Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

Abstract

Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.

The potential impact of the fetal genotype on maternal blood pressure during pregnancy

“…This suggests that genetics plays an important part in the overall control of blood pressure in pregnant women and that polymorphic genetic variation can contribute towards changes in a woman's risk of developing gestational hypertension (with its heritability of 0.24 [1]) or preeclampsia (heritability of 0.54 [1]) ( Table 1). Despite there being no shortage of family linkage studies, candidate gene association studies and genome-wide (essentially hypothesis-free) association studies (GWASs), the maternal genetic variants linked or associated with gestational hypertension, preeclampsia or changes in blood pressure (reviewed in [2]) itself only account for a small fraction of the heritability of pregnancy-induced hypertension [3]. The reasons for this apparent discrepancy may relate to a combination of the effects of the lack of sensitivity of even large GWASs for detecting associations with small effect sizes and genetic variation that would not be picked up in such studies, such as the effects of copy number variation, epistasis, rare variants with large effect sizes and epigenetics [such as changes in methylation, histone and microRNA (miRNA) expression].…”

Association of a CYP4A11 polymorphism and hypertension in the Mongolian and Han populations of China

“…However, the etiology and pathogenesis of essential hypertension remain unclear. A number of studies investigating over 15 rare Mendelian hypertensive syndromes have focused on variations in genes involved in renal sodium transport, adrenergic pathways, vascular-related genes and enzymes, and receptors in the aldosterone synthesis or signaling pathways (Basson et al, 2012).…”

Future Translational Applications From the Contemporary Genomics Era

“…Although unbiased genomic approaches alone have been successful, 2 there are limitations when applied to diseases of often vastly heterogeneous (sub) phenotypes (eg, hypertension, heart failure). 107 Layering on relevant biomarker modeling (eg, B-type natriuretic peptide levels) can generate important new discoveries 2 that not only improve our understanding of the disease process itself but may even suggest specific novel therapies. Opportunities for this type of approach abound, with a constant stream of new biomarkers and emerging technologies such as metabolomic profiling.…”