Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates BCAR1 and Suggests a Causal VariantCLINICAL PERSPECTIVE by Freya Boardman-Pretty,

Slides:

Advertisements

Similar presentations

Chapter 25 Chapter 25 Genetic Determinants of Osteoporosis Copyright © 2013 Elsevier Inc. All rights reserved.

Advertisements

Date of download: 11/12/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Influence of Child Abuse on Adult DepressionModeration.

Copyright © 2008 American Medical Association. All rights reserved.

Robert Shore, Rebeca Diaz, Yiwang Xu, Silvia Paracchini

Impact of Genetic Variants in Human Scavenger Receptor Class B Type I (SCARB1) on Plasma Lipid TraitsCLINICAL PERSPECTIVE by Vipavee Niemsiri, Xingbin.

Altered Expression of Raet1e, a Major Histocompatibility Complex Class 1–Like Molecule, Underlies the Atherosclerosis Modifier Locus Ath11 10bNovelty and.

Association of Rare Loss-Of-Function Alleles in HAL, Serum HistidineCLINICAL PERSPECTIVE by Bing Yu, Alexander H. Li, Donna Muzny, Narayanan Veeraraghavan,

by Hanna S. Radomska, Anne B

Integromic Analysis of Genetic Variation and Gene Expression Identifies Networks for Cardiovascular Disease PhenotypesCLINICAL PERSPECTIVE by Chen Yao,

by Kumar Kotlo, Douglas E. Hughes, Victoria L. M

Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive- Compulsive Disorder Xian-Zhang Hu, Robert H. Lipsky, Guanshan Zhu,

Novel Cis Element for Tissue-Specific Transcription of Rat Platelet-Derived Growth Factor β-Receptor Gene by Yasunori Takata, Yutaka Kitami, Tomikazu Fukuoka,

rs alters protein/DNA complex formation with the involvement of p300.

An IgE-associated polymorphism in STAT6 alters NF-κB binding, STAT6 promoter activity, and mRNA expression Michaela Schedel, PhD, Remo Frei, PhD, Christian.

by Hong Hao, Huiling Qi, and Manohar Ratnam

Promoter and 3′-Untranslated-Region Haplotypes in the Vitamin D Receptor Gene Predispose to Osteoporotic Fracture: The Rotterdam Study Yue Fang, Joyce.

Volume 134, Issue 3, Pages e2 (March 2008)

Jodie N. Painter, Susanne Kaufmann, Tracy A. O’Mara, Kristine M

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease Yi-An Ko, Huiguang Yi, Chengxiang Qiu, Shizheng.

Jesper T Troelsen, Jørgen Olsen, Jette Møller, Hans SjÖstrÖm

Functional characterization of the atopy-associated gene PHF11

Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol Tamara S. Roman, Amanda F. Marvelle,

Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression by Nauder Faraday, Lisa.

Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive- Compulsive Disorder Xian-Zhang Hu, Robert H. Lipsky, Guanshan Zhu,

Volume 136, Issue 5, Pages (May 2009)

High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans Winston Lau, Toby Andrew,

M. Ushita, T. Saito, T. Ikeda, F. Yano, A. Higashikawa, N. Ogata, U

Volume 19, Issue 2, Pages (August 2003)

Genetic association of acidic mammalian chitinase with atopic asthma and serum total IgE levels Rajshekhar Chatterjee, MSc, Jyotsna Batra, PhD, Sudipta.

The ETS-CRE array identifies genomic sequences specifically cobound by CREB1 and GABPα. The ETS-CRE array identifies genomic sequences specifically cobound.

Weight Loss after Gastric Bypass Is Associated with a Variant at 15q26

Single-nucleotide polymorphisms in the promoter region influence the expression of the human follicle-stimulating hormone receptor Alain Wunsch, M.Sc.,

Complex Role of TNF Variants in Psoriatic Arthritis and Treatment Response to Anti- TNF Therapy: Evidence and Concepts Ulrike Hüffmeier, Rotraut Mössner

Towfique Raj, Manik Kuchroo, Joseph M

Identification of a Novel Risk Locus for Progressive Supranuclear Palsy by a Pooled Genomewide Scan of 500,288 Single-Nucleotide Polymorphisms Stacey.

Role of Sp1 in Transcription of Human ATP2A2 Gene in Keratinocytes

Integrative Functional Genomics Implicates EPB41 Dysregulation in Hepatocellular Carcinoma Risk Xinyu Yang, Dianke Yu, Yanli Ren, Jinyu Wei, Wenting.

