scholarly journals IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

2013 ◽  
Vol 210 (6) ◽  
pp. 1109-1116 ◽  
Author(s):  
Stéphanie Bibert ◽  
Thierry Roger ◽  
Thierry Calandra ◽  
Murielle Bochud ◽  
Andreas Cerny ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Association Studies ◽  
Antiviral Agents ◽  
Genetic Regulation ◽  
World Population ◽  
Genome Wide Association Studies ◽  
Peripheral Blood Mononuclear ◽  
Genome Wide ◽  
Inducible Protein ◽  
Improve Patient Management

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ–inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management.

scholarly journals TTC7B Emerges as a Novel Risk Factor for Ischemic Stroke Through the Convergence of Several Genome-Wide Approaches

2012 ◽  
Vol 32 (6) ◽  
pp. 1061-1072 ◽  
Author(s):  
Tiago Krug ◽  
João Paulo Gabriel ◽  
Ricardo Taipa ◽  
Benedita V Fonseca ◽  
Sophie Domingues-Montanari ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Differentially Expressed ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Peripheral Blood Mononuclear ◽  
Pathogenic Potential ◽  
Novel Approach ◽  
Genome Wide

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5–intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

scholarly journals A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn’s Disease in Japanese Individuals

2018 ◽  
Vol 13 (5) ◽  
pp. 648-658 ◽  
Author(s):  
Yoichi Kakuta ◽  
Yosuke Kawai ◽  
Takeo Naito ◽  
Atsushi Hirano ◽  
Junji Umeno ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Genome Wide Association ◽  
Effector Memory ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract Background and Aims Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn’s disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10−26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10−19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10−6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10−8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions RAP1A is a novel susceptibility locus for CD in the Japanese population.

scholarly journals Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Tae-Joon Park ◽  
Heun-Sik Lee ◽  
Young Jin Kim ◽  
Bong-Jo Kim
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Multiple Testing ◽  
Association Studies ◽  
Linear Regression Analysis ◽  
Genetic Regulation ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.

scholarly journals Genetic structure of Photosystem II functionality in rice unraveled by GWAS analysis

2020 ◽  
Author(s):  
Juan Manuel Vilas ◽  
Estanislao Burgos ◽  
Maria Lucrecia Puig ◽  
Jose Colazo ◽  
Alberto Livore ◽  
...  
Keyword(s):  
Chlorophyll Fluorescence ◽  
Genetic Structure ◽  
Photosystem Ii ◽  
Association Studies ◽  
Rice Genome ◽  
Genome Wide Association ◽  
World Population ◽  
Genome Wide Association Studies ◽  
Chlorophyll Fluorescence Parameters ◽  
Genome Wide

AbstractRice production is a particularly important crop for the half-world population. Therefore, knowledge about which genes are implicated in the functionality of the Photosystem II, that are still poorly explored could collaborate in the assisted selection of rice improving. In the present study, we applied Genome wide Association Studies of PSII chlorophyll fluorescence under two contrasting environmental conditions in 283 rice accessions highly diverse. A total of 110 significant association SNP-phenotype were observed, and 69 quantitative trait loci identified with a total of 157 genes, of which 38 were highly significant, mapped spread out through rice genome. These underlying regions are enriched in genes related to biotic and abiotic stresses, transcription factors, Calvin cycle, senescence, and grain characters. The correlations analyses PSII chlorophyll fluorescence parameters and some panicle characteristics found here suggest the possibility of developing molecular markers to assist the breeding programs that improve photosynthesis and yield in rice.HighlightThe genetic structure of the Photosystem II functionality in rice was studied by using genome-wide association through chlorophyll fluorescence.

scholarly journals A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells

2020 ◽  
Vol 9 (3) ◽  
pp. 625
Author(s):  
Elia Gil-Varea ◽  
Maria Fedetz ◽  
Herena Eixarch ◽  
Nino Spataro ◽  
Luisa María Villar ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Luciferase Reporter ◽  
Regulatory Sequences ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Peripheral Blood Mononuclear

