scholarly journals Impact of regulatory variation from RNA to protein

Science ◽  
2014 ◽  
Vol 347 (6222) ◽  
pp. 664-667 ◽  
Author(s):  
Alexis Battle ◽  
Zia Khan ◽  
Sidney H. Wang ◽  
Amy Mitrano ◽  
Michael J. Ford ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Messenger Rna ◽  
Effect Sizes ◽  
Posttranslational Regulation ◽  
Transcript Expression ◽  
Protein Abundance ◽  
Expression Levels ◽  
Protein Levels ◽  
Potential Impact ◽  
The Impact

The phenotypic consequences of expression quantitative trait loci (eQTLs) are presumably due to their effects on protein expression levels. Yet the impact of genetic variation, including eQTLs, on protein levels remains poorly understood. To address this, we mapped genetic variants that are associated with eQTLs, ribosome occupancy (rQTLs), or protein abundance (pQTLs). We found that most QTLs are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, eQTLs tend to have significantly reduced effect sizes on protein levels, which suggests that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we identified a class of cis QTLs that affect protein abundance with little or no effect on messenger RNA or ribosome levels, which suggests that they may arise from differences in posttranslational regulation.

Genetic variants in R-Spondin/RNF43 complex and gene expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 190-190
Author(s):  
Francesca Battaglin ◽  
Yi Xiao ◽  
Joshua Millstein ◽  
Andreas Seeber ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Multivariable Analysis ◽  
Colorectal Carcinogenesis ◽  
Phase Iii ◽  
First Line ◽  
Tissue Samples ◽  
Expression Levels ◽  
The Impact ◽  
Gene Expression Levels

190 Background: Wnt signaling deregulation is a primary driver of colorectal carcinogenesis. RNF43 is a key suppressor of Wnt activation while R-Spodin inhibits RNF43 activity. RNF43 mutations are associated with the serrated neoplasia pathway, BRAF mutation and MSI. We hypothesized that genetic variants in the R-Spodin/RNF43 complex and corresponding genes expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 17 functional SNPs within RNF43/ ZNRF3, LGR4/5 and RSPO1/2/3 was analyzed in 129 pts treated with first-line FOLFIRI/cet and 107 pts treated with FOLFIRI/bevacizumab (bev). Gene expression levels were measured from tumor tissue samples from 102 pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. False discovery rate (FDR) for gene expression analysis was computed using the Benjamini-Hochberg approach (significant Q < 0.1). Results: In the cet cohort, pts with the C/C genotype of ZNRF3 rs132531 had significantly shorter overall survival compared to any T allele carriers (mOS: 20.3 vs 52 mo) in both univariable (HR 3.61, 95% CI 1.65-7.88, P < .001) and multivariable analysis (adjusted P = .01). Conversely, RSPO1 rs4652964 any G allele carriers showed increased tumor response (TR) rates compared to the A/A genotype (83 vs 66 %, P = .04). These associations were not observed in bev arm. Lower gene expression levels of RNF43 were associated with shorter PFS in pts with right-sided tumors receiving FOLFIRI/cet ( P = .006, Q < 0.1). RSPO1 expression levels were also associated with TR in the same subgroup (70 vs 10% in high vs low; P = .001, Q < .05). RNF43 expression was associated with TR in pts with left-sided tumors (82% in high vs 58% in low, P = .014, Q = 0.1). Conclusions: Our results provide the first evidence that germline polymorphisms and tumor gene expression levels of RNF43/ ZNRF3 and RSPO1 may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and contribute to modulate anti-EGFRs activity.

scholarly journals Effectiveness of nudges on small business tax compliance behavior

2020 ◽  
Vol 3 (2) ◽  
Author(s):  
Laura Leets ◽  
Amber Sprenger ◽  
Robert Hartman ◽  
Nicholas Kohn ◽  
Juli Simon Thomas ◽  
...  
Keyword(s):  
Tax Compliance ◽  
Business Owners ◽  
Decision Makers ◽  
Social Utility ◽  
Effect Sizes ◽  
Average Amount ◽  
Compliance Behavior ◽  
Potential Impact ◽  
Reminder Letters ◽  
The Impact

