scholarly journals Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3

2021 ◽  
Author(s):  
Nicholas B. Blackburn ◽  
Peter J. Meikle ◽  
Juan M. Peralta ◽  
Satish Kumar ◽  
Ana C. Leandro ◽  
...  
Keyword(s):  
Mexican Americans ◽  
Genetic Basis ◽  
Chromosome 1 ◽  
Gene Location ◽  
Atherosclerotic Cardiovascular Disease ◽  
Loss Of Function ◽  
Protein Levels ◽  
Extended Pedigrees ◽  
Heart Study ◽  
A Genome

Background - The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease (ASCVD) is of fundamental importance given its global health and economic burden. Inhibition of angiopoietin-like 3 (ANGPTL3) has demonstrated a cardioprotective effect, showing promise for ASCVD treatment, and is currently the focus of ongoing clinical trials. Here we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. Methods - We assayed ANGPTL3 protein levels in ~1,000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. Results - In a variance components framework we identified that variation in ANGPTL3 was significantly heritable (h 2 =0.33, P=1.31×10 -16 ). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (LOD = 6.18) to a locus on chromosome 1 at 90 cM, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss of function (LoF) variant, rs398122988 (N121Kfs*2), in ANGPTL3 , that was significantly associated with lower ANGPTL3 levels (β=−1.69 SDU, P=3.367×10 -13 ), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. Conclusions - Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and LoF variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for ASCVD.

scholarly journals A Quantitative Trait Locus on Chromosome 5p Influences D-Dimer Levels in the San Antonio Family Heart Study

2010 ◽  
Vol 2010 ◽  
pp. 1-6
Author(s):  
V. P. Diego ◽  
L. Almasy ◽  
D. L. Rainwater ◽  
M. C. Mahaney ◽  
A. G. Comuzzie ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Mexican Americans ◽  
San Antonio ◽  
Lod Score ◽  
Family Heart Study ◽  
Heart Study ◽  
A Genome ◽  
Increased Risk ◽  
Chromosome 5P ◽  
D Dimer

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD).Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P≈.00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM.Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.

scholarly journals A genome-wide association study of serum proteins reveals shared loci with common diseases

2021 ◽  
Author(s):  
Alexander Gudjonsson ◽  
Valborg Gudmundsdottir ◽  
Gisli T Axelsson ◽  
Elias F Gudmundsson ◽  
Brynjolfur G Jonsson ◽  
...  
Keyword(s):  
Genetic Association ◽  
Genetic Variants ◽  
Large Scale ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Serum Proteins ◽  
Association Studies ◽  
Loss Of Function ◽  
Protein Levels ◽  
A Genome

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,113 independent associations between genetic variants and 2,099 serum proteins, of which 37% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a proteins genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

scholarly journals LOXL1 confers antiapoptosis and promotes gliomagenesis through stabilizing BAG2

2020 ◽  
Vol 27 (11) ◽  
pp. 3021-3036 ◽  
Author(s):  
Hua Yu ◽  
Jun Ding ◽  
Hongwen Zhu ◽  
Yao Jing ◽  
Hu Zhou ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Glioma Cell ◽  
Lysyl Oxidase ◽  
The Cancer Genome Atlas ◽  
Loss Of Function ◽  
Protein Levels ◽  
Important Mediator ◽  
Cancer Genome Atlas ◽  
Potential Strategy ◽  
Glioma Progression

Abstract The lysyl oxidase (LOX) family is closely related to the progression of glioma. To ensure the clinical significance of LOX family in glioma, The Cancer Genome Atlas (TCGA) database was mined and the analysis indicated that higher LOXL1 expression was correlated with more malignant glioma progression. The functions of LOXL1 in promoting glioma cell survival and inhibiting apoptosis were studied by gain- and loss-of-function experiments in cells and animals. LOXL1 was found to exhibit antiapoptotic activity by interacting with multiple antiapoptosis modulators, especially BAG family molecular chaperone regulator 2 (BAG2). LOXL1-D515 interacted with BAG2-K186 through a hydrogen bond, and its lysyl oxidase activity prevented BAG2 degradation by competing with K186 ubiquitylation. Then, we discovered that LOXL1 expression was specifically upregulated through the VEGFR-Src-CEBPA axis. Clinically, the patients with higher LOXL1 levels in their blood had much more abundant BAG2 protein levels in glioma tissues. Conclusively, LOXL1 functions as an important mediator that increases the antiapoptotic capacity of tumor cells, and approaches targeting LOXL1 represent a potential strategy for treating glioma. In addition, blood LOXL1 levels can be used as a biomarker to monitor glioma progression.

