A large-scale candidate gene association study of blood pressure change in children and adolescents
Hypertension, which affects about one-third of adults worldwide, is a major risk factor for the morbidity and mortality associated with cardiovascular diseases (CVDs) and end-stage renal damage. Some of the genetic factors that contribute to high blood pressure (BP) have been identified. However, all genetic variants found through linkage and genome-wide association studies (GWAS) to date can explain only 1% to 2% of the population variation in blood pressure and hypertension in adults. To our knowledge no large-scale candidate gene studies have been carried out in children or adolescents. To increase our understanding of the etiology of the disease, the study aimed to identify SNPs associated with the change in blood pressure in children and adolescents. Data on systolic and diastolic blood pressure from 2 longitudinal cohort studies [the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB)] was used. Genopyping was performed with the MetaboChip (Illumina iSelect array) and the HumanCVD BeadChip (Illumina’s Infinium II Assay).^ Multilevel models of change were built, which included dependent variables (SBP, DBP), and explanatory variables (sex, centered age, centered age 2, centered age3, race, SNP, centered BMI). Three ways of combining data in analyses were used and compared to one another. First, analyses were run separately for BHS Non-Hispanic Whites, BHS African-Americans, PHB Non-Hispanic Whites and PHB African-Americans, and then united by meta-analysis. Second, separate models were created for the two ethnicities (BHS/PHB African-Americans and BHS/PHB Non-Hispanic Whites), and combined by meta-analysis. Finally, models containing all 4 cohorts, including terms for race and study, were analyzed without meta-analysis.^ The first analytic method (meta-analysis of 4 cohorts) was considered to be the most reliable. It identified several SNPs with statistically significant effects on SBP and DBP – rs2378597 (in the AIDA gene), rs61824282 (in MIA3), rs6130608 (in HNF4A), rs7572476 (near the BOK gene), and rs7831963 (in VPS13B), all of which are biologically plausible candidates that could affect blood pressure through various mechanisms, including apoptosis of smooth muscle cells, arterial remodeling, Ca2+ signaling, oxidative stress, and secondary involvement in the renin-angiotensin system. ^ The remaining 2 analytic methods (meta-analysis of 2 groups and combined analysis) also identified several other biologically plausible candidate genes (CPPED1, NPR3, XKR6, STX1A, CDK8 and SLC18A1).^
Feofanova, Elena Valeryevna, "A large-scale candidate gene association study of blood pressure change in children and adolescents" (2015). Texas Medical Center Dissertations (via ProQuest). AAI1604124.