title: Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
abstract: Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.
authors.affiliation: Centre for Cardiovascular Genetics, Department of Medicine, University College London, London WC1E 6JF, UK.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.forename: Sonia
authors.initials: S
authors.lastname: Shah
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.forename: Jutta
authors.initials: J
authors.lastname: Palmen
authors.forename: Claudio
authors.initials: C
authors.lastname: Verzilli
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.forename: Jacky
authors.initials: J
authors.lastname: Pallas
authors.forename: Ruth
authors.initials: R
authors.lastname: Lovering
authors.forename: Kawah
authors.initials: K
authors.lastname: Li
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Casas
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Newhouse
authors.forename: Anna
authors.initials: A
authors.lastname: Dominiczak
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.forename: Peter
authors.initials: P
authors.lastname: Sever
authors.forename: Alice
authors.initials: A
authors.lastname: Stanton
authors.forename: Denis C
authors.initials: DC
authors.lastname: Shields
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Claire
authors.initials: C
authors.lastname: Hastie
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Michael G
authors.initials: MG
authors.lastname: Marmot
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Ian N
authors.initials: IN
authors.lastname: Day
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
mesh_terms: D000328:Adult; D000483:Alleles; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000097:blood / Q000235:genetics*; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D003198:Computer Simulation; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008055:Lipids / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D014280:Triglycerides