A gene-environment interaction analysis of plasma selenium with prevalent and incident diabetes: The Hortega study.
ABSTRACT: Selenium and single-nucleotide-polymorphisms in selenoprotein genes have been associated to diabetes. However, the interaction of selenium with genetic variation in diabetes and oxidative stress-related genes has not been evaluated as a potential determinant of diabetes risk.We evaluated the cross-sectional and prospective associations of plasma selenium concentrations with type 2 diabetes, and the interaction of selenium concentrations with genetic variation in candidate polymorphisms, in a representative sample of 1452 men and women aged 18-85 years from Spain.The geometric mean of plasma selenium levels in the study sample was 84.2µg/L. 120 participants had diabetes at baseline. Among diabetes-free participants who were not lost during the follow-up (N=1234), 75 developed diabetes over time. The multivariable adjusted odds ratios (95% confidence interval) for diabetes prevalence comparing the second and third to the first tertiles of plasma selenium levels were 1.80 (1.03, 3.14) and 1.97 (1.14, 3.41), respectively. The corresponding hazard ratios (95% CI) for diabetes incidence were 1.76 (0.96, 3.22) and 1.80 (0.98, 3.31), respectively. In addition, we observed significant interactions between selenium and polymorphisms in PPARGC1A, and in genes encoding mitochondrial proteins, such as BCS1L and SDHA, and suggestive interactions of selenium with other genes related to selenoproteins and redox metabolism.Plasma selenium was positively associated with prevalent and incident diabetes. While the statistical interactions of selenium with polymorphisms involved in regulation of redox and insulin signaling pathways provide biological plausibility to the positive associations of selenium with diabetes, further research is needed to elucidate the causal pathways underlying these associations.
Project description:The relationship between selenium and metabolic syndrome (MetS) has been discussed controversially, and limited studies have examined the associations of single nucleotide polymorphisms in selenoproteins genes with MetS. Hence, to examine the associations of plasma selenium concentrations and selenoprotein P rs7579 polymorphism with MetS, a case-control study of 1279 MetS cases and 1279 sex- and age- (±2 years) matched controls was conducted based on the baseline data of the Tongji-Ezhou Cohort study. Plasma selenium concentrations were measured by inductively coupled plasma mass spectrometry. MetS was defined using the definition of the Joint Interim Statement, adjusted for the Chinese population. In addition, the rs7579 polymorphism was genotyped by the Agena MassARRAY System. Plasma selenium concentrations in the MetS group were higher than in the control group (93.88??g/L (83.17-107.41) vs. 92.66??g/L (82.36-103.53), P < 0.05). Compared with quartile 4 (?103.53??g/L), the multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) associated with MetS were 0.79 (0.59-1.06) for quartile 1 (<82.36??g/L), 0.75 (0.56-1.01) for quartile 2 (82.37-92.66??g/L), and 0.61 (0.45-0.83) for quartile 3 (92.67-103.52??g/L). The cubic spline analyses revealed a U-shaped association between plasma selenium and MetS, with the lowest risk at around 93.69??g/L. Moreover, in cubic spline analyses, plasma selenium showed U-shaped associations with central obesity and high blood pressure, positive associations with hypertriglyceridemia and hyperglycemia, and a negative association with low high-density lipoprotein cholesterol. Additionally, both the GA and GA+AA genotype carriers were associated with increased ORs of MetS comparing with the GG genotype carriers. Our findings suggested a U-shaped association between plasma selenium and MetS and diverse associations between plasma selenium and components of MetS. Furthermore, our study found that the A allele of rs7579 was associated with higher odds of MetS. Further studies are needed to confirm our findings and elucidate the underlying mechanisms.
