6533b7ddfe1ef96bd1275458
RESEARCH PRODUCT
A Genome-Wide Screen for Interactions Reveals a New Locus on 4p15 Modifying the Effect of Waist-to-Hip Ratio on Total Cholesterol
Nancy L. PedersenAntti J. KangasJames F. WilsonAnke ToenjesBen A. OostraJanina S. RiedTheodore PapamarkouTheodore PapamarkouAngela DoeringZoltán KutalikAndré G. UitterlindenNicholas G. MartinAntti JulaTõnu EskoBruce H. R. WolffenbuttelLennart C. KarssenPirkka-pekka LaurilaÅSa JohanssonGerjan NavisAarno PalotieChristian GiegerCisca WijmengaPeter P. PramstallerAaron IsaacsAaron IsaacsInga ProkopenkoJouke-jan HottengaMassimo ManginoAntti-pekka SarinIda SurakkaVeikko SalomaaTaina RantanenUlf GyllenstenNicole SoranzoNicole SoranzoJacqueline C.m. WittemanCornelia M. Van DuijnCornelia M. Van DuijnSamuli RipattiSamuli RipattiAlbert HofmanNicholas W.j. WainwrightNicholas W.j. WainwrightPasi SoininenLeena PeltonenRita P. S. MiddelbergPim Van Der HarstKirsten Ohm KyvikDorret I. BoomsmaHarry CampbellJohn WhitfieldAnn-kristin PetersenVasiliki LagouTim D. SpectorWilmar IglMarkus PerolaFlorian KronenbergMaksim StruchalinNelson B. FreimerMika KähönenJaakko KaprioIrene Mateo LeachFernando RivadeneiraMark I. MccarthyMika Ala-korpelaJorma ViikariAndres MetspaluJohan G. ErikssonEco J. C. De GeusH.-erich WichmannGrant W. MontgomeryM. S. SandhuM. S. SandhuOlli T. RaitakariMichael StumvollTerho LehtimäkiMarja-riitta TaskinenGonneke WillemsenAndrew C. HeathIgor RudanYurii S. AulchenkoMarjo-riitta JaervelinEmmi TikkanenClaudia LaminaDawn M. Waterworthsubject
Netherlands Twin Register (NTR)Adipose Tissue/metabolismAdipose Tissue/metabolism; Body Fat Distribution; Cadherins/genetics; Cholesterol/blood; Cholesterol/genetics; Chromosome Mapping; Chromosomes Human Pair 4/genetics; European Continental Ancestry Group/genetics; Genome-Wide Association Study; Genotype; Humans; Lipids/blood; Lipids/genetics; Lipoproteins/blood; Lipoproteins/genetics; Phenotype; Polymorphism Single Nucleotide; Quantitative Trait Loci/genetics; Risk Factors; Triglycerides/blood; Triglycerides/genetics; Waist-Hip RatioGenome-wide association study0302 clinical medicineGenetics(clinical)AetiologyEuropean Continental Ancestry Group/genetics0303 health scienceseducation.field_of_studyta3141ta3142ASSOCIATIONCadherinsLipids3. Good healthTriglycerides/bloodCholesterolAdipose TissueDENSITY-LIPOPROTEIN CHOLESTEROLTRIGLYCERIDEChromosomes Human Pair 4SMOKING/dk/atira/pure/subjectarea/asjc/1100/1105Human/dk/atira/pure/subjectarea/asjc/1300/1311/dk/atira/pure/subjectarea/asjc/1300/1312GenotypeLipoproteinseducationEuropean Continental Ancestry GroupQuantitative Trait LociLocus (genetics)Cholesterol/bloodWhite People03 medical and health sciencesSDG 3 - Good Health and Well-beingClinical ResearchGenome-Wide Association StudiesGeneticsHumansPolymorphismeducationBiologyMolecular BiologyPOLYMORPHISMSEcology Evolution Behavior and Systematics0604 GeneticsHDL CHOLESTEROLScience & TechnologyCadherins/geneticsChromosomes Human Pair 4/geneticsQuantitative Trait Loci/geneticsDensity-lipoprotein cholesterol; HDL chloesterol; Association; Gene; Smoking; Plasma; Triglyeride; Obesity; Lipids; PolymorphismsDevelopmental BiologyCancer Research030204 cardiovascular system & hematologyWaist–hip ratioRisk FactorsGenotype2.1 Biological and endogenous factorsBody Fat DistributionGENETICS & HEREDITYGenetics (clinical)GeneticsPLASMAChromosome MappingSingle NucleotideENGAGE ConsortiumPair 4/geneticsPhenotypePair 4OBESITY/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being/dk/atira/pure/subjectarea/asjc/1300/1306Life Sciences & BiomedicineResearch ArticleLIPIDSlcsh:QH426-470PopulationQuantitative trait locusBiologyPolymorphism Single NucleotideChromosomes/dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_Lipoproteins/bloodgene ; waist-to-hip ratio ; cholesterolAlleleTriglycerides030304 developmental biologyWhitesLipids/bloodWaist-Hip RatioHuman GenomeHuman Genetics/dk/atira/pure/subjectarea/asjc/2700/2716HeritabilityGENEProtocadherinslcsh:Genetics3111 BiomedicineGenome-Wide Association Studydescription
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-10-20 | PLoS Genetics |