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Ingenious strategy Swedish & British subjects 8k Cases – Hypertensive Age <60 years BP>160/100 NORDIL & ASCOT Controls – Age >50 years BP <120/80 Not on antiHTN No prevalent CVD (MI,CVA) No incident CVD on follow-up until 2001 8k 1M Illumina BeadChip=SNPs & CNVs Hypercontrols Increase odds ratio Increase power Better LD coverage using HapMap2 BRIGHT & InGenious HyperCare Investigators Cardiovascular Gene Centric Association Study of Metabolic Syndrome and Ambulatory Blood Pressure in the PAMELA Study Sandosh Padmanabhan, Cristina Menni, Wai K Lee, Stuart Laing, Paola Brambilla, Roberto Sega, Roberto Perego, Giancarlo Cesana, Giuseppe Mancia, Anna F Dominiczak BHF Glasgow Cardiovascular Research Centre, University of Glasgow University of Milano - Bicocca PAMELA STUDY M O N Z A PAMELA STUDY Pressioni Arteriose Monitorate E Loro Associazioni • 2051 people 25-64 males and females 200 from each decade of life randomly recruited from Monza • extensively phenotyped for BP • DNA available •Metabolic syndrome in 16.2% 1991 10 yrs follow up • 24H, CLINIC, HOME BP & HR • Waist, Hips, Weight, Height • Echo • Blood analysis • Drug treatment 2001 • 24H, CLINIC, HOME BP & HR • Waist, Hips, Weight, Height • Echo • Blood analysis • Drug treatment Metabolic Syndrome: NCEP ATP III Criteria Three or more of the following: Abdominal obesity waist: male >102 cm, female >88 cm Triglycerides 150 mg/dL (1.7 mmol/L) HDL cholesterol Male <40 mg/dL (1 mmol/L), female <50 mg/dL (1.3 mmol/L) SBP 130 mm Hg or DBP 85 mm Hg Fasting glucose 110 mg/dL (6.1 mmol/L) NCEP=National Cholesterol Education Program. ATP III=Third Report of NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Metabolic Syndrome Does Metabolic Syndrome exist or is it a sum of its risk components? •Components of the system occur more often than expected by chance –Common underlying process •Heritability of Metabolic Syndrome –26% - 48% •Linkage loci –Chromosomes 1,2,5,6,17,18 •Candidate Genes –LDLR, PPARG, APOA5, CYP3A4, C1QTNF5 Gene Selection Biological plausibility biochemical pathways that have been implicated in the development and progression of cardiovascular disease RAAS SNS OXIDATIVE SODIUM LIPID STRESS BALANCE METABOLISM OTHERS Prior evidence of potential association 1536 SNPs across 98 genes selected Illumina TagSNP selection and Genotyping Determine chromosomal location of target gene (+ 10kb) Raw Data submitted to BeadStudio Software Identify available SNP resources (HapMap, SeattleSNPs, PARC,) Genotype calls for locus 4517 2.40 2.20 2.00 1.80 AA 1.60 AB 1.40 1.20 BB 1 Colon normal 0.80 0.60 Colon tumor 0.40 0.20 0 -0.20 Samples are genotyped using GoldenGate AssayTm and processed samples are visualised using BeadArray Scanner Download SNP Identifiers,& submit to Illumina for scoring 9 0 0.20 23 0.40 0.60 0.80 71 Suitable Tagged SNPs submitted to Illumina for manufacture of Oligo Pool used in GoldenGate AssayTm Scoring by Illumina essential as it will determine as to whether scored SNP is suitable for GoldenGateTm Assay Illumina scored SNPs >0.6, MAF > 5% submitted to Tagger Software Statistical Analysis Quality Control Standard QC protocol involving manual review of all cluster plots, genotype frequency, Hardy Weinberg Equilibrium, call rates Association Analysis 1df Trend test for dichotomous traits and Linear regression analysis using an additive model for continuous traits All association analysis performed using PLINK BHF GLASGOW CARDIOVASCULAR RESEARCH CENTRE Acknowledgements All participants of the PAMELA Study Paolo Signorini, Rossana Cecere – Desio Hospital, Milan