Sex-specific autosomal genetic effects across 26 human complex traits

2020 ◽  
Vol 29 (7) ◽  
pp. 1218-1228 ◽  
Author(s):  
Wan-Yu Lin ◽  
Chang-Chuan Chan ◽  
Yu-Li Liu ◽  
Albert C Yang ◽  
Shih-Jen Tsai ◽  
...  
Keyword(s):  
Complex Traits ◽  
Cardiovascular Health ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Genetic Effects ◽  
P Value ◽  
Gene Expressions ◽  
Men And Women ◽  
Dna Materials ◽  
Kidney Liver

Abstract Previous studies have shown that men and women have different genetic architectures across many traits. However, except waist-to-hip ratio (WHR) and waist circumference (WC), it remains unknown whether the genetic effects of a certain trait are weaker or stronger on men/women. With ~18 000 Taiwan Biobank subjects, we comprehensively investigate sexual heterogeneity in autosomal genetic effects, for traits regarding cardiovascular health, diabetes, kidney, liver, anthropometric profiles, blood, etc. ‘Gene-by-sex interactions’ (G $\times$ S) were detected in 18 out of 26 traits, each with an interaction P-value (${{P}}_{{INT}}$) less than $0.05/104={0.00048}$, where 104 is the number of tests conducted in this study. The most significant evidence of G $\times$ S was found in WHR (${{P}}_{{INT}}$ = 3.2 $\times{{10}}^{-{55}}$) and WC (${{P}}_{{INT}}$ = 2.3$\times{{10}}^{-{41}}$). As a novel G$\times$S investigation for other traits, we here find that the autosomal genetic effects are weaker on women than on men, for low-density lipoprotein cholesterol (LDL-C), uric acid (UA) and diabetes-related traits such as fasting glucose and glycated hemoglobin. For LDL-C and UA, the evidence of G$\times$S is especially notable in subjects aged less than 50 years, where estrogen can play a role in attenuating the autosomal genetic effects of these two traits. Men and women have systematically distinct environmental contexts caused by hormonal milieu and their specific society roles, which may trigger diverse gene expressions despite the same DNA materials. As many environmental exposures are difficult to collect and quantify, sex can serve as a good surrogate for these factors.

scholarly journals Extremely elevated lipoprotein (a) as an independent risk factor for peripheral arterial disease in large patient cohort

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.R Poudel ◽  
S Kirana ◽  
D Stoyanova ◽  
K.P Mellwig ◽  
D Hinse ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Arterial Disease ◽  
P Value ◽  
Lipoprotein A ◽  
Large Patient ◽  
Increased Risk ◽  
Revascularization Therapy ◽  
Peripheral Arterial

Abstract Background Elevated lipoprotein (a) [LP (a)] levels are an independent, genetic, and causal factor for cardiovascular disease and associated with myocardial infarction (MI). Although the association between circulating levels of lipoprotein(a) [Lp(a)] and risk of coronary artery disease (CAD) is well established, its role in risk of peripheral arterial disease (PAD) remains unclear. PAD affects over 236 million individuals and follows ischaemic heart disease (IHD) and cerebrovascular disease (CVD) as the third leading cause of atherosclerotic cardiovascular morbidity worldwide. LP (a) is genetically determined, stable throughout life and yet refractory to drug therapy. While 30 mg/dl is considered the upper normal value for LP (a) in central Europe, extremely high LP (a) levels (>150mg/dl) are rare in the general population. The aim of our study was to analyse the correlation between lipoprotein (a) [LP (a)] levels and an incidence of PAD in high-risk patients. Patients and methods We reviewed the LP (a) concentrations of 52.898 consecutive patients admitted to our cardiovascular center between January 2004 and December 2014. Of these, 579 patients had LP (a) levels above 150 mg/dl (mean 181.45±33.1mg/dl). In the control collective LP (a) was <30mg/dl (n=350). Other atherogenic risk factors in this group were HbA1c 6.58±1.65%, low density lipoprotein (LDL) 141.99±43.76 mg/dl, and body mass index 27.81±5.61. 54.40% were male, 26.07% were smokers, 93.2% had hypertension, and 24% had a family history of cardiovascular diseases. More than 82.6% were under statins. The mean glomerular filtration rate (GFR) was 69.13±24.8 ml/min [MDRD (Modification of Diet in Renal Disease)]. Results 45.00% (n=261) of the patients with LP (a) >150mg/dl had PAD. The prevalence of PAD in patients with LP (a) <30mg/dl in our control collective was 15.8%. (P- Value 0.001). Patients with LP (a) >150mg/dl had a significantly increased risk for PAD (Odds ratio 4.36, 95% CI 2.94–6.72, p: 0.001). 19.1% of patients were re-vascularized by percutaneous angioplasty (PTA) and 7.09% of patients had to undergo peripheral vascular bypass (PVB). Mean LP (a) level in patients with PAD was 182.6±31.61. Conclusion Elevated LP (a) levels above 150 mg/dl are associated with a significantly increased risk of PAD in our collective and it confirms our hypothesis. Over one fourth of these patients had severe PAD and requiring revascularization therapy. We need more prospective studies to confirm our findings. Funding Acknowledgement Type of funding source: None