Figure 2 LocusZoom plots

Volume 13, Issue 6, Pages (November 2015)

Volume 70, Issue 7, Pages (October 2006)

Identification and Functional Characterization of RSPO2 as a Susceptibility Gene for Ossification of the Posterior Longitudinal Ligament of the Spine

A T Cell–Specific Enhancer in the Interleukin-3 Locus Is Activated Cooperatively by Oct and NFAT Elements within a DNase I–Hypersensitive Site Kym N.

Transcriptional Regulation of ATP2C1 Gene by Sp1 and YY1 and Reduced Function of its Promoter in Hailey–Hailey Disease Keratinocytes Hiroshi Kawada,

Volume 128, Issue 6, Pages (March 2007)

Leslie A. Bruggeman, Scott H. Adler, Paul E. Klotman

Volume 16, Issue 8, Pages (August 2016)

Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association James R. Elmore, MD, Melissa.

Volume 167, Issue 2, Pages e10 (October 2016)

Are Interactions between cis-Regulatory Variants Evidence for Biological Epistasis or Statistical Artifacts? Alexandra E. Fish, John A. Capra, William.

Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1 Matthew J. Bown, Gregory T. Jones, Seamus C.

A Distinct DNA-Methylation Boundary in the 5′- Upstream Sequence of the FMR1 Promoter Binds Nuclear Proteins and Is Lost in Fragile X Syndrome Anja Naumann,

MyoD Targets TAF3/TRF3 to Activate Myogenin Transcription

The G/G Genotype of a Resistin Single-Nucleotide Polymorphism at −420 Increases Type 2 Diabetes Mellitus Susceptibility by Inducing Promoter Activity.

An Expanded View of Complex Traits: From Polygenic to Omnigenic

Fig. 2 Genotype-induced differential gene expression is different in MDMi cells compared to monocytes. Genotype-induced differential gene expression is.

Regulation of the Expression of Peptidylarginine Deiminase Type II Gene (PADI2) in Human Keratinocytes Involves Sp1 and Sp3 Transcription Factors Sijun.

A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Increases Familial Risk of Autism Dan E. Arking, David J. Cutler, Camille W. Brune,

Repression of MYBL2 by Both microRNA858a and HY5 Leads to the Activation of Anthocyanin Biosynthetic Pathway in Arabidopsis Yulong Wang, Yiqing Wang,

A Genome-Wide Association Study of Basal Transepidermal Water Loss Finds that Variants at 9q34.3 Are Associated with Skin Barrier Function Manfei Zhang,

Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct (DFNB4) Tao Yang, Hilmar Vidarsson,

Defining the Regulatory Elements in the Proximal Promoter of ΔNp63 in Keratinocytes: Potential Roles for Sp1/Sp3, NF-Y, and p63 Rose-Anne Romano, Barbara.

CaQTL analysis identifies genetic variants affecting human islet cis-RE use. caQTL analysis identifies genetic variants affecting human islet cis-RE use.

Discovery and analysis of methylation quantitative trait loci (mQTLs) mapping to novel osteoarthritis genetic risk signals S.J. Rice, K. Cheung, L.N.

Volume 125, Issue 4, Pages (October 2003)

NF-Y binds the −4,425/−4,392 G6PC2 promoter region in vitro.

The 3D Genome in Transcriptional Regulation and Pluripotency

Volume 129, Issue 2, Pages (August 2005)

CCA1 Binds the Promoter of GI in Vitro and in Vivo.

HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region Nicolas Vince, Hongchuan Li, Veron Ramsuran, Vivek Naranbhai,

Integrated analysis of gene expression and copy number alterations.

Presentation transcript:

Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates BCAR1 and Suggests a Causal VariantCLINICAL PERSPECTIVE by Freya Boardman-Pretty, Andrew J.P. Smith, Jackie Cooper, Jutta Palmen, Lasse Folkersen, Anders Hamsten, Alberico L. Catapano, Olle Melander, Jacqueline F. Price, Meena Kumari, John E. Deanfield, Mika Kivimäki, Karl Gertow, Andrea Baragetti, Giuseppe Danilo Norata, and Steve E. Humphries Circ Genom Precis Med Volume 8(5):696-706 October 20, 2015 Copyright © American Heart Association, Inc. All rights reserved.

rs4888378 allele is associated with differential expression depending on sequence elements. rs4888378 allele is associated with differential expression depending on sequence elements. Luciferase reporter assay data. Fragments 1 and 2 show no significant differential expression (A and B). Fragments 3 and 4 show a decrease in expression for the A allele, with the decrease in fragment 4 being much more pronounced (C and D). Expression values are normalized to pGL3-promoter control. P values derive from unpaired t test. Error bars show SEM (4 plates of 12 replicates each.)‏ Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

