title: Adiposity significantly modifies genetic risk for dyslipidemia.
abstract: Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (P(Interaction) = 2.87 × 10(-4)) and HDLc (P(Interaction) = 1.05 × 10(-3)). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (P(Interaction) = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability.
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cole
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Nikpay
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Paulina
authors.initials: P
authors.lastname: Lau
authors.affiliation: Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Davies
authors.affiliation: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: George A
authors.initials: GA
authors.lastname: Wells
authors.affiliation: Bariatric Centre of Excellence, Ottawa Hospital, Ottawa, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Dent
authors.affiliation: Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
mesh_terms: D050154:Adiposity; D000368:Aged; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D014280:Triglycerides
keywords: genetic risk score; lipoproteins; obesity; single nucleotide polymorphism; statistical interaction