A STUDY OF FASTING LIPID PROFILE IN CHRONIC KIDNEY DISEASE PATIENTS AT MEDICINE DEPARTMENT OF ANMMCH, GAYA, BIHAR

2021 ◽  
pp. 75-76
Author(s):  
Bharat Bhushan ◽  
Debarshi Jana
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
P Value ◽  
Low Density ◽  
Healthy Controls ◽  
Group 3 ◽  
Group 2

Background: Dyslipidemia is very much common in chronic kidney disease patients and is responsible for cardiovascular disease (CKD) which is most common cause of mortality in them. So, it is necessary to study the lipid prole in CKD patients to prevent morbidity and mortality. Methods: Subjects each of 50 in number are grouped into healthy controls (group-1), CKD patients without hemodialysis (group-2), CKD patients with hemodialysis (group-3). After fasting of 12 hours, lipid prole is assessed in all cases. Results: In this study, there is increase in Total cholesterol (TC), Low Density lipoprotein (LDL), very Low-Density lipoprotein (VLDL) and Triglycerides (TG) and decrease in High Density Lipoprotein (HDL) in all CKD patients compared to healthy controls (p-value for each parameter <0.001). There is increase in TC, TG and VLDL in diabetic CKD patients compare to non-diabetic CKD patients and p-value for each parameter is <0.05. It was found that TG and VLDL increase and HDL decrease in group-3 compare to group-2 is statistically signicant (p-value for each <0.05) and no signicant variation in TC and LDL in these groups. Conclusions: Present study demonstrated that there is dyslipidemia in CKD patients irrespective of mode of management, but the derangement is much more common and signicant in CKD with hemodialysis group and they are at risk of cardiovascular disease. It is better to start lipid lowering drugs which decreases disease progression and dyslipidemia.

scholarly journals Study of gallbladder lesions and its relationship with serum lipid profile

2018 ◽  
Vol 5 (5) ◽  
pp. 1245
Author(s):  
Sushama Bhatta ◽  
Samir Singh
Keyword(s):  
Lipid Profile ◽  
Serum Lipid ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chronic Cholecystitis ◽  
Lipoprotein Cholesterol ◽  
Serum Lipid Profile ◽  
P Value ◽  
Low Density Lipoprotein Cholesterol ◽  
Histopathological Lesion

Background: Gallbladder disease is one of the most common gastrointestinal diseases. Various studies have shown association between gallstone and alteration in serum lipids. The objective of this study was to evaluate histological patterns of cholecystectomy specimens and compare serum lipid profile of gallstone patients with controls.Methods: This study was conducted over a period of two years (April 2016 to April 2018). Records of 287 specimens who underwent cholecystectomy were analysed in which gallstones were found only in 186 patients. Out of 186 patients with gallstones, records of serum lipid profile were available in 32 patients which were compared with 32 control of similar age. Independent t- test was used to compare the data between cases and control.Results: Out of 287 cases, 68 were male and 219 were female with male to female ratio of 1:3.2. The predominant histopathological lesion was chronic cholecystitis (73.17%). Malignancy was observed in 0.7% cases. Serum total cholesterol, triglycerides and low density lipoprotein cholesterol were found to be higher and statistically significant in patients with gallstone compared to controls (p value 0.024, <0.001and 0.016 respectively). Serum High density lipoprotein cholesterol was lower in gallstone patient than in control but not statistically significant (p value 0.23).Conclusions: Chronic cholecystitis was the most common histopathological lesion. Serum total cholesterol, triglyceride and low density lipoprotein cholesterol level were elevated and statistically significant in patients with gallstone.

