The macrophage acknowledges various evolutionary hypotheses of hypertension indicating a genetic basis—is hypertension a maladaptive response of genes that were selected for salt retention when life moved from salt-rich oceans to salt-poor land? More recently, is the increased risk of salt-sensitive hypertension among African Americans related to enrichment of salt conserving gene variants amongst the survivors of the brutal transatlantic slave transports? [7, 8] Curiously, the maladaptive gene theory stumbles with data showing lower prevalence of hypertension among rural populations and in unacculturated societies like the Yanomami Indians [9]. Furthermore, migration of rural individuals to urban areas results in an increased incidence of hypertension [10]. All these point to an environmental cause. There were other inconsistencies: the peculiar cases of Gitelman Syndrome (affected individuals would crave salt but maintained low blood pressure despite high salt intake) and Glucocorticoid-remediable aldosteronism (high blood pressure paradoxically resolved with corticosteroid treatment) clearly show the role of genes with mutations identified in SLC12A1 gene for the former and a chimeric translocation between CYP11B1 and CYP11B2 genes for the latter [3]. The INTERSALT study [11] demonstrated a causal effect of sodium intake on blood pressure, but salt-sensitivity is a normally distributed phenotype implying multifactorial influences—both genetic and environmental.

The fraction of population blood pressure variation explained by genetic variation is quantified as heritability and the estimated heritability of blood pressure is modest at around 15–40% for clinic blood pressure but higher for ambulatory blood pressure (50–69%) [12]. This formed the basis for the highly successful drive to discover the polygenic architecture of blood pressure and hypertension. The genomic era over the last 15 years, specifically through a plethora of genome wide association studies (GWAS) identified over 1500 single nucleotide polymorphisms (SNPs) associated with blood pressure and hypertension [12]. Yet it also carried a sense of disappointment as researchers struggled to translate genetic signals into clinical applications. All the GWAS SNPs together explained only approximately 27% of the estimated blood pressure heritability and 5.7% of the phenotypic variance of SBP [12]. Combining all the SNPs into a polygenic score to predict hypertension has not yet shown clinical utility. GWAS in general have shown potential to discover novel pathways, but clinical translation is challenging. The deflated expectations from GWAS for rapidly using genomics to understand and treat hypertension echoed the similar over-expectations following the first sequencing of the human genome in 2001 [13]. It dawns on the macrophage that the experimental data on blood pressure and hypertension seemed to suggest either an environmental or a genetic causal mechanism, depending on who conducted the studies, indicating a form of confirmation bias. ‘Perhaps, like quantum particles, hypertension exists in a state of causal superposition, where seemingly incongruous factors intertwine to shape its manifestation,’ it mused. The macrophage’s early criticism of the quantum physicist considerably waned, sympathising with the physicist likening the whirlwind of contradictory information to the complex interplay of subatomic particles (or waves) entangled in a quantum dance.