There has been a surge of basic and applied interest in exploring how small changes in decision contexts might be used to improve heuristic decision-making, “nudging” decision-makers toward choices that increase individual and social utility. The present study tested the impact of three types of nudges on tax compliance among delinquent businesses (n=3,130) in the state of Pennsylvania: (1) sending reminder letters that almost identically matched original tax delinquency notices, (2) sending redesigned reminder letters that simplified text and layout, increased the salience of critical information, and included an “Act Now” urgency statement, and (3) sending redesigned reminder letters with handwritten notes on the envelope. Redesigned reminder letters significantly increased the number of business owners who responded and the amount of delinquency paid within 15 days of receiving the notices. The addition of a handwritten note on the outside of the envelope did not additionally increase response rates or payment amount. Although the effect sizes observed in this study were small, the potential impact is large given the number of delinquent businesses and the average amount of taxes owed in Pennsylvania.

Genetic variants in the lipopolysaccharide (LPS) receptor complex and TLR4 expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 564-564
Author(s):  
Francesca Battaglin ◽  
Alberto Puccini ◽  
Shu Cao ◽  
Joshua Millstein ◽  
Ryuma Tokunaga ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Receptor Complex ◽  
Tlr4 Expression ◽  
First Line ◽  
Expression Levels ◽  
Ras Status ◽  
In Fire ◽  
The Impact

564 Background: Large metagenomic studies associate disrupted gut microbiome signatures, comprising more prevalently gram-negative bacteria, with CRC carcinogenesis. TLR4, the LPS receptor, has been involved in microbiota-mediated tumorigenesis. High TLR4 expression is associated with poor prognosis in CRC and TLR4 can activate EGFR through ligands epiregulin and amphiregulin. Hence, we hypothesized that genetic variants in the LPS receptor complex and TLR4 expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 5 functional SNPs within TLR4, MD2 and CD14 was analyzed in 129 pts treated with first-line FOLFIRI/cet (discovery, mPFS/OS: 12.8/49.8 mo) and 107 pts treated with FOLFIRI/bevacizumab (bev) (mPFS/OS: 11.5/31.4 mo). Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the discovery cohort, pts carrying the C/T variant of TLR4 rs4986791 had significantly shorter mPFS and OS compared to the C/C genotype in both uni- and multivariable analysis (PFS: 5.4 vs 13.3 mo, adjusted P[ Padj] = .01; OS: 21.7 vs 40.7 mo, Padj= .03). Conversely, C/C carriers of rs12377632 had a longer mPFS compared to any T in uni- and multivariable analysis (15.8 vs 12.2 mo, Padj< .001). Any A allele carriers of MD2 rs12546552 and any G allele carriers of CD14 rs2569190 showed shorter mPFS in multivariable analyses. These associations were not observed in bev arm. Significant interaction was found between TLR4 rs12377632 and RAS status ( P= .015). High TLR4 expression (log2 > 10.93) was associated with worse mPFS (7.2 vs 11 mo, P= .003) and OS (19.1 vs 29.8 mo, P< .001) in FIRE-3 cet arm. Conclusions: Our results provide the first evidence that polymorphisms in the LPS receptor complex and TLR4 expression levels may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and, overall, contribute to resistance to anti-EGFRs.

scholarly journals Selection-adjusted inference: an application to confidence intervals for cis-eQTL effect sizes

Biostatistics ◽  
2019 ◽  
Author(s):  
Snigdha Panigrahi ◽  
Junjie Zhu ◽  
Chiara Sabatti
Keyword(s):  
Confidence Intervals ◽  
Genetic Polymorphisms ◽  
Genetic Variants ◽  
Tissue Sample ◽  
Practical Importance ◽  
Small Sample ◽  
Conditional Inference ◽  
Effect Sizes ◽  
Expression Levels ◽  
Testing Procedures

