A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1405-1416 ◽  
Author(s):  
Chris I. Jones ◽  
Sarah Bray ◽  
Stephen F. Garner ◽  
Jonathan Stephens ◽  
Bernard de Bono ◽  
...  
Keyword(s):  
Protein Expression ◽  
Signaling Pathways ◽  
Adenosine Diphosphate ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Platelet Response ◽  
Single Nucleotide ◽  
Northern European ◽  
Platelet Signaling ◽  
Selection Of

AbstractPlatelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3′ untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca2+ levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks.

scholarly journals 173 The role of an intronic single nucleotide polymorphism within the dopamine receptor type-2 gene on pituitary prolactin protein expression in bulls

2020 ◽  
Vol 98 (Supplement_2) ◽  
pp. 37-37
Author(s):  
Andrea N DeCarlo ◽  
Keelee J McCarty ◽  
Sarah K Richey ◽  
Nathan Long ◽  
Scott Pratt
Keyword(s):  
Protein Expression ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Genotypic Effect ◽  
Single Nucleotide ◽  
Detection Range ◽  
Cull Cows ◽  
Densitometry Analysis ◽  
Pcr Products

Abstract Detrimental effects to male reproductive physiology have been observed due to changes in prolactin (PRL) serum concentration. Regulation of PRL by dopamine binding to the dopamine type-2 receptor (DRD2) is well defined and associations between male physiology and single nucleotide polymorphisms (SNPs) within the DRD2 gene have been observed. The objective of the study was to evaluate association of a DRD2 SNP to PRL protein expression in bulls. Testis and epididymis were collected from bulls grazing a forage containing or lacking a dopamine agonist at the end of a 126 d study (n = 14). Bovine pituitaries (n = 587) were collected randomly over 3 mo from a local abattoir which processes cull cows and bulls. Sex of pituitaries was verified (n = 259 males) by duplex PCR for amplification of SRY and b-actin followed by Southern blotting of PCR products for selection of male. Prolactin protein expression was assessed in testis, epididymis, and pituitary by western blotting. Expression of PRL protein was below detection range in reproductive tissues but was present in pituitary, therefore experiments continued in pituitary. Restriction fragment length polymorphism genotyping was performed on pituitaries by amplification of the DRD2 SNP region followed by digestion with a Tfil enzyme. Digested of products produced 3,2, or 1 band (AG, AA, GG, respectively). A subset of male pituitaries was blotted by slot blot manifold and PRL protein expression assessed by immunodetection and densitometry analysis normalized to GAPDH expression. Pituitary genotype distribution was 17.4% AA (n = 16), 63% AG (n = 58), and 19.6% GG (n = 18). Prolactin protein expression in the pituitary was similar across genotype (P = 0.23). These findings indicate that the DRD2 SNP has no genotypic effect on PRL protein expression in bovine pituitary.

Abstract 14359: Single Nucleotide Polymorphisms in Genes Involved in L-arginine / Dimethylarginine Metabolism Predispose for Pulmonary Hypertension and Acute Mountain Sickness at High Altitude

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Juliane Hannemann ◽  
Julia Zummack ◽  
PATRICIA SIQUES ◽  
JULIO BRITO ◽  
Rainer Boeger
Keyword(s):  
Pulmonary Hypertension ◽  
Relative Risk ◽  
Genetic Variability ◽  
High Altitude ◽  
Acute Mountain Sickness ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Mountain Sickness ◽  
Study Participants

Introduction: Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension. Hypothesis: We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension. Methods: We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation. Results: Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p<0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p<0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (>25 mm Hg) of 1.70 (1.56-1.85; p<0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (>30 mm Hg) of 1.58 (1.47-1.69; p<0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness. Conclusions: We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.

scholarly journals Selection of X-chromosome Inactivation Model

2017 ◽  
Vol 16 ◽  
pp. 117693511774727 ◽  
Author(s):  
Jian Wang ◽  
Rajesh Talluri ◽  
Sanjay Shete
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Association Test ◽  
Chromosome Inactivation ◽  
Simulation Studies ◽  
Nucleotide Polymorphisms ◽  
Unified Approach ◽  
Cancer Genetic ◽  
Single Nucleotide ◽  
Selection Of

