Genetic and phenotypic architecture of metabolic syndrome-associated components in dyslipidemic and normolipidemic subjects: the GEMS Study.
Atherogenic dyslipidemia, manifest by low HDL-cholesterol and high TG levels, is an important component of ATP-III defined metabolic syndrome. Here, we dissected the phenotypic and genetic architecture of these traits by assessing their relationships with other metabolically relevant measures, including plasma adipo-cytokines, highly sensitive C-reactive protein (hsCRP) and LDL particle size, in a large family data set (n=2800) and in an independent set of dyslipidemic cases (n=716) and normolipidemic controls (n=1073). We explored the relationships among these phenotypes using variable clustering and then estimated their genetic heritabilities and cross-trait correlations. In families, four clusters explained 61% of the total variance, with one adiposity-related cluster (including hsCRP), one BP-related cluster, and two lipid-related clusters (HDL-C, TG, adiponectin and LDL particle size; apoB and non-HDL-C). A similar structure was observed in dyslipidemic cases and normolipidemic controls. The genetic correlations in the families largely paralleled the phenotype clustering results, suggesting that common genes having pleiotropic effects contributed to the correlations observed. In summary, our analyses support a model of metabolic syndrome with two major components, body fat and lipids, each with two subcomponents, and quantifies their degree of overlap with each other and with metabolic-syndrome related measures (adipokines, LDL particle size and hsCRP).
Stirnadel
Heide
H
World Wide Epidemiology, GlaxoSmithKline, Harlow, UK.
Lin
Xiwu
X
Ling
Hua
H
Song
Kijoung
K
Barter
Philip
P
Kesäniemi
Y Antero
YA
Mahley
Robert
R
McPherson
Ruth
R
Waeber
Gérard
G
Bersot
Thomas
T
Cohen
Jonathan
J
Grundy
Scott
S
Mitchell
Braxton
B
Mooser
Vincent
V
Waterworth
Dawn
D
D000273:Adipose Tissue; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D016000:Cluster Analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics*; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D019655:Quantitative Trait, Heritable