suggested as potential radiosensitizing agents. The radiosensitizing action of these compounds can at least partly be ascribed to an enhanced reactivity towards secondary low-energy electrons generated along the radiation track of the high-energy primary radiation, or to an additional emission of secondary reactive electrons close to the tumor tissue. This is referred to as physico-chemical radiosensitization. In this Concept article we present current experimental methods used to study fundamental processes of physico-chemical radiosensitization and discuss the most relevant classes of radiosensitizers. Open questions in the current discussions are identified and future directions outlined, which can lead to optimized treatment protocols or even novel therapeutic concepts.
Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid–lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased. Taken together, these findings suggest that the mechanism of action of EPC3 could be linked to its effects on fundamental biophysical properties of lipid membranes, as well as on lipid metabolism in cancer cells.
Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid–lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased. Taken together, these findings suggest that the mechanism of action of EPC3 could be linked to its effects on fundamental biophysical properties of lipid membranes, as well as on lipid metabolism in cancer cells.
Selenium (Se) is an essential micronutrient for human health. Se deficiency affects hundreds of millions of people worldwide, particularly in developing countries, and there is increasing awareness that suboptimal supply of Se can also negatively affect human health. Selenium enters the diet primarily through the ingestion of plant and animal products. Although, plants are not dependent on Se they take it up from the soil through the sulphur (S) uptake and assimilation pathways. Therefore, geographic differences in the availability of soil Se and agricultural practices have a profound influence on the Se content of many foods, and there are increasing efforts to biofortify crop plants with Se. Plants from the Brassicales are of particular interest as they accumulate and synthesize Se into forms with additional health benefits, such as methylselenocysteine (MeSeCys). The Brassicaceae are also well-known to produce the glucosinolates; S-containing compounds with demonstrated human health value. Furthermore, the recent discovery of the selenoglucosinolates in the Brassicaceae raises questions regarding their potential bioefficacy. In this review we focus on Se uptake and metabolism in the Brassicaceae in the context of human health, particularly cancer prevention and immunity. We investigate the close relationship between Se and S metabolism in this plant family, with particular emphasis on the selenoglucosinolates, and consider the methodologies available for identifying and quantifying further novel Se-containing compounds in plants. Finally, we summarize the research of multiple groups investigating biofortification of the Brassicaceae and discuss which approaches might be most successful for supplying Se deficient populations in the future.
Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals’ use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue.
Accumulating data indicates a link between a pro-inflammatory status and occurrence of chronic disease-related fatigue. The questions are whether the observed inflammatory profile can be (a) improved by anti-inflammatory diets, and (b) if this improvement can in turn be translated into a significant fatigue reduction. The aim of this narrative review was to investigate the effect of anti-inflammatory nutrients, foods, and diets on inflammatory markers and fatigue in various patient populations. Next to observational and epidemiological studies, a total of 21 human trials have been evaluated in this work. Current available research is indicative, rather than evident, regarding the effectiveness of individuals’ use of single nutrients with anti-inflammatory and fatigue-reducing effects. In contrast, clinical studies demonstrate that a balanced diet with whole grains high in fibers, polyphenol-rich vegetables, and omega-3 fatty acid-rich foods might be able to improve disease-related fatigue symptoms. Nonetheless, further research is needed to clarify conflicting results in the literature and substantiate the promising results from human trials on fatigue.