To address the complexity of the X-chromosome inactivation (XCI) process, we previously developed a unified approach for the association test for X-chromosomal single-nucleotide polymorphisms (SNPs) and the disease of interest, accounting for different biological possibilities of XCI: random, skewed, and escaping XCI. In the original study, we focused on the SNP-disease association test but did not provide knowledge regarding the underlying XCI models. One can use the highest likelihood ratio (LLR) to select XCI models (max-LLR approach). However, that approach does not formally compare the LLRs corresponding to different XCI models to assess whether the models are distinguishable. Therefore, we propose an LLR comparison procedure (comp-LLR approach), inspired by the Cox test, to formally compare the LLRs of different XCI models to select the most likely XCI model that describes the underlying XCI process. We conduct simulation studies to investigate the max-LLR and comp-LLR approaches. The simulation results show that compared with the max-LLR, the comp-LLR approach has higher probability of identifying the correct underlying XCI model for the scenarios when the underlying XCI process is random XCI, escaping XCI, or skewed XCI to the deleterious allele. We applied both approaches to a head and neck cancer genetic study to investigate the underlying XCI processes for the X-chromosomal genetic variants.

scholarly journals A Novel Test System for Genotyping rs43703016 Single-nucleotide Substitutions in the Bovine CSN3 Gene

2019 ◽  
pp. 1-5
Author(s):  
Svetlana Kovalchuk ◽  
Arina Tagmazyan ◽  
Eugene Klimov
Keyword(s):  
Nucleotide Substitution ◽  
Milk Proteins ◽  
Test System ◽  
Nucleotide Polymorphisms ◽  
Dna Testing ◽  
Nucleotide Substitutions ◽  
Single Nucleotide ◽  
Allele Specific ◽  
Selection Of

Aims: Caseins are among the main milk proteins that determine many of its properties. Bovine kappa-casein (CSN3) is associated with the qualitative composition of milk, as well as with the quality of cheese obtained from this milk. The rs43703016 single-nucleotide substitution (g.88532332A>C; Asp148Ala) in exon 4 of the bovine CSN3 gene plays an important role in the production of quality hard cheeses. Various methods for the DNA testing of this substitution have been developed in the last three decades. Emergent DNA technologies provide an opportunity to modernize methods of genotyping single-nucleotide polymorphisms. Results: We have developed and verified a method to differentiate A/C alleles of the rs43703016 substitution in the bovine CSN3 gene by real-time PCR using allele-specific fluorescent probes. Conclusion: Our new method allows fast genotyping of animals, and may be used for selection of cows carrying the CC genotype, which determines good cheese-making properties of milk.

scholarly journals Genetic Association Study of KCNQ5 Polymorphisms with High Myopia

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Xuan Liao ◽  
Maurice K. H. Yap ◽  
Kim Hung Leung ◽  
Patrick Y. P. Kao ◽  
Long Qian Liu ◽  
...  
Keyword(s):  
Refractive Error ◽  
Odds Ratio ◽  
High Myopia ◽  
Permutation Test ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Association Testing ◽  
Hypersensitive Sites

Identification of genetic variations related to high myopia may advance our knowledge of the etiopathogenesis of refractive error. This study investigated the role of potassium channel gene (KCNQ5) polymorphisms in high myopia. We performed a case-control study of 1563 unrelated Han Chinese subjects (809 cases of high myopia and 754 emmetropic controls). Five tag single-nucleotide polymorphisms (SNPs) of KCNQ5 were genotyped, and association testing with high myopia was conducted using logistic regression analysis adjusted for sex and age to give Pasym values, and multiple comparisons were corrected by permutation test to give Pemp values. All five noncoding SNPs were associated with high myopia. The SNP rs7744813, previously shown to be associated with refractive error and myopia in two GWAS, showed an odds ratio of 0.75 (95% CI 0.63–0.90; Pemp = 0.0058) for the minor allele. The top SNP rs9342979 showed an odds ratio of 0.75 (95% CI 0.64–0.89; Pemp = 0.0045) for the minor allele. Both SNPs are located within enhancer histone marks and DNase-hypersensitive sites. Our data support the involvement of KCNQ5 gene polymorphisms in the genetic susceptibility to high myopia and further exploration of KCNQ5 as a risk factor for high myopia.

scholarly journals Molecular Screening and Association Analyses of the Interleukin 6 Receptor Gene Variants with Type 2 Diabetes, Diabetic Nephropathy, and Insulin Sensitivity

2005 ◽  
Vol 90 (2) ◽  
pp. 1123-1129 ◽  
Author(s):  
Hua Wang ◽  
Zhengxian Zhang ◽  
Winston Chu ◽  
Terri Hale ◽  
Judith J. Cooper ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Insulin Sensitivity ◽  
Single Nucleotide Polymorphisms ◽  
Untranslated Region ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Northern European ◽  
A Minor

