PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European Youth Heart Study.
OBJECTIVE
The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study.


METHODS
Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively.


RESULTS
In adjusted models, nominally significant associations were observed for BMI (rs10018239, p = 0.039), waist circumference (rs7656250, p = 0.012; rs8192678 [Gly482Ser], p = 0.015; rs3755863, p = 0.02; rs10018239, beta = -0.01 cm per minor allele copy, p = 0.043), systolic blood pressure (rs2970869, p = 0.018) and fasting glucose concentrations (rs11724368, p = 0.045). Stronger associations were observed for aerobic fitness (rs7656250, p = 0.005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant.


CONCLUSIONS
Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.
Brito
E C
EC
Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Umeå University Hospital, Medicine Clinic, Level 4, Stair B, Umeå, 901 87, Sweden.
Vimaleswaran
K S
KS
Brage
S
S
Andersen
L B
LB
Sardinha
L B
LB
Wareham
N J
NJ
Ekelund
U
U
Loos
R J F
RJ
Franks
P W
PW
D000293:Adolescent; D000595:Amino Acid Sequence; D001794:Blood Pressure; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D004777:Environment; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood; D008019:Life Style; D015810:Linkage Disequilibrium; D008297:Male; D009043:Motor Activity; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D050177:Overweight / Q000453:epidemiology / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010809:Physical Fitness; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
D006360:Heat-Shock Proteins; D007328:Insulin; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors