scholarly journals Long Leukocyte Telomere Length Is Associated with Increased Risks of Soft Tissue Sarcoma: A Mendelian Randomization Study

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 594 ◽  
Author(s):  
Yifan Xu ◽  
Junfeng Xu ◽  
Haidee Chancoco ◽  
Maosheng Huang ◽  
Keila E. Torres ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Telomere Length ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Leukocyte Telomere Length ◽  
Nucleotide Polymorphisms ◽  
Individual Snps ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

Background: Leukocyte telomere length (LTL) has been associated with the risks of several cancers in observational studies. Mendelian randomization (MR) studies, using genetic variants as instrumental variables, have also shown associations of genetically predicted LTL with cancer risks. In this study, we performed the first MR analysis on soft tissue sarcoma (STS) to investigate the causal relationship between LTL and the risk of STS. Methods: Genotypes from eleven LTL-associated single nucleotide polymorphisms (SNPs) in 821 STS cases and 851 cancer-free controls were aggregated into a weighted genetic risk score (GRS) to predict LTL. Multivariate logistic regression was used to assess the association of STS risk with individual SNPs and aggregated GRS. Results: Four SNPs displayed evidence for an individual association between long LTL-conferring allele and increased STS risk: rs7675998 (odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.02–1.43), rs9420907 (OR = 1.31, 95% CI = 1.08–1.59), rs8105767 (OR = 1.18, 95% CI = 1.02–1.37), and rs412658 (OR = 1.18, 95% CI = 1.02–1.36). Moreover, longer genetically predicted LTL, calculated as GRS, was strongly associated with an increased risk of STS (OR = 1.44, 95% CI = 1.18–1.75, p < 0.001), and there was a significant dose-response association (p for trend <0.001 in tertile and quartile analyses). The association of longer LTL with higher STS risk was more evident in women than in men. In stratified analyses by major STS subtypes, longer LTL was significantly associated with higher risks of leiomyosarcoma and gastrointestinal stromal tumors. Conclusions: Longer LTL is associated with increased risks of STS.

scholarly journals Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: A Mendelian randomization study

2021 ◽  
Author(s):  
Resham L Gurung ◽  
Rajkumar Dorajoo ◽  
Yiamunaa M ◽  
Ling Wang ◽  
Sylvia Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Telomere Length ◽  
Mendelian Randomization ◽  
Random Effect ◽  
Leukocyte Telomere Length ◽  
Increased Risk ◽  
Genetically Determined

Abstract Background Chronic kidney disease (CKD) is common among type 2 diabetes (T2D) and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length is associated with CKD in patients with T2D. We previously reported single nucleotide polymorphisms (SNPs) associated with leukocyte telomere length in Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using Mendelian randomization (MR) approach. Methods The cross-sectional association of 16 leukocyte telomere length SNPs with CKD, defined as an estimated glomerular filtration rate of less than 60 ml/min/1.73m2 was assessed among 4,768 (1,628 cases, 3,140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analysed. Results Genetically determined shorter leukocyte telomere length was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio = 1.51 [95% confidence interval, 1.12 - 2.12; P = 0.007; Phet= 0.547]). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (β  =  0.010, P = 0.751). Conclusions Our findings suggest that genetically determined leukocyte telomere length is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.

Common variants in the haemostatic gene pathway contribute to risk of early-onset myocardial infarction in the Italian population

2011 ◽  
Vol 106 (10) ◽  
pp. 855-864 ◽  
Author(s):  
Ilaria Guella ◽  
Diego Ardissino ◽  
Pier Merlini ◽  
Flora Peyvandi ◽  
Pier Mannucci ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Genome Wide Association Study ◽  
Thrombus Formation ◽  
Genetic Risk Score ◽  
Control Analysis ◽  
Italian Population ◽  
Nucleotide Polymorphisms ◽  
Standard Case ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

SummaryOcclusive coronary thrombus formation superimposed on an atherosclerotic plaque is the ultimate event leading to myocardial infarction (MI). Therefore, haemostatic proteins may represent important players in the pathogenesis of MI. It was the objective of this study to evaluate, in a comprehensive way, the role of haemostatic gene polymorphisms in predisposition to premature MI. A total of 810 single nucleotide polymorphisms (SNPs) in 37 genes were assessed for association with MI in a large cohort (1,670 males, 210 females) of Italian patients who suffered from an MI event before the age of 45, and an equal number of controls. Thirty-eight SNPs selected from the literature were genotyped using the SNPlex technology, whereas genotypes for the remaining 772 SNPs were extracted from a previous genome-wide association study. Genotypes were analysed by a standard case-control analysis corrected for classical cardiovascular risk factors, and by haplotype analysis. A weighted Genetic Risk Score (GRS) was calculated. Evidence for association with MI after covariate correction was found for 35 SNPs in 12 loci: F5, PROS1, F11, ITGA2, F12, F13A1, SERPINE1, PLAT, VWF, THBD, PROCR, and F9. The weighted GRS was constructed by including the top SNP for each of the 12 associated loci. The GRS distribution was significantly different between cases and controls, and subjects in the highest quintile had a 2.69-fold increased risk for MI compared with those in the lowest quintile. Our results suggest that a GRS, based on the combined effect of several risk alleles in different haemostatic genes, is associated with an increased risk of MI.

scholarly journals Midlife Leukocyte Telomere Length as an Indicator for Handgrip Strength in Late Life

2020 ◽  
Vol 76 (1) ◽  
pp. 172-175
Author(s):  
Xuling Chang ◽  
Kevin Yiqiang Chua ◽  
Ling Wang ◽  
Jianjun Liu ◽  
Jian-Min Yuan ◽  
...  
Keyword(s):  
Telomere Length ◽  
Structural Equation ◽  
Handgrip Strength ◽  
Genetic Risk Score ◽  
Health Study ◽  
Equation Modeling ◽  
Leukocyte Telomere Length ◽  
Timed Up And Go ◽  
Telomere Attrition ◽  
Weighted Genetic Risk Score

Abstract Background Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality. Methods In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581). Results We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010). Conclusions Longer midlife LTL was associated with increased handgrip strength later in life.

scholarly journals Relating C-reactive Protein to Psychopathology after Cardiac Surgery and Intensive Care Unit Admission: A Mendelian Randomization Study

2017 ◽  
Author(s):  
Lotte Kok ◽  
Bochao Danae Lin ◽  
Juliette Broersen ◽  
Erwin Bekema ◽  
Jelena Medic ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Post Traumatic Stress ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Individual Snps

AbstractPatients admitted to an intensive care unit (ICU) are subjected to a high burden of stress, rendering them prone to develop stress-related psychopathology. Dysregulation of inflammation and, more specifically, upregulation of inflammatory markers such as C-reactive protein (CRP) is potentially key in development of post-ICU psychopathology.To investigate the effects of state-independent CRP on symptoms of post-traumatic stress disorder (PTSD) and depression after ICU admission, we analysed the three leading single nucleotide polymorphisms (SNPs) of loci most strongly associated with blood CRP levels (i.e. rs2794520, rs4420638, and rs1183910) in an ICU survivor cohort. Genetic association was estimated by linear and logistical regression models of individual SNPs and genetic risk score (GRS) profiling. Mendelian Randomization (MR) was used to investigate potential causal relationships.Single-SNP analyses were non-significant for both quantitative and binary trait analyses after correction for multiple testing. In addition, GRS results were non-significant and explained little variance in psychopathology. Moreover, MR analysis did not reveal any causality and MR-Egger regression showed no evidence of pleiotropic effects (p-pleiotropy >0.05). Furthermore, estimation of causality between these loci and other psychiatric disorders was similarly non-significant.In conclusion, by applying a range of statistical models we demonstrate that the strongest plasma CRP-influencing genetic loci are not associated with post-ICU PTSD and depressive symptoms. Our findings add to an expanding body of literature on the absence of associations between trait CRP and neuropsychiatric phenotypes.