scholarly journals Chemerin, A Novel Adipokine in the Regulation of Angiogenesis

2010 ◽  
Vol 24 (4) ◽  
pp. 874-874
Author(s):  
Kiymet Bozaoglu ◽  
Joanne E. Curran ◽  
Claire J. Stocker ◽  
Mohamed S. Zaibi ◽  
David Segal ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mexican American ◽  
Large Family ◽  
Disease Status ◽  
Human Endothelial Cells ◽  
Gene Encoding ◽  
The Metabolic Syndrome ◽  
Heart Study ◽  
A Genome ◽  
Family Based

Abstract Context: Chemerin is a new adipokine associated with obesity and the metabolic syndrome. Gene expression levels of chemerin were elevated in the adipose depots of obese compared with lean animals and was markedly elevated during differentiation of fibroblasts into mature adipocytes. Objective: To identify factors that affect the regulation and potential function of chemerin using a genetics approach. Design, setting, patients and intervention: Plasma chemerin levels were measured in subjects from the San Antonio Family Heart Study (SAFHS), a large family-based genetic epidemiological study including 1354 Mexican American individuals. Individuals were randomly sampled without regard to phenotype or disease status. Main Outcome Measures: A genome wide association analysis using 542,944 SNPs in a subset of 523 of the same subjects was undertaken. The effect of chemerin on angiogenesis was measured using human endothelial cells and interstitial cells in co-culture in a specially formulated medium. Results: Serum chemerin levels were found to be highly heritable (h2 = 0.25; P = 1.4 x 10−9). The SNP showing strongest evidence of association (rs347344; P = 1.4 x 10−6) was located within the gene encoding EDIL3, which has a known role in angiogenesis. Functional angiogenesis assays in human endothelial cells confirmed that chemerin significantly mediated the formation of blood vessels to a similar extent as VEGF. Conclusion: Here we demonstrate for the first time that plasma chemerin levels are significantly heritable and identified a novel role for chemerin as a stimulator of angiogenesis.

scholarly journals TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chengwu Xiao ◽  
Wei Zhang ◽  
Meimian Hua ◽  
Huan Chen ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

scholarly journals Genetic basis and identification of candidate genes for wooden breast and white striping in commercial broiler chickens

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Juniper A. Lake ◽  
Jack C. M. Dekkers ◽  
Behnam Abasht
Keyword(s):  
Candidate Genes ◽  
Broiler Chickens ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Specific Protein ◽  
Chromosome 11 ◽  
A Genome ◽  
White Striping ◽  
Commercial Broiler ◽  
Wooden Breast

AbstractWooden breast (WB) and white striping (WS) are highly prevalent and economically damaging muscle disorders of modern commercial broiler chickens characterized respectively by palpable firmness and fatty white striations running parallel to the muscle fiber. High feed efficiency and rapid growth, especially of the breast muscle, are believed to contribute to development of such muscle defects; however, their etiology remains poorly understood. To gain insight into the genetic basis of these myopathies, a genome-wide association study was conducted using a commercial crossbred broiler population (n = 1193). Heritability was estimated at 0.5 for WB and WS with high genetic correlation between them (0.88). GWAS revealed 28 quantitative trait loci (QTL) on five chromosomes for WB and 6 QTL on one chromosome for WS, with the majority of QTL for both myopathies located in a ~ 8 Mb region of chromosome 5. This region has highly conserved synteny with a portion of human chromosome 11 containing a cluster of imprinted genes associated with growth and metabolic disorders such as type 2 diabetes and Beckwith-Wiedemann syndrome. Candidate genes include potassium voltage-gated channel subfamily Q member 1 (KCNQ1), involved in insulin secretion and cardiac electrical activity, lymphocyte-specific protein 1 (LSP1), involved in inflammation and immune response.