scholarly journals Efficiency of Barley Bran and Oat Bran in Ameliorating Blood Lipid Profile and the Adverse Histological Changes in Hypercholesterolemic Male Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Haddad A. El Rabey ◽  
Madeha N. Al-Seeni ◽  
Hanan M. Amer
Keyword(s):  
High Density Lipoprotein ◽  
Lipid Profile ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Negative Control ◽  
High Density ◽  
Low Density ◽  
Oat Bran ◽  
Barley Bran ◽  
Kidney Liver

The efficiency of oat bran and barley bran in lowering the induced hyperlipidemia and hypercholesterolemia in blood of male Albino rats (Rattus rattus) was studied. Twenty rats were divided into four groups each consisted of five rats and fed the specified test diets for eight weeks. The first group (G1) is the negative group which was fed basal diet, the second group (G2) was fed 1.0% cholesterol, was the third group (G3) fed 1.0% cholesterol and 10% oats bran, and the fourth group (G4) was fed 1.0% cholesterol and 10% barley bran. Feeding rats on 1% cholesterol significantly increased serum total cholesterol, low density lipoprotein, and very low density lipoprotein and triglyceride and decreased serum high density lipoprotein. Furthermore, enzyme activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase was increased, and lipid peroxide was increased, whereas catalase and glutathione-S-transferase were decreased. Kidney functions parameters in the cholesterol supplemented group were elevated compared with the negative control. In addition, histological alteration in kidney, liver, heart, and testes was observed, compared with the negative control. Hypercholesterolemic rats supplemented with oat bran and barley bran showed significant decrease in lipid parameters, significant increase in high density lipoprotein-cholesterol, improved antioxidant enzyme, and improved histopathology of kidney, liver, heart, and testes. In conclusion, both oat bran and barley bran had protective effects against induced hyperlipidemia and improved histological alterations. Oat bran appeared more efficient than barley bran in lowering the lipid profile levels in hypercholesterolemic rats.

P5322Oxidized phospholipids on apolipoprotein B-100 among black US adults with and without PCSK9 loss-of-function variants

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Mefford ◽  
S Marcovina ◽  
V Bittner ◽  
M Cushman ◽  
T Brown ◽  
...  
Keyword(s):  
Racial Differences ◽  
Apolipoprotein B ◽  
Population Distribution ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
P Value ◽  
Loss Of Function ◽  
Black Adults ◽  
Lipoprotein A ◽  
Increased Risk

Abstract Background High oxidized phospholipid-apolipoprotein B-100 (OxPL-apoB) levels are associated with an increased risk for coronary heart disease (CHD). Genetic PCSK9 loss-of-function (LOF) variants result in life-long lower levels of LDL-C and lipoprotein(a) and reduced CHD risk, but the association with OxPL-apoB is unknown. Purpose To estimate the association between PCSK9 LOF variants and OxPL-apoB levels among black adults. Methods Genotyping for LOF variants (Y142X and C679X) was conducted for 10,196 black Reasons for Geographic And Racial Differences in Stroke study participants. OxPL-apoB was measured using antibody E06 for all participants with LOF variants (n=241) and randomly selected participants, matched at a 1:3 ratio, without LOF variants (n=723). Low OxPL-apoB was defined as the bottom quartile of the population distribution (<1.6 nM). Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated for the association between PCSK9 LOF variants and low OxPL-apoB levels adjusting for age, sex, and estimated glomerular filtration rate. Results Adults with versus without PCSK9 LOF variants had lower LDL-C and lipoprotein(a) and were less likely to be taking a statin. (Table) A higher proportion of adults with versus without PCSK9 LOF variants had low OxPL-apoB levels (30.3 vs 23.4, p=0.03). After adjustment for covariates, the PR of low OxPL-apoB was increased for participants with compared to without LOF variants (PR 1.31, 95% CI 1.00, 1.72). Characteristics of REGARDS participants PCSK9 loss-of-function variant p-value Yes (n=241) No (n=723) Age, years, mean (SD) 63.7 (9.2) 63.8 (8.6) 0.81 Female, % 61.4 60.6 0.82 Diabetes, % 34.4 27.4 0.04 LDL-C, mg/dL, mean (SD) 85 (32) 118 (37) <0.001 Lp(a), nmol/L, median (25th, 75th percentile) 63.2 (30.4, 119.6) 80.4 (39.7, 138.4) 0.02 Statin use, % 13.3 30.4 <0.001 OxPL-apoB <1.6 nM, % 30.3 23.4 0.03 Abbreviations: LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); LOF, loss-of-function; nM, nanomolar; OxPL-apoB, oxidized phospholipids on apolipoprotein B-100; PCSK9, proprotein convertase subtilisin/kexin type-9; REGARDS, REasons for Geographic And Racial Differences in Stroke; SD, standard deviation. Conclusion Among black adults, PCSK9 LOF variants were associated with lower OxPL-apoB levels. Acknowledgement/Funding Industry/academic collaboration between Amgen Inc., University of Alabama at Birmingham and the Icahn School of Medicine at Mt. Sinai; and U01NS041588