Joint effect of multiple prothrombotic genotypes and obesity on the risk of incident venous thromboembolism

2021 ◽  
Author(s):  
Tobias Frischmuth ◽  
Kristian Hindberg ◽  
Maiken Elvestad Gabrielsen ◽  
Ben Michael Brumpton ◽  
Kristian Hveem ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Genetic Risk Score ◽  
Joint Effect ◽  
Additive Effect ◽  
Health Study ◽  
Nucleotide Polymorphisms ◽  
Risk Alleles ◽  
Individual Snps ◽  
Increased Risk ◽  
The Impact

Background: The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear. Objective: To investigate the joint effect of obesity and a genetic risk score (GRS) comprised of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case-cohort. Methods: Cases with incident VTE (n=1,470) and a subcohort (n=12,826) were derived from the Tromsø Study (1994‐2012) and the Trøndelag Health Study (HUNT) (1995‐2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0-1, 2, 3, ≥4 alleles). Results: The combination of obesity (BMI≥30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e. no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence intervals [CI] 2.05-3.96) increased risk of overall VTE compared to those with BMI<25kg/m2 and 0-1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR 3.20, 95% CI 2.09-4.90) and unprovoked VTE (HR 3.82, 95% CI 2.25-6.47), suggesting a supra-additive effect. Conclusion: Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE.

Abstract 16819: Sequencing of Genetic Loci Associated With Leukocyte Telomere Length Reveals New Intronic Variants in African Americans

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Rasika Mathias ◽  
Kruthika Iyer ◽  
Margaret Taub ◽  
Lisa Yanek ◽  
Diane Becker ◽  
...  
Keyword(s):  
African Americans ◽  
Telomere Length ◽  
Risk Score ◽  
Genetic Risk Score ◽  
African Ancestry ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Leukocyte Telomere Length ◽  
Increased Risk ◽  
Intronic Variants

Background: Shorter telomere length is associated with an increased risk of coronary artery disease (CAD). A prior genomewide association study (GWAS) on 37,684 European ancestry individuals identified seven loci determining leukocyte telomere length (LTL). A genetic risk score across all 7 loci showed an association with CAD. In this study we sequenced these loci to determine whether the same risk variants could be replicated in African admixed individuals. Methods: We used whole genome sequence data (WGS) in 127 healthy African American subjects from GeneSTAR, a family study of early-onset CAD. LTL was calculated from WGS raw bam data (>30x coverage on the Illumina HiSeq platform) for 7 contiguous repeats of the telomere motif (TTAGGG or CCCTAA, Ding et al., 2014). Tests for association for LTL adjusting for age and sex were performed for a total of 55,821 called variants from ~1Mb subset regions of WGS genotype data centered on each of the 7 European peak GWAS SNPs. Results: We identified a total of 17 variants with p<5x10 -4 mapping to 6 of the 7 regions examined; none of the prior European GWAS peak SNPs were significant. The peak SNP per region in the African Americans included intronic variants rs77138331 in ACYP2 (p=0.0005, MAF = 7%), rs149577640 in NAF1 (p=0.002, MAF=1%), rs35387865 in TERT (p=0.003, MAF = 1%) and rs186486116 in OBFC1 (p=0.004, MAF=1%). Additionally, novel intronic variants not previously observed in dbSNP located at chr19: 22190184 (p=0.005, MAF=1%) and chr2:62445438 (0.005, MAF=2%), mapping to ZNF208 and RTEL1 , were also identified as determinants of LTL. Discussion: This is the first study of telomere length in African Americans using a sequencing approach. We are unable to confirm the European-based GWAS variants but identify several associations mapping to genes of importance in telomere biology. Our results provide evidence that the set of SNPs to be included in calculation of a telomeric genetic CAD risk score may be different in populations of European and African ancestry.

scholarly journals Predicted Leukocyte Telomere Length and Risk of Myeloid Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1335-1335
Author(s):  
Jenny Poynter ◽  
Spencer Kelley ◽  
Marina Marcato ◽  
Erica Langer ◽  
Anthony J Hooten ◽  
...  
Keyword(s):  
Telomere Length ◽  
Myeloid Leukemia ◽  
Mendelian Randomization ◽  
Conflicts Of Interest ◽  
Case Control ◽  
Leukocyte Telomere Length ◽  
Case Control Studies ◽  
Myeloid Malignancy ◽  
Individual Snps ◽  
The Individual