scholarly journals A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 643
Author(s):  
Thibaud Kuca ◽  
Brandy M. Marron ◽  
Joana G. P. Jacinto ◽  
Julia M. Paris ◽  
Christian Gerspach ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Homozygosity Mapping ◽  
Mendelian Inheritance ◽  
Large Animal Model ◽  
Large Animal ◽  
Loss Of Function ◽  
Protein Coding ◽  
Positional Candidate ◽  
Genome Wide ◽  
A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

scholarly journals Candidate genes and SNPs associated with stomatal conductance under drought stress in Vitis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Massimiliano Trenti ◽  
Silvia Lorenzi ◽  
Pier Luigi Bianchedi ◽  
Daniele Grossi ◽  
Osvaldo Failla ◽  
...  
Keyword(s):  
Drought Stress ◽  
Stomatal Conductance ◽  
Candidate Genes ◽  
Water Deficit ◽  
Genetic Basis ◽  
Phenotypic Diversity ◽  
Snp Array ◽  
A Genome ◽  
Raffinose Synthase ◽  
Response To Water

Abstract Background Understanding the complexity of the vine plant’s response to water deficit represents a major challenge for sustainable winegrowing. Regulation of water use requires a coordinated action between scions and rootstocks on which cultivars are generally grafted to cope with phylloxera infestations. In this regard, a genome-wide association study (GWAS) approach was applied on an ‘ad hoc’ association mapping panel including different Vitis species, in order to dissect the genetic basis of transpiration-related traits and to identify genomic regions of grape rootstocks associated with drought tolerance mechanisms. The panel was genotyped with the GrapeReSeq Illumina 20 K SNP array and SSR markers, and infrared thermography was applied to estimate stomatal conductance values during progressive water deficit. Results In the association panel the level of genetic diversity was substantially lower for SNPs loci (0.32) than for SSR (0.87). GWAS detected 24 significant marker-trait associations along the various stages of drought-stress experiment and 13 candidate genes with a feasible role in drought response were identified. Gene expression analysis proved that three of these genes (VIT_13s0019g03040, VIT_17s0000g08960, VIT_18s0001g15390) were actually induced by drought stress. Genetic variation of VIT_17s0000g08960 coding for a raffinose synthase was further investigated by resequencing the gene of 85 individuals since a SNP located in the region (chr17_10,497,222_C_T) was significantly associated with stomatal conductance. Conclusions Our results represent a step forward towards the dissection of genetic basis that modulate the response to water deprivation in grape rootstocks. The knowledge derived from this study may be useful to exploit genotypic and phenotypic diversity in practical applications and to assist further investigations.

scholarly journals A Genome-Wide Linkage Scan for Diabetic Retinopathy Susceptibility Genes in Mexican Americans With Type 2 Diabetes From Starr County, Texas

Diabetes ◽  
2007 ◽  
Vol 56 (4) ◽  
pp. 1167-1173 ◽  
Author(s):  
D. M. Hallman ◽  
E. Boerwinkle ◽  
V. H. Gonzalez ◽  
B. E. K. Klein ◽  
R. Klein ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Mexican Americans ◽  
Susceptibility Genes ◽  
Genome Wide ◽  
A Genome ◽  
Starr County

scholarly journals The genomics of adaptation

2012 ◽  
Vol 279 (1749) ◽  
pp. 5024-5028 ◽  
Author(s):  
Jacek Radwan ◽  
Wiesław Babik
Keyword(s):  
Genetic Variation ◽  
Natural Selection ◽  
Royal Society ◽  
Genetic Basis ◽  
Genomic Data ◽  
Evolutionary Change ◽  
Introductory Article ◽  
Technological Advances ◽  
A Genome ◽  
Genome Level

The amount and nature of genetic variation available to natural selection affect the rate, course and outcome of evolution. Consequently, the study of the genetic basis of adaptive evolutionary change has occupied biologists for decades, but progress has been hampered by the lack of resolution and the absence of a genome-level perspective. Technological advances in recent years should now allow us to answer many long-standing questions about the nature of adaptation. The data gathered so far are beginning to challenge some widespread views of the way in which natural selection operates at the genomic level. Papers in this Special Feature of Proceedings of the Royal Society B illustrate various aspects of the broad field of adaptation genomics. This introductory article sets up a context and, on the basis of a few selected examples, discusses how genomic data can advance our understanding of the process of adaptation.

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