Project description:Observational studies suggest an inverse association between selenium and risk of prostate cancer. However, randomized controlled trials of selenium supplementation have reported conflicting results. Thus, we examined plasma selenium and selenium-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with non-metastatic disease.We measured plasma selenium and genotyped 73 single nucleotide polymorphisms in TXNRD1, TXNRD2, GPX1, GPX3, GPX4, SEP15, SEPP1, SELENBP1, OGG1, and CAT among 568 men with non-metastatic prostate cancer who underwent radical prostatectomy. We examined associations between plasma selenium, genotypes, and risk of high-grade prostate cancer (Gleason grade ?8 or 7 with primary score ?4; n?=?111) using logistic regression, and risk of prostate cancer recurrence (61 events; 3.8 y median follow-up) using Cox proportional hazards regression.Plasma selenium was not associated with risk of high-grade prostate cancer or prostate cancer recurrence. Less common alleles of rs11913319 in TXNRD2 and rs125701 in OGG1 were associated with an increased risk of high-grade prostate cancer. We observed associations between the risk of prostate cancer recurrence and multiple SNPs in TXNRD1, TXNRD2, GPX3, and SEP15. These associations were no longer statistically significant after adjustment for multiple comparisons.Among men with non-metastatic prostate cancer, there is suggestive evidence that genetic variation in selenoproteins and related antioxidant enzymes may be associated with risk of high-grade disease at diagnosis and prostate cancer recurrence.
Project description:BACKGROUND:Genetic variations in some of the selenoprotein genes, alone or together with an individual's selenium status, may influence risk or progression of prostate cancer. We investigated the impact of genetic variants of selenoproteins on plasma selenium levels and cancer aggressiveness at diagnosis in men with localized prostate cancer (PCa). METHODS:The study cohort comprised 722 patients seen at Dana-Farber Cancer Institute who had localized/locally advanced PCa (i.e., stage T3 or less, N0, and M0) from 1994 to 2001. Fifty-five tagging single nucleotide polymorphisms (SNPs) from six selenoprotein genes (TXNRD1, TXNRD2, SEP15, GPX3, SELENBP1, and SEPP1) were analyzed. Logistic regression is used to examine associations of genotypes and plasma selenium levels with risk of aggressive disease, defined as D'Amico intermediate/high risk categories. Step down permutation was applied to adjust for multiple comparisons. RESULTS:Three hundred and forty-eight patients (48%) had aggressive disease at diagnosis. Two SNPs were associated with cancer aggressiveness at diagnosis (unadjusted P?=?0.017 and 0.018, respectively). The odds ratio for aggressive disease in patients carrying TXNRD2 rs1005873-AG/GG genotypes or SELENBP1 rs10788804-AG/AA genotypes was 1.54 (95% CI?=?1.08, 2.20) and 1.45 (95% CI?=?1.07, 1.98), respectively, compared to TXNRD2 rs1005873-AA or SELENBP1 rs10788804-GG carriers. Four SNPs in TXNRD2 (rs1005873, rs13054371, rs3788310, and rs9606174) and the rs230820 in SEPP1 were associated with plasma selenium levels (unadjusted P?<?0.05). Permutation adjusted P-values were not statistically significant for all these comparisons at the cut-off point of 0.05. CONCLUSION:We identified polymorphisms in selenoproteins that may influence the plasma selenium levels and may be associated with the risk of presenting with aggressive PCa in men with localized or locally advanced PCa. These results should be validated in other independent datasets.
Project description:Glutathione peroxidase 1 (GPX1) is a selenium-dependent enzyme that reduces intracellular hydrogen peroxide and lipid peroxides. While past research explored regulations of gene expression and biochemical function of this selenoperoxidase, GPX1 has recently been implicated in the onset and development of chronic diseases. Clinical data have shown associations of human GPX1 gene variants with elevated risks of diabetes. Knockout and overexpression of Gpx1 in mice may induce types 1 and 2 diabetes-like phenotypes, respectively. This review assembles the latest advances in this new field of selenium biology, and attempts to postulate signal and molecular mechanisms mediating the role of GPX1 in glucose and lipid metabolism-related diseases. Potential therapies by harnessing the beneficial effects of this ubiquitous redox-modulating enzyme are briefly discussed.
Project description:Recent findings have raised concern about possible associations of high selenium exposure with diabetes and hyperlipidemia in the US, a population with high selenium status. In the UK, a population with lower selenium status, there is little data on the association of selenium status with cardio-metabolic risk factors in the general population. We examined the association of plasma selenium concentration with blood lipids in a nationally representative sample of British adults. A cross-sectional study was conducted among 1042 white participants (aged 19-64 y) in the 2000-2001 UK National Diet and Nutrition Survey. Plasma selenium was measured by inductively coupled-plasma mass spectrometry. Total and HDL cholesterol were measured in nonfasting plasma samples. Mean plasma selenium concentration was 1.10 +/- 0.19 micromol/L. The multivariate adjusted differences between the highest (> or =1.20 micromol/L) and lowest (<0.98 micromol/L) quartiles of plasma selenium were 0.39 (95% CI 0.18, 0.60) mmol/L for total cholesterol, 0.38 (0.17, 0.59) for non-HDL cholesterol, and 0.01 (-0.05, 0.07) for HDL cholesterol. Higher plasma selenium (i.e., > or =1.20 micromol/L) was associated with increased total and non-HDL cholesterol levels but not with HDL in the UK adult population. These findings raise additional concern about potential adverse cardio-metabolic effects of high selenium status. Randomized and mechanistic evidence is necessary to assess causality and to evaluate the impact of this association on cardiovascular risk.
Project description:Although literature has been consistently showing an increased risk of type 2 diabetes (T2DM) in populations with high exposure to selenium, there is a lack of information quantifying the association between diabetes-related markers and the nutritional status of selenium. Therefore, we aimed to investigate the association between blood selenium concentration and glucose markers in a representative sample of the US population, which is known to have moderate to high exposure to selenium. This cross-sectional analysis included 4,339 participants ≥18 years from the 2013 to 2018 National Health and Nutrition Examination Survey (NHANES). All participants were assessed for whole blood selenium concentration, fasting plasma insulin and glucose, HbA1c, and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance). In this cohort, all participants presented with adequate selenium status [196.2 (SD: 0.9) μg/L] and 867 (15%) had diabetes mellitus. Selenium was positively associated with insulin, glucose and HOMA-IR in models adjusted for age and sex. When the models were further adjusted for smoking status, physical activity, metabolic syndrome and BMI, the associations with insulin and HOMA-IR remained but the association with glucose was no longer significant. A 10 μg/L increase in selenium was associated with 1.5% (95% CI: 0.4-2.6%) increase in insulin and 1.7% (95% CI: 0.5-2.9%) increase in HOMA-IR in fully adjusted models. There was no evidence of an association between selenium and diabetes prevalence. Our findings corroborate the notion that selenium supplementation should not be encouraged in populations with high dietary intake of selenium.
Project description:The prostate is an important organ for the maintenance of sperm health with prostate cancer being a common disease for which there is a critical need to distinguish indolent from aggressive disease. Several selenium-containing proteins have been implicated in prostate cancer risk or outcome due to either enzyme function, the reduced levels of these proteins being associated with cancer recurrence after prostatectomy or their corresponding genes containing single-nucleotide polymorphisms associated with increased risk. Moreover, experimental data obtained from the manipulation of either cultured cells or animal models have indicated that some of these proteins are contributing mechanistically to prostate cancer incidence or progression. Among these are selenocysteine-containing proteins selenoprotein P (SELENOP), glutathione peroxidase (GPX1), and selenoprotein 15 (SELENOF); and the selenium-associated protein selenium-binding protein 1 (SBP1). Genotyping of some of the genes for these proteins has identified functional single-nucleotide polymorphisms that are associated with prostate cancer risk and the direct quantification of these proteins in human prostate tissues has not only revealed associations to clinical outcomes but have also identified unique properties that are different from what is observed in other tissue types. The location of GPX1 in the nucleus and SELENOF in the plasma membrane of prostate epithelial cells indicates that these proteins may have functions in normal prostate tissue that are distinct from that of the other tissue types.
