Genes for blood pressure: an opportunity to understand hypertension

Hypertension (HTN) is quantitatively the major cardiovascular risk factor and responsible for ∼50% of cardiovascular morbidity and mortality. Blood pressure (BP) is also a classical complex genetic trait with heritability estimates of 30-50%. Although much is known about BP regulation, the intrinsic origin of essential HTN remains obscure although many environmental factors are known. Analyses of rare monogenic syndromes of HTN have focused attention on pathways that involve renal sodium handling, and steroid hormone metabolism including the mineralocorticoid receptor activity. The genetic basis of common essential HTN on the other hand is only just becoming accessible through high-throughput approaches. Unbiased genome-wide analyses of BP genomics have identified 43 genetic variants associated with systolic, diastolic BP, and HTN. It is highly likely based on current findings that there are hundreds of such loci with small effects on BP, opening a perspective on the genetic architecture of BP that was unknown before. It is our hope that the knowledge of these and further loci will lead to improved understanding of BP pathophysiology and to the identification of new targets for drug therap

Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension

The 15q24.1 locus, including CYP1A2, is associated with blood pressure (BP). The CYP1A2 rs762551 C allele is associated with lower CYP1A2 enzyme activity. CYP1A2 metabolizes caffeine and is induced by smoking. The association of caffeine consumption with hypertension remains controversial. We explored the effects of CYP1A2 variants and CYP1A2 enzyme activity on BP, focusing on caffeine as the potential mediator of CYP1A2 effects. Four observational (n = 16 719) and one quasi-experimental studies (n = 106) including European adults were conducted. Outcome measures were BP, caffeine intake, CYP1A2 activity and polymorphisms rs762551, rs1133323 and rs1378942. CYP1A2 variants were associated with hypertension in non-smokers, but not in smokers (CYP1A2-smoking interaction P = 0.01). Odds ratios (95% CIs) for hypertension for rs762551 CC, CA and AA genotypes were 1 (reference), 0.78 (0.59-1.02) and 0.66 (0.50-0.86), respectively, P = 0.004. Results were similar for the other variants. Higher CYP1A2 activity was linearly associated with lower BP after quitting smoking (P = 0.049 and P = 0.02 for systolic and diastolic BP, respectively), but not while smoking. In non-smokers, the CYP1A2 variants were associated with higher reported caffeine intake, which in turn was associated with lower odds of hypertension and lower BP (P = 0.01). In Mendelian randomization analyses using rs1133323 as instrument, each cup of caffeinated beverage was negatively associated with systolic BP [−9.57 (−16.22, −2.91) mmHg]. The associations of CYP1A2 variants with BP were modified by reported caffeine intake. These observational and quasi-experimental results strongly support a causal role of CYP1A2 in BP control via caffeine intak

Positional identification of variants of Adamts16 linked to inherited hypertension

A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling B

Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using $\sim$2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant $(p<5 \times 10^{-8})$ or suggestive associations $(p<4 \times 10^{-7})$ were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding $(p<4 \times 10^{-7})$. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels

Genetic Implication of a Novel Thiamine Transporter in Human Hypertension

ObjectivesThis study coupled 2 strategies—trait extremes and genome-wide pooling—to discover a novel blood pressure (BP) locus that encodes a previously uncharacterized thiamine transporter.BackgroundHypertension is a heritable trait that remains the most potent and widespread cardiovascular risk factor, although details of its genetic determination are poorly understood.MethodsRepresentative genomic deoxyribonucleic acid (DNA) pools were created from male and female subjects in the highest- and lowest-fifth percentiles of BP in a primary care population of >50,000 patients. The peak associated single-nucleotide polymorphisms were typed in individual DNA samples, as well as in twins/siblings phenotyped for cardiovascular and autonomic traits. Biochemical properties of the associated transporter were evaluated in cellular assays.ResultsAfter chip hybridization and calculation of relative allele scores, the peak associations were typed in individual samples, revealing an association between hypertension, systolic BP, and diastolic BP and the previously uncharacterized solute carrier SLC35F3. The BP genetic association at SLC35F3 was validated by meta-analysis in an independent sample from the original source population, as well as the International Consortium for Blood Pressure Genome-Wide Association Studies (across North America and western Europe). Sequence homology to a putative yeast thiamine (vitamin B1) transporter prompted us to express human SLC35F3 in Escherichia coli, which catalyzed [3H]-thiamine uptake. SLC35F3 risk-allele homozygotes (T/T) displayed decreased erythrocyte thiamine content on microbiological assay. In twin pairs, the SLC35F3 risk allele predicted heritable cardiovascular traits previously associated with thiamine deficiency, including elevated cardiac stroke volume with decreased vascular resistance, and elevated pressor responses to environmental (cold) stress. Allelic expression imbalance confirmed that cis variation at the human SLC35F3 locus influenced expression of that gene, and the allelic expression imbalance peak coincided with the hypertension peak.ConclusionsNovel strategies were coupled to position a new hypertension-susceptibility locus, uncovering a previously unsuspected thiamine transporter whose genetic variants predicted several disturbances in cardiac and autonomic function. The results have implications for the pathogenesis and treatment of systemic hypertension

A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10-6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations

SNPs and Other Features as They Predispose to Complex Disease: Genome-Wide Predictive Analysis of a Quantitative Phenotype for Hypertension

Though recently they have fallen into some disrepute, genome-wide association studies (GWAS) have been formulated and applied to understanding essential hypertension. The principal goal here is to use data gathered in a GWAS to gauge the extent to which SNPs and their interactions with other features can be combined to predict mean arterial blood pressure (MAP) in 3138 pre-menopausal and naturally post-menopausal white women. More precisely, we quantify the extent to which data as described permit prediction of MAP beyond what is possible from traditional risk factors such as blood cholesterol levels and glucose levels. Of course, these traditional risk factors are genetic, though typically not explicitly so. In all, there were 44 such risk factors/clinical variables measured and 377,790 single nucleotide polymorphisms (SNPs) genotyped. Data for women we studied are from first visit measurements taken as part of the Atherosclerotic Risk in Communities (ARIC) study. We begin by assessing non-SNP features in their abilities to predict MAP, employing a novel regression technique with two stages, first the discovery of main effects and next discovery of their interactions. The long list of SNPs genotyped is reduced to a manageable list for combining with non-SNP features in prediction. We adapted Efron's local false discovery rate to produce this reduced list. Selected non-SNP and SNP features and their interactions are used to predict MAP using adaptive linear regression. We quantify quality of prediction by an estimated coefficient of determination (R2). We compare the accuracy of prediction with and without information from SNPs

Silent brain infarcts impact on cognitive function in atrial fibrillation

Aims: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients. Methods and results: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [-0.12 (-0.22; -0.07)] than patients without new brain infarcts [0.07 (-0.09; 0.25)]. New WML or Mb were not associated with cognitive decline. Conclusion: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline. Clinical trial registration: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844. Keywords: Atrial fibrillation; Brain infarction; Cognitive function; Magnetic resonance imaging; Oral anticoagulation