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.

scholarly journals Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1044 ◽  
Author(s):  
Valeria Lodde ◽  
Giampaolo Murgia ◽  
Elena Rita Simula ◽  
Maristella Steri ◽  
Matteo Floris ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Drug Targets ◽  
Association Studies ◽  
Genetic Regulation ◽  
Response To Therapy ◽  
Circular Rnas ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Substantial Progress

Immune responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled, autoimmune diseases can occur. Autoimmune diseases (ADs) are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage. Despite enormous efforts to identify new drug targets and develop new therapies to prevent and ameliorate AD symptoms, no definitive solutions are available today. Additionally, while substantial progress has been made in drug development for some ADs, most treatments only ameliorate symptoms and, in general, ADs are still incurable. Hundreds of genetic loci have been identified and associated with ADs by genome-wide association studies. However, the whole list of molecular factors that contribute to AD pathogenesis is still unknown. Noncoding (nc)RNAs, such as microRNAs, circular (circ)RNAs, and long noncoding (lnc)RNAs, regulate gene expression at different levels in various diseases, including ADs, and serve as potential drug targets as well as biomarkers for disease progression and response to therapy. In this review, we will focus on the potential roles and genetic regulation of ncRNA in four autoimmune diseases—systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes mellitus.

scholarly journals Iron Biofortification of Staple Crops: Lessons and Challenges in Plant Genetics

2019 ◽  
Vol 60 (7) ◽  
pp. 1447-1456 ◽  
Author(s):  
James M Connorton ◽  
Janneke Balk
Keyword(s):  
Association Studies ◽  
Total Concentration ◽  
Iron Concentration ◽  
World Population ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Global Health Issue ◽  
Iron And Zinc ◽  
Staple Crops ◽  
Zinc Levels

Abstract Plants are the ultimate source of iron in our diet, either directly as staple crops and vegetables or indirectly via animal fodder. Increasing the iron concentration of edible parts of plants, known as biofortification, is seen as a sustainable approach to alleviate iron deficiency which is a major global health issue. Advances in sequencing and gene technology are accelerating both forward and reverse genetic approaches. In this review, we summarize recent progress in iron biofortification using conventional plant breeding or transgenics. Interestingly, some of the gene targets already used for transgenic approaches are also identified as genetic factors for high iron in genome-wide association studies. Several quantitative trait loci and transgenes increase both iron and zinc, due to overlap in transporters and chelators for these two mineral micronutrients. Research efforts are predominantly aimed at increasing the total concentration of iron but enhancing its bioavailability is also addressed. In particular, increased biosynthesis of the metal chelator nicotianamine increases iron and zinc levels and improves bioavailability. The achievements to date are very promising in being able to provide sufficient iron in diets with less reliance on meat to feed a growing world population.

scholarly journals Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

2016 ◽  
Vol 75 (11) ◽  
pp. 2007-2013 ◽  
Author(s):  
Yun Deng ◽  
Jian Zhao ◽  
Daisuke Sakurai ◽  
Andrea L Sestak ◽  
Vadim Osadchiy ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Antinuclear Antibody ◽  
Mononuclear Cells ◽  
Risk Allele ◽  
Association Studies ◽  
Luciferase Reporter ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Peripheral Blood Mononuclear

ObjectivesFollowing up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case–control multi-ancestry population and tested functions of identified variants.MethodsWe performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA.ResultsWe confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10−8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10−3 and 6.8×10−8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=−0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10−5 and 2.0×10−4, respectively).ConclusionWe confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

scholarly journals mGWAS identification of six novel single nucleotide polymorphism loci with strong correlation to gastric cancer

