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Ingenious strategy

Ingenious strategy. Swedish & British subjects. Controls – Age >50 years BP <120/80 Not on antiHTN No prevalent CVD (MI,CVA) No incident CVD on follow-up until 2001. Cases – Hypertensive Age <60 years BP>160/100 NORDIL & ASCOT. 8k. 8k. 1M Illumina BeadChip=SNPs & CNVs. Hypercontrols

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Ingenious strategy

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  1. Ingenious strategy Swedish & British subjects Controls – Age >50 years BP <120/80 Not on antiHTN No prevalent CVD (MI,CVA) No incident CVD on follow-up until 2001 Cases – Hypertensive Age <60 years BP>160/100 NORDIL & ASCOT 8k 8k 1M Illumina BeadChip=SNPs & CNVs Hypercontrols Increase odds ratio Increase power Better LD coverage using HapMap2 BRIGHT & InGenious HyperCare Investigators

  2. 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

  3. PAMELA STUDY M O N Z A PAMELA STUDY Pressioni Arteriose Monitorate ELoro 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% 10 yrs follow up 1991 2001 • 24H, CLINIC, HOME BP & HR • Waist, Hips, Weight, Height • Echo • Blood analysis • Drug treatment • 24H, CLINIC, HOME BP & HR • Waist, Hips, Weight, Height • Echo • Blood analysis • Drug treatment

  4. Three or more of the following: Abdominal obesitywaist: male >102 cm, female >88 cm Triglycerides 150 mg/dL (1.7 mmol/L) HDL cholesterolMale <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) Metabolic Syndrome: NCEP ATP III Criteria NCEP=National Cholesterol Education Program.ATP III=Third Report of NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.

  5. 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

  6. Gene Selection • Biological plausibility • biochemical pathways that have been implicated in the development and progression of cardiovascular disease • RAAS • SNS • OXIDATIVE STRESS • SODIUM BALANCE • LIPID METABOLISM • OTHERS • Prior evidence of potential association • 1536 SNPs across 98 genes selected

  7. Illumina TagSNP selection and Genotyping Raw Data submitted to BeadStudio Software Samples are genotyped using GoldenGate AssayTm and processed samples are visualised using BeadArray Scanner Download SNP Identifiers,& submit to Illumina for scoring Determine chromosomal location of target gene (+ 10kb) Identify available SNP resources (HapMap, SeattleSNPs, PARC,) 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 Suitable Tagged SNPs submitted to Illumina for manufacture of Oligo Pool used in GoldenGate AssayTm

  8. 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

  9. BHF GLASGOW CARDIOVASCULAR RESEARCH CENTRE Acknowledgements All participants of the PAMELA Study Paolo Signorini, Rossana Cecere – Desio Hospital, Milan

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