Interactive molecular causal networks of hypertension using a fast machine learning algorithm MRdualPC.

BACKGROUND: Understanding the complex interactions between genes and their causal effects on diseases is crucial for developing targeted treatments and gaining insight into biological mechanisms. However, the analysis of molecular networks, especially in the context of high-dimensional data, presents significant challenges. METHODS: This study introduces MRdualPC, a computationally tractable algorithm based on the MRPC approach, to infer large-scale causal molecular networks. We apply MRdualPC to investigate the upstream causal transcriptomics influencing hypertension using a comprehensive dataset of kidney genome and transcriptome data. RESULTS: Our algorithm proves to be 100 times faster than MRPC on average in identifying transcriptomics drivers of hypertension. Through clustering, we identify 63 modules with causal driver genes, including 17 modules with extensive causal networks. Notably, we find that genes within one of the causal networks are associated with the electron transport chain and oxidative phosphorylation, previously linked to hypertension. Moreover, the identified causal ancestor genes show an over-representation of blood pressure-related genes. CONCLUSIONS: MRdualPC has the potential for broader applications beyond gene expression data, including multi-omics integration. While there are limitations, such as the need for clustering in large gene expression datasets, our study represents a significant advancement in building causal molecular networks, offering researchers a valuable tool for analyzing big data and investigating complex diseases.

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.

A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions.

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

Kidney omics in hypertension: from statistical associations to biological mechanisms and clinical applications.

Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage.

Analysis of the impact of sex and age on the variation in the prevalence of antinuclear autoantibodies in Polish population: a nationwide observational, cross-sectional study.

The detection of antinuclear autoantibody (ANA) is dependent on many factors and varies between the populations. The aim of the study was first to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cutoff threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA-staining patterns. We tested 1731 patient samples using commercially available IIFA using two cutoff thresholds of 1:100 and 1:160. We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cutoff level. For a cutoff threshold 1:100, the positive population was 19.5% and for the 1:160 cutoff threshold, it was 11.7%. The most prevalent ANA-staining pattern was AC-2 Dense Fine speckled (50%), followed by AC-21 Reticular/AMA (14.38%) ANA more common in women (72%); 64% of ANA-positive patients were over 50 years of age. ANA prevalence in the Polish population is at a level observed in other highly developed countries and is more prevalent in women and elderly individuals. To reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cutoff threshold.

Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study.

BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. RESULTS: In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.

A call to action for new global approaches to cardiovascular disease drug solutions.

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

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 used 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, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. 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 postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.

Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis.

AIM: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers. MATERIALS AND METHODS: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs). RESULTS: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was -4.3 mmHg [95%CI: -9.10-0.48], p = 0.08 and -3.16 mmHg [95%CI: -6.51-0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = -11.41 mmHg (95%CI: -13.66, -9.15) P < 0.00001] and DBP [WMD = -8.43 mmHg (95%CI: -10.96,-5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints. CONCLUSIONS: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals.

May Measurement Month 2019: an analysis of blood pressure screening results from the United Kingdom and Republic of Ireland.

In the UK, heart and circulatory diseases account for 29% of all deaths (14% through coronary heart disease and 8% through stroke). In 2015, the prevalence of hypertension was 20% in the UK and 23% in the Republic of Ireland. In 2019, 14% of people registered with a UK general practice had hypertension and yet it was the attributable risk factor for around half of all deaths from coronary heart disease or stroke. We participated in May Measurement Month 2019 to increase awareness of blood pressure (BP) measurement, and to identify the proportion of undiagnosed hypertension and degree of uncontrolled hypertension in the community. The 2019 campaign set up screening sites within the community at places of worship, supermarkets, GP surgeries, workplaces, charity events, community pharmacies, gyms, and various other public places. We screened 10194 participants (mean age 51 ± 18 years, 60% women) and found that 1013 (9.9%) were on antihypertensive treatment, while 3408 (33.4%) had hypertension. Of the 3408 participants with hypertension, only 33.5% were aware of their condition despite 98.8% having previous BP measurements. In those on antihypertensive medication, only 38.2% had controlled BP (<140 and <90 mmHg). Our UK and Republic of Ireland data demonstrate concerning levels of undiagnosed hypertension and sub-optimal BP control in many individuals with a diagnosis. This evidence supports a critical need for better systematic community and primary care screening initiatives.

May Measurement Month 2019: an analysis of blood pressure screening results from Poland.

May Measurement Month 2019 is the third edition of a global initiative organized by the International Society of Hypertension aimed at raising awareness of hypertension and the need for blood pressure (BP) screening. We present data analysis from Poland. To evaluate the potential of opportunistic BP measurements as a tool for cardiovascular disease prevention programmes. To collect new country data for further annual comparisons. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in 201 sites in May 2019. BP was measured in 7072 subjects (mean age: 54 ± 15 years; 62.3% females). After multiple imputation, the age- and sex-standardized systolic BP (SBP) and diastolic BP (DBP) was 125.4/78.5 mmHg in the whole group, 133.3/82.8 mmHg in individuals on antihypertensive medication and 123.3/77.7 mmHg in those not taking antihypertensive drugs. The proportion of subjects with high BP (≥140/90 mmHg) were 41.8% in subjects taking antihypertensive drugs, and 19.6% in those not taking any antihypertensive drugs. Overall, hypertension was present in 55.4% of participants (3917 out of 7072), of whom 83.0% were aware of their diagnosis. 80.4% of hypertensives were taking antihypertensive medication. 46.7% of all hypertensives had BP controlled to target (<140/90 mmHg). Higher BP correlated with body mass index and age but not tobacco smoking. SBP but not DBP was higher in diabetic participants. These data provide evidence on the current epidemiology of hypertension and may serve as a source of information to introduce primary and secondary prevention programmes to reduce cardiovascular risk in Poland.