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shuangfeng Yang ◽  
Yuan-Liang Wang ◽  
Yanping Lyu ◽  
Yu Jiang ◽  
Jianjun Xiang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Association Studies ◽  
Genetic Regulation ◽  
Population Data ◽  
Cell Receptor ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide

Abstract Background Metabolite genome-wide association studies (mGWAS) are key for understanding the genetic regulation of metabolites in complex diseases including cancers. Although mGWAS has revealed hundreds of metabolomics quantitative trait loci (mQTLs) in the general population, data relating to gastric cancer (GC) are still incomplete. Methods We identified mQTLs associated with GC by analyzing genome-wide and metabolome-wide datasets generated from 233 GC patients and 233 healthy controls. Results Twenty-two metabolites were statistically different between GC cases and healthy controls, and all of them were associated with the risk of gastric cancer. mGWAS analyses further revealed that 9 single nucleotide polymorphisms (SNPs) were significantly associated with 3 metabolites. Of these 9 SNPs, 6 loci were never reported in the previous mGWAS studies. Surprisingly, 4 of 9 SNPs were significantly enriched in genes involved in the T cell receptor signaling pathway. Conclusions Our study unveiled several novel GC metabolite and genetic biomarkers, which may be implicated in the prevention and diagnosis of gastric cancer.

scholarly journals Genome-wide analyses of multiple obesity-related cytokines and hormones informs biology of cardiometabolic traits

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Karlijn A. C. Meeks ◽  
Amy R. Bentley ◽  
Mateus H. Gouveia ◽  
Guanjie Chen ◽  
Jie Zhou ◽  
...  
Keyword(s):  
African Americans ◽  
Association Studies ◽  
African Ancestry ◽  
Interleukin 1 ◽  
Genetic Regulation ◽  
Interleukin 10 ◽  
Genome Wide Association Studies ◽  
Plasminogen Activator Inhibitor 1 ◽  
Genome Wide ◽  
Cardiometabolic Traits

Abstract Background A complex set of perturbations occur in cytokines and hormones in the etiopathogenesis of obesity and related cardiometabolic conditions such as type 2 diabetes (T2D). Evidence for the genetic regulation of these cytokines and hormones is limited, particularly in African-ancestry populations. In order to improve our understanding of the biology of cardiometabolic traits, we investigated the genetic architecture of a large panel of obesity- related cytokines and hormones among Africans with replication analyses in African Americans. Methods We performed genome-wide association studies (GWAS) in 4432 continental Africans, enrolled from Ghana, Kenya, and Nigeria as part of the Africa America Diabetes Mellitus (AADM) study, for 13 obesity-related cytokines and hormones, including adipsin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), interleukin-1 receptor antagonist (IL1-RA), interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, visfatin, insulin, glucagon, and ghrelin. Exact and local replication analyses were conducted in African Americans (n = 7990). The effects of sex, body mass index (BMI), and T2D on results were investigated through stratified analyses. Results GWAS identified 39 significant (P value < 5 × 10−8) loci across all 13 traits. Notably, 14 loci were African-ancestry specific. In this first GWAS for adipsin and ghrelin, we detected 13 and 4 genome-wide significant loci respectively. Stratified analyses by sex, BMI, and T2D showed a strong effect of these variables on detected loci. Eight novel loci were successfully replicated: adipsin (3), GIP (1), GLP-1 (1), and insulin (3). Annotation of these loci revealed promising links between these adipocytokines and cardiometabolic outcomes as illustrated by rs201751833 for adipsin and blood pressure and locus rs759790 for insulin level and T2D in lean individuals. Conclusions Our study identified genetic variants underlying variation in multiple adipocytokines, including the first loci for adipsin and ghrelin. We identified population differences in variants associated with adipocytokines and highlight the importance of stratification for discovery of loci. The high number of African-specific loci detected emphasizes the need for GWAS in African-ancestry populations, as these loci could not have been detected in other populations. Overall, our work contributes to the understanding of the biology linking adipocytokines to cardiometabolic traits.

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