Project description:<b>Background:</b> Excess selenium has been related with adverse lipid levels in previous epidemiological studies. Meanwhile, a functional variant in <i>SEPP1</i> (encodes selenoprotein P), namely rs7579, has been suggested to modulate lipid metabolism. However, the interactions between selenium status and rs7579 polymorphism on lipid changes remain unclear. <b>Objective:</b> To examine whether the associations between plasma selenium and 3-year lipid changes is modified by rs7579 polymorphism. <b>Methods:</b> A prospective cohort study was conducted among 1,621 individuals to examine the associations between baseline plasma selenium and 3-year lipid changes, as well as the interactions between plasma selenium and rs7579 polymorphism on lipid changes. <b>Results:</b> The median (interquartile range) concentration of plasma selenium was 91.68 (81.55-104.92) μg/L. Higher plasma selenium was associated with adverse 3-year lipid changes. Comparing the highest to the lowest quartiles of plasma selenium concentrations, 3-year lipid changes were elevated by 8.25% (95% CI: 1.54-14.96%) for triglycerides (<i>P</i> = 0.016), 5.88% (3.13-8.63%) for total cholesterol (<i>P</i> < 0.001), 7.37% (3.07-11.67%) for low-density lipoprotein cholesterol (<i>P</i> = 0.0008), 6.44% (2.66-10.21%) for non-high-density lipoprotein cholesterol (<i>P</i> = 0.0009), 4.99% (0.62-9.36%) for total cholesterol/high-density lipoprotein cholesterol ratio (<i>P</i> = 0.025), and 7.00% (1.55-12.46%) for low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (<i>P</i> = 0.012). In analyses stratified by rs7579 genotypes, positive associations between plasma selenium concentrations and 3-year changes in triglycerides, TC, LDL-C, non-HDL-C, TC/HDL-C ratio, and LDL-C/HDL-C ratio were observed among CC genotype carriers, but negative associations between plasma selenium and TC/HDL-C ratio, and LDL-C/HDL-C ratio were observed among TT genotype carriers. <b>Conclusions:</b> Our findings suggested that plasma selenium was associated with 3-year lipid changes differentially by rs7579 genotypes, and higher plasma selenium was associated with adverse lipid changes among rs7579 CC genotype carriers, but not among T allele carriers.
Project description:<h4>Background</h4>Elevated heavy metals and fasting plasma glucose (FPG) levels were both associated with increased risk of cardiovascular diseases. However, studies on the associations of heavy metals and essential elements with altered FPG and diabetes risk were limited or conflicting. The objective of this study was to evaluate the potential associations of heavy metals and essential trace elements with FPG and diabetes risk among general Chinese population.<h4>Methods</h4>We conducted a cross-sectional study to investigate the associations of urinary concentrations of 23 metals with FPG, impaired fasting glucose (IFG) and diabetes among 2242 community-based Chinese adults in Wuhan. We used the false discovery rate (FDR) method to correct for multiple hypothesis tests.<h4>Results</h4>After adjusting for potential confounders, urinary aluminum, titanium, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, antimony, barium, tungsten and lead were associated with altered FPG, IFG or diabetes risk (all P< 0.05); arsenic was only dose-dependently related to diabetes (P< 0.05). After additional adjustment for multiple testing, titanium, copper, zinc, selenium, rubidium, tungsten and lead were still significantly associated with one or more outcomes (all FDR-adjusted P< 0.05).<h4>Conclusions</h4>Our results suggest that multiple metals in urine are associated with FPG, IFG or diabetes risk. Because the cross-sectional design precludes inferences about causality, further prospective studies are warranted to validate our findings.
Project description:<h4>Background</h4>Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen.<h4>Methods</h4>In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 µg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available.<h4>Results</h4>Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96).<h4>Conclusions</h4>These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status.