IL-6 levels and polymorphisms have been implicated in type 2 diabetes mellitus (T2DM) and insulin resistance. The IL-6 receptor (IL-6R) comprises two subunits, IL-6R and gp130, of which IL-6R confers specificity to IL-6 action and is located in a region of replicated linkage to T2DM on chromosome 1q21. We screened this gene for variation in Northern European Caucasian and African-American ethnic groups. We identified 11 variants with a minor allele frequency over 5%, including two amino acid changes (D358A and V385I) and four variants in the 3′ untranslated region. No variant was associated with obesity or measures of insulin sensitivity, but two single nucleotide polymorphisms in the 3′ untranslated region showed a trend to an association with T2DM in all Caucasians, and three single nucleotide polymorphisms, including D358A, showed a trend (P &lt; 0.06) to an association with T2DM among the subset of Northern European Caucasians. Variant V385I was unique to African-Americans and was significantly associated with diabetes and diabetic nephropathy (P &lt; 0.05). Among individuals heterozygous for the four variants in the transcribed sequence, one allele was significantly overrepresented, thus suggesting the existence of a regulatory variant controlling mRNA stability or expression. IL-6R is not likely to explain the linkage to diabetes in this region, but our work supports a minor role of variants in T2DM risk and suggests that sequence variants may alter IL-6R mRNA levels and possibly levels of soluble IL-6R.

scholarly journals Genome-Wide Association Study of Body Weight Traits in Chinese Fine-Wool Sheep

Animals ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 170 ◽  
Author(s):  
Zengkui Lu ◽  
Yaojing Yue ◽  
Chao Yuan ◽  
Jianbin Liu ◽  
Zhiqiang Chen ◽  
...  
Keyword(s):  
Body Weight ◽  
Muscle Development ◽  
Genome Wide Association Study ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Economic Trait ◽  
Significance Levels ◽  
Genomic Regions ◽  
Selection Of

Body weight is an important economic trait for sheep and it is vital for their successful production and breeding. Therefore, identifying the genomic regions and biological pathways that contribute to understanding variability in body weight traits is significant for selection purposes. In this study, the genome-wide associations of birth, weaning, yearling, and adult weights of 460 fine-wool sheep were determined using resequencing technology. The results showed that 113 single nucleotide polymorphisms (SNPs) reached the genome-wide significance levels for the four body weight traits and 30 genes were annotated effectively, including AADACL3, VGF, NPC1, and SERPINA12. The genes annotated by these SNPs significantly enriched 78 gene ontology terms and 25 signaling pathways, and were found to mainly participate in skeletal muscle development and lipid metabolism. These genes can be used as candidate genes for body weight in sheep, and provide useful information for the production and genomic selection of Chinese fine-wool sheep.

Use of CA9 gene single nucleotide polymorphisms to predict prognosis and treatment response of metastatic renal cell carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5003-5003
Author(s):  
M. de Martino ◽  
T. Klatte ◽  
D. B. Seligson ◽  
J. LaRochelle ◽  
B. Shuch ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Single Nucleotide Polymorphisms ◽  
Protein Expression ◽  
Renal Cell ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Allele Variant ◽  
Caix Expression

5003 Background: Carbonic anhydrase 9 gene (CA9) is located in a prognostically relevant chromosomal area on chromosome 9p and is encoding for one of the most significant protein markers in metastatic renal cell carcinoma (MRCC), CAIX. In contrast to CAIX protein, however, no efforts have been made to date to study CA9 gene in metastatic RCC. Here, we test the hypotheses that single nucleotide polymorphisms (SNPs) and mutations of the CA9 gene are associated with CAIX expression, response to immunotherapy and survival. Methods: Genomic DNA was extracted from frozen tumor samples of 54 patients with clear cell MRCC. All exons of the CA9 gene were PCR-amplified and sequenced. The antibody M75 was used to evaluate CAIX protein expression immunohistochemically. Statistical associations of CA9 gene status and CAIX protein expression with response to IL-2 based immunotherapy and overall survival were assessed with chi-square tests, t-tests, Kaplan-Meier survival estimates and Cox proportional hazards regression models. Results: CA9 reference SNP (rs) 2071676 was found in 59%, rs12553173 in 15%, rs3829078 in 11% and rs1048638 in 33% of the patients. The deletion c.376del393 was observed in two patients. CAIX expression was high (>85%) in 65% of the patients. None of the SNPs was significantly associated with CAIX expression. Patients with the C allele variant of rs12553173 had improved median survival (27.3 vs. 13.6 months, p = 0.0431) and a greater likelihood of response to IL-2 (57% vs. 22%, p = 0.081) Likewise, high CAIX expression was associated with longer median survival (25.5 vs. 8.5 months, p < 0.0001) and a greater IL-2 response rate (37% vs. 8%, p = 0.070). In a multivariate Cox model, both C allele variant of CA9 SNP rs12553173 and CAIX expression were retained as independent prognostic factors. Conclusions: CA9 SNPs are frequently found in patients with MRCC. The C allele variant of rs12553173 is associated with improved overall survival and a greater likelihood of response to IL-2. CA9 rs12553173 and CAIX are both independent prognostic factors of overall survival and complementary in predicting prognosis of MRCC. No significant financial relationships to disclose.

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