Summary The goal of expression quantitative trait loci (eQTL) studies is to identify the genetic variants that influence the expression levels of the genes in an organism. High throughput technology has made such studies possible: in a given tissue sample, it enables us to quantify the expression levels of approximately 20 000 genes and to record the alleles present at millions of genetic polymorphisms. While obtaining this data is relatively cheap once a specimen is at hand, obtaining human tissue remains a costly endeavor: eQTL studies continue to be based on relatively small sample sizes, with this limitation particularly serious for tissues as brain, liver, etc.—often the organs of most immediate medical relevance. Given the high-dimensional nature of these datasets and the large number of hypotheses tested, the scientific community has adopted early on multiplicity adjustment procedures. These testing procedures primarily control the false discoveries rate for the identification of genetic variants with influence on the expression levels. In contrast, a problem that has not received much attention to date is that of providing estimates of the effect sizes associated with these variants, in a way that accounts for the considerable amount of selection. Yet, given the difficulty of procuring additional samples, this challenge is of practical importance. We illustrate in this work how the recently developed conditional inference approach can be deployed to obtain confidence intervals for the eQTL effect sizes with reliable coverage. The procedure we propose is based on a randomized hierarchical strategy with a 2-fold contribution: (1) it reflects the selection steps typically adopted in state of the art investigations and (2) it introduces the use of randomness instead of data-splitting to maximize the use of available data. Analysis of the GTEx Liver dataset (v6) suggests that naively obtained confidence intervals would likely not cover the true values of effect sizes and that the number of local genetic polymorphisms influencing the expression level of genes might be underestimated.

scholarly journals Association of the Adipokines Chemerin, Apelin, Vaspin and Omentin and Their Functional Genetic Variants with Rheumatoid Arthritis

2021 ◽  
Vol 11 (10) ◽  
pp. 976
Author(s):  
Alaa S. Wahba ◽  
Maha E. Ibrahim ◽  
Dina M. Abo-elmatty ◽  
Eman T. Mehanna
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Genetic Variants ◽  
Serum Levels ◽  
Expression Levels ◽  
Protein Levels ◽  
Egyptian Patients ◽  
Gene Expression Levels ◽  
Increased Susceptibility

Adipokines were shown to exert crucial roles in rheumatic diseases. This study aimed to assess the role of chemerin, apelin, vaspin, and omentin adipokines and their genetic variants rs17173608, rs2235306, rs2236242, and rs2274907, respectively, in rheumatoid arthritis (RA) pathogenesis in Egyptian patients. A total of 150 RA patients and 150 healthy individuals were recruited. Blood samples were collected and used for genotyping. Serum was separated and used for expression analysis by quantitative PCR, and various biochemical markers determination by ELISA. Serum protein levels of chemerin and vaspin, as well as their gene expression levels were higher, while those of apelin and omentin were lower in RA patients and were associated with most of RA clinical and laboratory characteristics. G allele of chemerin rs17173608, T allele of vaspin rs2236242, and T allele of omentin rs2274907 were more frequent in RA patients. Serum levels and gene expression levels of chemerin in GG genotype carriers and vaspin in TT genotype group were significantly higher, while those of omentin in TT genotype carriers were significantly lower than RA patients with other genotypes. There was no association between apelin rs2235306 and RA. Chemerin rs17173608, vaspin rs2236242, and omentin rs2274907 polymorphisms were associated with increased susceptibility to RA.

Lung cancer susceptibility genetic variants modulate HOXB2 expression in the lung

2018 ◽  
Vol 62 (11-12) ◽  
pp. 857-864 ◽  
Author(s):  
Alisson Clemenceau ◽  
Olivier Boucherat ◽  
Kim Landry-Truchon ◽  
Maxime Lamontagne ◽  
Sabrina Biardel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Tissue ◽  
Genetic Variants ◽  
Hox Genes ◽  
Cancer Susceptibility ◽  
Ectopic Expression ◽  
Gene Clusters ◽  
Tissue Samples ◽  
Expression Levels ◽  
Protein Levels