Background Maintenance of telomere length has long been established to play a role in the biology of cancer, and several lines of evidence suggest that it may be especially important in myeloid malignancy. Measuring leukocyte telomere length (LTL) directly in case control studies is problematic because telomere length is likely to be influenced by the disease process. Recent studies have led to the identification of a robust genetic predictor of LTL, which we have used to compare differences in predicted telomere length in case control studies of myeloid leukemia and myelodysplastic syndromes (MDS) using Mendelian randomization (MR). MR is a method used to measure the association between a trait (e.g. telomere length) and an outcome (e.g. myeloid malignancy) that can't be measured directly by utilizing genetic variants known to be associated with the trait as instrumental variables. The use of genetic predictors of telomere length reduces the possibility that the association is explained by reverse causation and confounding likely to be relevant in case-control studies where telomere length is measured directly because genotypes in the general population should be randomly distributed. Additionally, predicted telomere length has the added advantage of representing telomere length over the lifetime of the individual while measuring LTL directly will represent only one time point in an individual's life. Methods Myeloid leukemia (AML and CML) and MDS cases were identified by rapid case ascertainment through the Minnesota Cancer Surveillance System (MCSS). Centralized pathology and cytogenetics reviews were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. We used the Sequenom platform to genotype seven SNPs that were validated predictors of LTL in a recently published meta-analysis. We estimated associations between individual SNPs and myeloid malignancy using multivariable logistic regression. Mendelian randomization was used to evaluate the association between predicted LTL and risk of myeloid malignancy. Results We included 253 AML cases, 353 MDS cases, 145 CML cases, and 1,042 controls. We observed a significant association between longer predicted telomere length and AML in analyses adjusted for sex and age (OR 4.82 per additional kilobase of average telomere length, 95% CI 1.32-17.63). The individual SNP analyses suggest that the association is largely driven by rs10936599, located in TERC (OR 1.47 per allele, 95% CI 1.14-1.90; Figure). We did not observe statistically significant associations between predicted LTL and MDS or CML. Discussion In this analysis of predicted telomere length and myeloid malignancy, we identified a significant association between longer predicted leukocyte telomere length and AML. In contrast, no significant association was observed for MDS or CML although we did observe an elevated OR for longer predicted telomere length and MDS that did not reach statistical significance. Figure Disclosures No relevant conflicts of interest to declare.

EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

2021 ◽  
pp. 174749302110062
Author(s):  
Bin Yan ◽  
Jian Yang ◽  
Li Qian ◽  
Fengjie Gao ◽  
Ling Bai ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Ischemic Stroke ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Visceral Adiposity ◽  
Large Artery ◽  
Nucleotide Polymorphisms ◽  
Genetic Liability ◽  
A Genome ◽  
Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5×10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48×10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01×10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16×10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

Causal associations of obesity with chronic kidney disease and arterial stiffness: a Mendelian randomization study

2021 ◽  
Author(s):  
Chaojie Ye ◽  
Lijie Kong ◽  
Zhiyun Zhao ◽  
Mian Li ◽  
Shuangyuan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Standard Deviation ◽  
Kidney Disease ◽  
Single Nucleotide Polymorphisms ◽  
Arterial Stiffness ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Abstract Purpose Observational studies have associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. We aimed to investigate the causality of obesity with CKD and arterial stiffness using Mendelian randomization (MR) analysis. Methods We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single nucleotide polymorphisms were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate &lt;60 mL/min/1.73 m 2. Arterial stiffness was defined as brachial-ankle pulse wave velocity &gt;1550 cm/s. Results Using the genetic risk score as the IV, we demonstrated causal relations of each 1-standard deviation increment in BMI with CKD (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI: 1.22-2.39). Using the 14 single nucleotide polymorphisms individually as IVs, each 1-standard deviation increment in BMI casually associated with CKD (OR: 2.58; 95% CI: 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI: 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (Both P for intercept≥0.34). The causality between obesity and CKD was validated in two-sample MR analysis among Europeans (681275 of Genetic Investigation of ANthropometric Traits and 133413 of CKD Genetics). Conclusions This study provided novel insights into causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.

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