Annual change in intima-media thickness (IMT) in Progressione della Lesione Intimale Carotidea by rs4888378 genotype. Annual change in intima-media thickness (IMT) in Progressione della Lesione Intimale Carotidea by rs4888378 genotype. A, Overall, despite a trend for lower ΔIMT with each A allele, no significant association was seen with genotype. B, In women only, ΔIMT in the AA genotype was lower than in the GG genotype (P=0.04), although the overall trend was not significant. C, In men only, no trend or significant association was seen. Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

Forest plot showing intima-media thickness (IMT) by rs4888378 allele in (A) men and (B) women. Forest plot showing intima-media thickness (IMT) by rs4888378 allele in (A) men and (B) women. Overall no significant association between the single nucleotide polymorphism and IMT is seen in men (β=−0.0030, P=0.0591), whereas in women, the A allele is associated with a decrease in IMT for each A allele (β=−0.0046, P=1.59×10–4). IMT is here common carotid IMT (the IMT variable common to all cohorts). CI indicates confidence interval; EAS, Edinburgh Artery Study; IMPROVE, IMT and IMT-Progression as Predictors of Vascular Events; MDC, Malmö Diet and Cancer study; PLIC, Progressione della Lesione Intimale Carotidea; and WHII, Whitehall II. Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

Linkage disequilibrium plot for lead single nucleotide polymorphism (SNP) rs4888378. Linkage disequilibrium plot for lead single nucleotide polymorphism (SNP) rs4888378. Data from 1000 Genomes (Pilot 1); graph plotted with data and script from SNP Annotation and Proxy Search.18 Lead SNP rs4888378 is shown in red; other SNPs are shown relative to their position at the locus (x axis) and linkage disequilibrium (LD; r2) with rs4888378 (y axis). The majority of strong LD SNPs lie within CFDP1 and TMEM170A; they may affect these genes, or lie within enhancer regions which affect expression of other genes. Chromosome coordinates are based on NCBI Build 36.1 (hg18). Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

Single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium selected for further analysis. Single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium selected for further analysis. The locations of the SNPs are shown with SNP name, alleles, minor allele frequency, and evidence used for selection. Gene coordinate data from UCSC Genome Browser.20 Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

Electrophoretic mobility shift assays (EMSAs) show differential protein binding for rs4888378 and competition of the protein-binding band. Electrophoretic mobility shift assays (EMSAs) show differential protein binding for rs4888378 and competition of the protein-binding band. Bands show the position of biotin-labeled probe on the gel (direction from top to bottom). Probes unbound by DNA run fastest and are not visible on the picture; bands here are protein-bound probe that migrates more slowly. A and G refer to the respective alleles of rs4888378. Competitor probes (unlabelled) are added in excess to nuclear extract 30 minutes before labeled probe; hence, a probe-protein band will disappear when the protein binds first to the competitor. A, Differential protein binding to rs4888378. Lane 1 shows binding of the control protein, nuclear factor (NF)-κB, to the control band (NF-κB consensus); lane 2 shows band being competed out by unlabelled NF-κB probe. Lanes 3 and 5 show weak and strong protein binding to the A and G probes, respectively. Lanes 4 and 6 show the binding to be competed out by respective unlabelled probes. B, Multiplex competitor EMSA. Lanes 1 and 2 show NF-κB control as above. Lanes 3 to 14 show protein binding to the G probe is competed out only by the unlabelled G probe, as expected, and by the FOXA competitor. Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

FOXA consensus sequence used in multiplex competitor electrophoretic mobility shift assay compared with genomic sequence around rs4888378. FOXA consensus sequence used in multiplex competitor electrophoretic mobility shift assay compared with genomic sequence around rs4888378. The single nucleotide polymorphism G allele matches more closely with the consensus sequence, suggesting FOXA may be the protein binding here. Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.

BCAR1 expression by rs4888378 genotype in (A) aortic artery and (B) tibial artery. BCAR1 expression by rs4888378 genotype in (A) aortic artery and (B) tibial artery. Data and graph from Genotype–Tissue Expression Portal.21 Of the 9 genes analyzed at the locus, only BCAR1 remained significant after correction for multiple testing; expression of BCAR1 increased with each allele of the high-risk G allele. eQTL indicates expression quantitative trait loci. Freya Boardman-Pretty et al. Circ Cardiovasc Genet. 2015;8:696-706 Copyright © American Heart Association, Inc. All rights reserved.