Novel immune mechanisms in hypertension and cardiovascular risk

Purpose of Review: Hypertension is a common disorder with substantial impact on public health due to highly elevated cardiovascular risk. The mechanisms still remain unclear and treatments are not sufficient to reduce risk in majority of patients. Inflammatory mechanisms may provide an important mechanism linking hypertension and cardiovascular risk. We aim to review newly identified immune and inflammatory mechanisms of hypertension with focus on their potential therapeutic impact. Recent Findings: In addition to the established role of the vasculature, kidneys and central nervous system in pathogenesis of hypertension, low-grade inflammation contributes to this disorder as indicated by experimental models and GWAS studies pointing to SH2B3 immune gene as top key driver of hypertension. Immune responses in hypertension are greatly driven by neoantigens generated by oxidative stress and modulated by chemokines such as RANTES, IP-10 and microRNAs including miR-21 and miR-155 with other molecules under investigation. Cells of both innate and adoptive immune system infiltrate vasculature and kidneys, affecting their function by releasing pro-inflammatory mediators and reactive oxygen species. Summary: Immune and inflammatory mechanisms of hypertension provide a link between high blood pressure and increased cardiovascular risk, and reduction of blood pressure without attention to these underlying mechanisms is not sufficient to reduce risk

Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases

Hypertension (HT) is a modifiable risk factor for life-threatening cardiovascular diseases (CVDs) including coronary artery disease, heart failure or stroke. Despite significant progress in understanding of the pathophysiological mechanisms of the disease, the molecular pathways targeted by HT treatment still remain largely unchanged. This warrants the necessity for searching novel biomarkers, which are causally related to persistent high blood pressure (BP) and may be pharmacologically targeted. Data from large-scale biobanks, containing high-throughput genetic and biochemical data, such as OLINK and SomaScan-based proteomics or Nuclear Magnetic Resonance-based metabolomics, as well as novel analytical tools including Mendelian randomisation (MR) approach enabling genetic casual inference, may create new treatment opportunities for HT and related CVDs. MR analysis may constitute an additional proof for observational studies and facilitate selection of druggable targets for clinical testing and have been already used to nominate potentially causal biomarkers for HT and CVDs such as circulating glycine, branched-chain amino acids, insulin-like growth factor 1 or fibronectin 1. Using MR framework, genetic proxies for targets of already known drugs, such as statins, PCSK9 and ACE inhibitors, may additionally inform about potential side effects and eventually contribute to a more personalized medicine. Finally, genetic causal inference may disentangle independent, direct effects of correlated traits such as lipid classes or markers of inflammation on cardiovascular clinical outcomes such as atherosclerosis and HT. While several novel HT-targeting drugs are currently under clinical investigation (e.g. brain renin-angiotensin-aldosterone system inhibitors or endothelin-1 receptor antagonists), analysis of high-throughput proteomic and metabolomic data from well-powered studies may deliver novel druggable molecular targets for HT and associated CVDs

Th17 responses are not altered by natural exposure to seasonal allergens in pollen-sensitive patients

Background: Allergic rhinitis affects 10–30 % of the global population and this number is likely to increase in the forthcoming years. Moreover, it commonly co-exists with allergic asthma as a chronic allergic respiratory syndrome. While the involvement of Th2 cells in allergy is well understood, alterations of pro-inflammatory Th17 responses remain poorly characterized. The aim of our study was to determine whether natural seasonal allergen exposure causes changes in T cell subset characteristics in patients with allergic rhinitis and asthma. Methods: Sixteen patients with allergic rhinitis/atopic asthma (9M, 7F; age 31.8 ± 12.1) and 16 healthy controls were recruited into the study (9M, 7F; age 31.2 ± 5.3). Blood samples were collected from the patients 1–3 months before pollen season (visit 1), within 7 days of the appearance of pollen/initiation of allergic symptoms (visit 2) and 2 weeks after visit 2 following the introduction of symptomatic treatment with antihistamines (visit 3). Flow cytometry was used to assess major T cell subsets (naïve, central memory, effector memory and CD45RA+ effector) and key T cell cytokine production (IFNγ, IL-17A, TNF and IL-4) using intracellular staining. Data were analyzed using repeated measures ANOVA and paired t test. Results: As expected, an increase in the percentage of IL‐4+ CD4+ cells was observed during natural pollen exposure in patients with allergic respiratory syndrome. No significant changes were observed in the production of other cytokines, including Th17 cells, which tended to be lower than in the control population but unchanged during pollen exposure. Introduction of antihistamine treatment led to only moderate changes in cytokine production from CD4 and CD8 T cells. Selective changes in CD8+ T cells were observed during natural pollen exposure including a decrease in transient cells (with features of CD45RA+ and CD45RO+ cells) and a decrease in the percentage of central memory cells in the peripheral circulation. Within the CD4 cell group the total percentage of CD45RA positive CD4 cells was increased during pollen exposure. Conclusions: Th1 and Th17 responses are not altered during pollen season but allergen exposure affects T cell activation and memory cell status in patients with allergic respiratory syndrome

Response

We thank Dr. Rasmussen and colleagues for their comments on our work outlined in “Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels” (FASEB J. 28, 923–934) and the opportunity to respond to key points

Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure

Background and aims Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function. Methods and results Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [−0.044 standard deviation (SD); 95% confidence interval (CI) −0.066, −0.021] with the MR estimate strengthening (−0.087 SD; 95% CI −0.132, −0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule. Conclusion Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance

Genome-wide association study of smoking behaviours in patients with COPD

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2x10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10(-6). Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (CHRNA3/CHRNA5; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6; eg, p=2.78x10(-5) for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in DBH was significantly (p=0.015) associated with smoking cessation. Conclusion The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD

White blood cells and blood pressure: a Mendelian randomization study

Background: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. Methods: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and employed Mendelian randomization (MR) analyses using the ∼750,000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. Results: A positive association between quintiles of lymphocyte, monocyte, neutrophil counts and increased systolic (SBP), diastolic (DBP) and pulse pressure (PP) was observed (e.g. adjusted SBP mean±SE for 1st vs 5th quintile respectively: 140.13±0.08 vs. 141.62±0.07 mmHg for lymphocyte, 139.51±0.08 vs. 141.84±0.07 mmHg for monocyte, and 137.96±0.08 vs. 142.71±0.07 mmHg for neutrophil counts, all p&lt;10-50). Using 121 SNPs in MR implemented through the inverse-variance weighted (IVW) approach, we identified a potential causal relationship of lymphocyte count with SBP and DBP (causal estimates: 0.69 (95%CI: 0.19-1.20) and 0.56 (95%CI: 0.23-0.90) of mmHg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These IVW estimates were consistent with other, robust MR methods. Interestingly, the exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils and eosinophils, but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and post-exercise heart rate demonstrated a positive association of lymphocyte count with urinary albumin to creatinine ratio. Conclusions: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with SBP and DBP