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Human Y Chromosome Exerts Pleiotropic Effects on Susceptibility to Atherosclerosis.

OBJECTIVE: The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis. Approach and Results: Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD-carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04-1.18; P=6.8×10-4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1-specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal. CONCLUSIONS: Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY.

May Measurement Month 2018: an analysis of blood pressure screening results from the UK and the Republic of Ireland.

Raised blood pressure (BP) was the biggest contributor to the global burden of disease in 2017, with lack of awareness and adequate control of BP identified as the main drivers of this disease burden. In 2017, an opportunistic BP screening and awareness campaign called May Measurement Month (MMM) in the UK and Republic of Ireland (RoI) highlighted that levels of undiagnosed hypertension and uncontrolled hypertension in the community screened were approximately 23% and 40%, respectively. MMM18 was undertaken to further the campaign's efforts to increase awareness and create an evidence base of population risk associated with high BP. MMM18 BP screenings were conducted in the community at places of worship, supermarkets, GP surgeries, workplaces, community pharmacies, gyms, and various other public places. A total of 5000 volunteers, aged 47.3 (±17.2) years, 60% female were screened. Of all 5000 individuals screened, 1716 (34.3%) were hypertensive, of which only 51.3% were aware of their condition, 42.8% on antihypertensive treatment, and only 51.5% of those on medication controlled to target BP of <140/90 mmHg. Furthermore, obese, overweight, and underweight participants all had significantly higher BP values compared to individuals with a healthy body mass index (BMI). The 2018 MMM campaign in the UK and the RoI confirmed approximately one in three adults were hypertensive, with more than half having uncontrolled BP. In addition, these findings show that people with low BMI are at risk of having high BP. Finally, with only one in two people aware of their high BP, awareness remains a significant public health concern.

Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy.

AIMS: Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension. METHODS AND RESULTS: We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of -11.1 mmHg; 95% CI 6.5-15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension. CONCLUSION: A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.

May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension.

AIMS: Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. METHODS AND RESULTS: Eighty-nine countries participated in MMM 2018. Volunteers (≥18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) hypertension. CONCLUSION: May Measurement Month expanded significantly compared with 2017, including more participants in more countries. The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk.

Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics.

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.

Do we know more about hypertension in Poland after the May Measurement Month 2017?-Europe.

Elevated blood pressure (BP) is a worldwide burden, leading to over 10 million deaths yearly. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed at raising awareness of hypertension and the need for BP screening. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. BP measurement, the definition of hypertension and statistical analysis followed the globally approved MMM17 Study Protocol. In Poland 5834 (98.9%, Caucasian) individuals were screened. After multiple imputation, 2601 (35.3%) had hypertension. Of individuals not receiving anti-hypertensive medication, 976 (20.6%) were hypertensive. Of individuals receiving anti-hypertensive medication, 532 (49.1%) had uncontrolled BP. In the crude screened group, 81.4% declared to not receive any anti-hypertensive treatment, while the remaining 18.6% were on such medications. In overweight and obese patients both systolic and diastolic BP were significantly higher than in normal weight and underweight subjects. In addition, BP measured on Sundays was significantly lower than on Mondays. MMM17 was one of the largest recent BP screening campaigns in Poland. We found that over 1/3 of participants were hypertensive. Almost half of the treated subjects had uncontrolled BP. These results suggest that opportunistic screening can identify substantial numbers with raised BP.

May Measurement Month 2017: an analysis of blood pressure screening results from the United Kingdom and the Republic of Ireland-Europe.

Elevated blood pressure (BP), or hypertension, is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative aimed at raising awareness of high BP and acting as a stimulus to improving screening programmes worldwide. In the United Kingdom (UK) nearly 1 in 5 people, and in the Republic of Ireland (RoI) 3 out of 10, have hypertension, of which a large proportion remains undiagnosed. An opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2017. Blood pressure measurement, the definition of hypertension and statistical analysis followed a standardized protocol. Screenings sites in hospitals, universities, shopping centres, workplaces, sports clubs, community centres, GP practices, and pharmacies were set up across the UK and RoI as part of this initiative. Seven thousand seven hundred and fourteen individuals were screened during MMM17. After multiple imputation, 3099 (40.3%) had hypertension. Of individuals not receiving antihypertensive medication, 1406 (23.4%) were hypertensive. Of individuals receiving antihypertensive medication, 682 (40.5%) had uncontrolled BP. MMM17 was the largest BP screening campaign ever undertaken in the UK and RoI. These data prove for the first time that a relatively inexpensive, volunteer based, convenience sampling of screening BP in the community identified two out of five individuals as hypertensive, with one in four not receiving treatment. Of major concern is that these data demonstrate that of those individuals receiving treatment, two out of five still did not have controlled BP.

Analysis with the exome array identifies multiple new independent variants in lipid loci.

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.