The HOX genes are transcription factors that are expressed in coordinated spatiotemporal patterns to ensure normal development. Ectopic expression may instead lead to the development and progression of tumors. Genetic polymorphisms in the regions of four HOX gene clusters were tested for association with lung cancer in 420 cases and 3,151 controls. The effect of these variants on lung gene expression (expression quantitative trait loci, eQTL) was tested in a discovery set of 409 non-tumor lung samples and validated in two lung eQTL replication sets (n = 287 and 342). The expression levels of HOXB2 were evaluated at the mRNA and protein levels by quantitative real-time PCR and immunohistochemistry in paired tumor and non-tumor lung tissue samples. The most significant SNP associated with lung cancer in the HOXB cluster was rs10853100 located upstream of the HOXB cluster. HOXB2 was the top eQTL-regulated gene with several polymorphisms associated with its mRNA expression levels in lung tissue. This includes the lung cancer SNP rs10853100 that was significantly associated with HOXB2 expression (P=3.39E-7). In the lung eQTL discovery and replication sets, the lung cancer risk allele (T) for rs10853100 was associated with lower HOXB2 expression levels. In paired normal-tumor samples, HOXB2 mRNA and protein levels were significantly reduced in tumors when compared to non-tumor lung tissues. Genetic variants in the HOXB cluster may confer susceptibility to lung cancer by modulating the expression of HOXB2 in the lung.

scholarly journals Rare Genetic Variants Underlie Outlying levels of DNA Methylation and Gene-Expression

2020 ◽  
Author(s):  
V. Kartik Chundru ◽  
Riccardo E. Marioni ◽  
James G. D. Pendergast ◽  
Tian Lin ◽  
Allan J. Beveridge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Phenotypic Variation ◽  
Genetic Variants ◽  
Rare Variants ◽  
Effect Sizes ◽  
Expression Levels ◽  
Low Level ◽  
Rare Genetic Variants ◽  
Gene Expression Levels

AbstractTesting the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on low-level genomic traits, such as gene expression or DNA methylation (DNAm), as effect sizes are expected to be larger for low-level compared to higher-order complex traits. Here, we investigate DNAm in healthy ageing populations - the Lothian Birth cohorts of 1921 and 1936 and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic variants within 1kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels towards the tails of the population distribution. Overall, this study demonstrates the role of rare variants in the phenotypic variation of low-level genomic traits, and the effect of extreme levels of DNAm on gene expression.

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

Pengaruh Lama Pengasinan Terhadap Kadar Protein Putih Telur Itik

2014 ◽  
Vol 1 (1) ◽  
pp. 36 ◽  
Author(s):  
Siti Fatimah ◽  
Muji Rahayu ◽  
Siti Aminah
Keyword(s):  
Protein Level ◽  
Egg White ◽  
Special Treatment ◽  
Egg White Protein ◽  
Protein Levels ◽  
Duck Egg ◽  
Egg Period ◽  
Graph Presentation ◽  
And Control ◽  
The Impact

Background : Egg  is one of the animal protein source, which has delicious taste, easy to digest and highly nutritious. Besides its affordable price, its supply availability is unquestionable as well. However, due to its short storability, it requires special treatment, such as preserving, to store it for long period. One way to preserve the egg is by pickling egg, which generally requires seven to ten days of marinating. During the process of marinating, there will be a visual change of egg white and yolk. Their structures  will be more solid (the occurrence of thickening process) because salinization will lead to protein denaturalization. Consequently, it has an influence as well towards the content of egg white protein of duck egg. This study is aimed to explore the impact of various time of pickling egg towards egg white protein of duck egg. Method  : The study where takes place in a laboratories, is a true experimental study for the reason that the researcher must provide intervention, hence all of potentially confounding variables are manageable. Samples that had been used in this study are duck eggs which were bought from North Brebes. This study is expected to generate data from four various time of pickling egg and control (no treatment). Since there are four samples, accordingly the number of data resulted are twenty. The resulted data will be descriptively presented in table, graph, presentation, and narration. Result  : Protein level examination within duck white egg shows changes  in protein levels that occurs in every variation of pickling egg time, where the average results of the assay of duck egg white protein is 14.94% without treatment (control), in five days of pickling time is 13.68%, in seven days of pickling time is 13.29%, in nine days of pickling time is 12.87% and eleven days of pickling time is 12.78%. Conclusion  : There is a significant impact among the period of pickling time to the protein level degradation of duck white egg. Keywords : Duck egg, period of pickling time, level protein of duck white egg.

Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels

2007 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen M. Riordan ◽  
Narelle A. Skinner ◽  
Christopher J. Mciver ◽  
Qing Liu ◽  
Stig Bengmark ◽  
...  
Keyword(s):  
Liver Function ◽  
Messenger Rna ◽  
Protein Levels ◽  
Cirrhotic Patients
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