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Genetic variations linked to cardiovascular disease risk factors from childhood to adulthood
September 22, 2010
Common variants that can be identified in a child’s DNA may help predict the genetic predisposition for developing cardiovascular disease (CVD) risk factors later in life, according to research findings published in a Sept. 2010 issue of PLoS Genetics.
The research project, headed by scientists at Scripps Translational Science Institute (STSI), is the first genome-wide association study to evaluate the role of common genetic variants in the development of CVD risk factors in adults whose health has been tracked from childhood.
The individuals whose DNA codes were analyzed are part of the Bogalusa Heart Study (BHS), the longest and most detailed epidemiologic investigation of the origins of adult heart disease and high blood pressure. Since childhood and for almost 40 years, their blood pressure, heart rate, blood cholesterol levels and nine other traits that characterize CVD have been periodically measured.
STSI’s longitudinal genome-wide association study of a subset of 525 individuals in the BHS population spotlighted two million single-nucleotide polymorphisms (SNPs) associated with such cardiovascular traits as diastolic blood pressure, the bottom number in a blood pressure reading that represents the pressure in blood vessels between heart beats.
The scientists detected seven significant (SNPs) linked to diastolic blood pressure; blood levels of HDL (high density lipoprotein, or the “good cholesterol”) and LDL (low density lipoprotein, or the “bad cholesterol”); and triglycerides, insulin and glucose.
The research team* subsequently confirmed two of these genetic variants as “strongly significant” in a review of the DNA codes of 2,400 participants in the Young Finns Study (YFS). YFS is a longitudinal population investigation on the evolution of cardiovascular risk factors from childhood to adulthood based in Finland.
Previous research showed that these two SNPs are linked to CVD. (The SNP linked to HDL is rs247616 in the CETP gene. The SNP linked to LDL is rs445925 in the APOE gene.) The STSI study determined for the first time that both SNPs were time-independent, because their effects on HDL and LDL remained relatively constant over time, from childhood to adulthood. In the analysis, rs445925 emerged as being associated with high LDL levels during adult years that is above and beyond its effect on blood cholesterol levels during childhood, suggesting that this genetic information may help identify children who do not yet have high LDL but will go on to develop high levels of “bad cholesterol.”
The researchers also discovered two novel SNPs whose influence on blood triglyceride levels strengthened with age. These time-dependent SNPs were linked to variations in the linear trajectory of triglyceride levels from childhood through adulthood.
“The discovery of time-dependent variants that influence CVD trait values over time can potentially be used to screen young individuals who are pre-symptomatic and provide the opportunity for preventive measures decades before disease onset,” said Sarah S. Murray, Ph.D., Director of Genetics at STSI and the study leader.
The most significant time-dependent SNP (rs7890572 in the IL1RAPL1 gene) was found near the gene encoding glycerol kinase. Mutations of this gene are associated with pseudo-hypertriglyceridemia, which occurs when triglyceride levels are in the normal range even though lab test results indicate otherwise. The second significant time-dependent SNP, rs12280753, also was associated with triglyceride levels. The scientists detected it near the APOA5 gene, which previous research has linked to triglyceride levels.
Neither SNP was confirmed as strongly significant in the Finnish group, Dr. Murray pointed out. Whether the two SNPs can ever be used in a screening test to help predict a child’s potential risk for CVD during adulthood must be determined by research with larger populations of people.
The STSI project, and in particular the discovery of the two novel time-dependent SNPs, highlight the value of longitudinal studies for identifying genetic predictors of adult traits, Dr. Murray noted. While previous genome-wide association studies have pinpointed DNA factors that influence risk for developing CVD, these projects focused on specific groups of people at defined times. Unlike the STSI project, these studies were not longitudinal and thus could not provide insight about the genetic components of risk factors over time.
Because all participants in the BHS and YFS were of European ancestry, STSI’s results may not apply to African-Americans, Asians or other racial groups, Dr. Murray added.
* In addition to scientists at STSI, the research team included investigators at Tulane University in New Orleans; Broad Institute of MIT and Harvard; University of Tampere Medical School, University of Turku and the Institute of Molecular Medicine in Finland; and the Wellcome Trust Sanger Institute in the UK.