Blockage of Wnt/B-Catenin Signaling By Nanoparticles Reduces Survival and Proliferation of CLL Cells in Vitro

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3699-3699
Author(s):  
Ida Franiak-Pietryga ◽  
Henryk Maciejewski ◽  
Barbara Ziemba ◽  
Dietmar Appelhans ◽  
Brigitte Voit ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Integration Site ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
P Value ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Genes Expression ◽  
Density Lipoprotein Receptor

Abstract The Wnt pathway is critical for the proliferation and cell fate determination of many cell types, including B cells of chronic lymphocytic leukemia (CLL). Wnt proteins act on target cells by binding to the Frizzled (Fz)/low-density lipoprotein (LRP) complex at the cell membrane. In the hematopoietic system, Wnt/β-catenin signaling pathway has been shown to be important in the control of the survival, proliferation and differentiation of hematopoietic cells. Nanotechnology, a new and promising field, may be of use in medicine and the pharmaceutical industry. Dendrimers are nanoparticles of dendritic architecture. We have already proved the influence of PPI-G4-OS-M3 dendrimers in cultures in vitro on CLL cells apoptosis. CLL lymphocytes are characterized by the failure in the apoptosis pathway, but it is also proved that they manifest increased proliferation. Herein, the objective was to evaluate how MEC-1 cells survival and proliferation in vitro is affected by blockage of Wnt pathway by PPI-G4-OS-M3 dendrimer comparing to FA. Material and methods Dendrimer, in which approximately 35% of peripheral amino groups, was coated with maltotriose have been defined as PPI-G4-OS-M3 and was used in concentration of 8 mg/ml (the IC50 value for this dendrimer). 'OS' abbreviation stands for the open shell structure of carbohydrate-modified dendrimers. The molar mass of this PPI dendrimer was 31000 g/mol. Fludarabine (FA, Genzyme) in concentration of 1.6 µ M, based on previous studies, was used. MEC-1 (DSMZ no. ACC 497) was used as a homogenous cell line with del(17p)(11q). In cultures the percentage of apoptotic cells was verified using AnnV and PI by means of flow cytometer. Cells predominated in the early stage of apoptosis. A microarray gene expression (Agilent SurePrint Technologies) was performed. Samples were hybridized to a whole human genome microarray 8x60K. Arrays were scanned on Agilent DNA Microarray Scanner. Data were deposited at Gene Expression Omnibus (GEO) (accession number GSE68094). Analysis of differential expression of genes was done with the limma method (Smyth, G. K., 2004) as implemented in R/Bioconductor software. We used the FDR multiple testing adjustment. We declared as differentially expressed the genes with FDR-adjusted p-value <0.1, which means that 10% of genes declared as DE are expected to be false positives. Results PPI-G4-OS-M3 dendrimer depicts the ability to inhibit the proliferation increases with the rise in dendrimer concentration (MethoCultTM Assay, Stemcell Technology). Microarray data analysis pointed 7 out of 100 members of Wnt genes whose expression was significantly important. Details concerning genes description and expression are collected in the table 1. Table 1. Wnt genes expression in MEC-1 cells under influence of dendrimers and FA in 4-hour-cultures. PPI-G4-OS-M3 FA Probe set Gene symbol Gene full name logFC adj P value logFC adj P value P102117 WNT10A Wingless-type MMTV integration site family, member 10A -0.59 0.04 -0.56 0.03 P81103 SFRP2 Secreted frizzled-related protein 2 0.96 0.04 -0.59 0.07 P65518 DACT1 Dishevelled-binding antagonist of beta-catenin 1 0.66 0.05 0.81 0.03 P206359 CDH1 Cadherin 1 type 1 -0.71 0.05 -0.99 0.03 P119916 WNT6 Wingless-type MMTV integration site family, member 6 -1.93 0.1 -0.23 0.8 (NS) P1505 LRP5 Low density lipoprotein receptor-related protein 5 0.39 0.1 -0.28 0.1 P117029 LDLR Low density lipoprotein receptor 0.21 0.1 -0.49 0.03 Conclusion: Our results show significant changes and differences in some of Wnt/β-catenin pathway genes expression in CLL influenced by glycodendrimer and FA treatment. The downregulation in WNT10A, WNT6, SFRP2 expression results in β-catenin less phosphorylation and is subjected to proteosomal degradation. LRP5 and LDLR genes expression is also weak thus a reaction cascade is blocked and transcription process is suppressed. The loss of Wnt signals by dendrimers and FA treatment induces a reduction in the proliferation and survival of treatment resistant cell line MEC-1. To summarize, the PPI-G4-OS-M3 dendrimer demonstrated inhibition of proliferation beside higher cytotoxicity towards CLL cells. Its potency is similar to FA widely used in CLL therapy. Thus, dendrimers are a potential tool for CLL treatment. The study was partially supported by Grant No. DEC-2011/01/B/NZ5/01371from the National Science Centre, Poland Disclosures Robak: Novartis: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding.

Effect of Prunus Dulcis & Álpha-Tocopherol in Ethanol Induced Dyslipidemia In Wistar Rats

2020 ◽  
Vol 13 (4) ◽  
pp. 1619-1624
Author(s):  
Samuel Sundar Doss ◽  
J. Vijayakumar ◽  
E. Sukumar ◽  
K. Rekha
Keyword(s):  
Wistar Rats ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Prunus Dulcis ◽  
Alpha Tocopherol ◽  
Control Group ◽  
P Value ◽  
Low Density ◽  
Ethanol Group ◽  
Beneficial Effects

The study is aimed at assessing the effect of Prunus dulcis and alpha-tocopherol treatment against ethanol induced dyslipidemia in Wistar rats. 30 albino Wistar rats were selected based on the selection criteria and equally distributed into 5 groups – Control, ethanol, Prunus dulcis, alpha-tocopherol and combination of alpha-tocopherol + Prunus dulcis treated for 40 days. After the treatment for 40 days, all the animals were euthanized and a retro-orbital puncture was made to collect the blood samples for biochemical investigations. Obtained results were statistically analysed using ANOVA. Compared to ethanol group alpha tocopherol, Prunus dulcis and alpha tocopherol + Prunus dulcis treatment significantly decreased total cholesterol and triglycerides levels with p value <0.001. High density lipoprotein (66.31%) levels in the ethanol group were decreased compared to the control group and were significantly increased in other groups. Low density lipoprotein and Very low density lipoprotein levels were higher in the ethanol group compared with the control group and were significantly reduced in other groups with p value <0.001. Results suggest that ethanol has an ill effect on the lipid profile. Treatment with Prunus dulcius and alpha-tocopherol both solely or in combination has produced beneficial effects against dyslipidemia.

scholarly journals A novel Mendelian randomization method identifies causal relationships between gene expression and low-density lipoprotein cholesterol levels

2019 ◽  
Author(s):  
Adriaan van der Graaf ◽  
Annique Claringbould ◽  
Antoine Rimbert ◽  
Harm-Jan Westra ◽  
Yang Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Causal Relationships ◽  
Low Density Lipoprotein Cholesterol ◽  
Individual Level

AbstractRobust inference of causal relationships between gene expression and complex traits using Mendelian Randomization (MR) approaches is confounded by pleiotropy and linkage disequilibrium (LD) between gene expression quantitative loci (eQTLs). Here we propose a new MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data. In simulations, MR-link shows false positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other MR methods we tested, even when only one eQTL variant is present. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals and eQTLs summary statistics from whole blood and liver identified 19 genes causally linked to LDL-C. These include the previously functionally validatedSORT1gene, and thePVRL2gene, located in theAPOElocus, for which a causal role in liver was yet unknown. Our results showcase the strength of MR-link for transcriptome-wide causal inferences.

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