Search

Aims Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. Methods and results We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13–16% and 21–26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. Conclusions Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.

Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally- integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV- 6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

No abstract available.

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.

Background and Aims Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. We aim to examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease. Method We performed conventional observational and Mendelian randomisation (MR) study to examine if modifiable anthropometric indices of obesity exert putatively causal effects on different kidney health and disease-related phenotypes. These analyses were conducted using approximately 300,000 participants of white-British ancestry from UK Biobank and up to 480,000 participants of predominantly European ancestry from genome-wide association studies. Results The Mendelian randomisation analysis indicated that increasing values of genetically predicted BMI and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration (PeGFRcystatineC=5.96 × 10-59 for BMI and PeGFRcystatineC=1.72 × 10-69 for waist circumference) and increased blood urea nitrogen (PBUN=2.01 × 10-10 for BMI and PBUN=4.54 × 10-12 for waist circumference) in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals (PeGFRcystatineC=1.47 × 10-5 for BMI and PeGFRcystatineC=7.63 × 10-5 for waist circumference; PBUN=1.96 × 10-4 for BMI and PBUN=3.10 × 10-3 for waist circumference). One standard deviation increase in genetically-predicted BMI and waist circumference decreased the relative odds of kidney health index by 14% and 18% (OR=0.86; 95%CI: 0.82-0.92; P=9.18 × 10-6 for BMI and OR=0.82; 95%CI: 0.75-0.90; P=2.12 × 10-5 for waist circumference). Approximately 13-16% of the causal effect of obesity indices on kidney health was mediated by blood pressure. Obesity increased the risk of both acute and chronic kidney disease of several aetiologies including hypertensive renal disease (OR=1.79; 95%CI: 1.14-2.82; P=1.15 × 10-2 for BMI and OR=2.41; 95%CI: 1.30-4.45; P=5.03 × 10-3 for waist circumference), renal failure (OR=1.51; 95%CI: 1.25-1.83; P=2.60 × 10-5 for BMI and OR=1.86; 95%CI: 1.43-2.42; P=4.16 × 10-6 for waist circumference) and CKD (OR=1.50; 95%CI: 1.16-1.96; P=2.44 × 10-3 for BMI and OR=1.83; 95%CI: 1.28-2.63; P=9.49 × 10-4 for waist circumference) and diabetic nephropathy (OR=1.92; 95%CI: 1.44-2.54; P=6.86 × 10-6 for BMI). Conclusion These findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease.

Objectives: Diagnosis of Systemic Autoimmune Rheumatic Diseases using antinuclear autoantibodies (ANA) is dependent on many factors and varies between populations, such that the screening dilution used for indirect immunofluorescence assay (IIFA) should be defined locally for each population. The aim of the study was firstly, to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cut-off threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA staining patterns.Methods: The tested material included serum samples from 1731 participants (1043 women and 688 men) that were tested with the commercially available IIFA using two cut-off thresholds 1:100 and 1:160.Results: We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cut-off level. For a cut-off threshold 1:100, the positive population was 19.5% and for the 1:160 cut-off 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 were more common in women (72%); 64% of ANA positive patients were over 50 years of age.Conclusion: ANA prevalence in the Polish population is at a level observed in other highly developed countries. ANA were more prevalent in women and elderly individuals. In order to reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cut-off threshold.

IntroductionWhether ACE inhibitors (ACEi) or angiotensin II receptor blocker (ARB) therapy should be continued, initiated or ceased in patients with COVID-19 is uncertain. Given the widespread use of ACEi/ARBs worldwide, guidance on the use of these drugs is urgently needed. This prospective meta-analysis aims to pool data from randomised controlled trials (RCTs) to assess the safety and efficacy of ACEi/ARB therapy in adults infected with SARS-CoV-2.Methods and analysisRCTs will be eligible if they compare patients with COVID-19 randomised to ACEi/ARB continuation or commencement versuss no ACEi/ARB therapy; study duration ≥14 days; recruitment completed between March 2020 and May 2021. The primary outcome will be all-cause mortality at ≤30 days. Secondary outcomes will include mechanical ventilation, admission to intensive care or cardiovascular events at short-term follow-up (≤30 days) and all-cause mortality at longer-term follow-up (>1 month). Prespecified subgroup analyses will assess the effect of sex; age; comorbidities; smoking status; ethnicity; country of origin on all-cause mortality. A search of ClinicalTrials.gov has been performed, which will be followed by a formal search of trial registers, preprint servers, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify RCTs that meet inclusion criteria. To date, a search of ClinicalTrials.gov identified 21 potentially eligible trials for this meta-analysis. We will request trial investigators/sponsors to contribute standardised grouped tabular outcome data.Ethics and disseminationEthics approval and informed consent will be the responsibility of the individual RCTs. Dissemination of results will occur by peer-reviewed publication. The results of our analysis can inform public health policy and clinical decision making regarding ACEi/ARB use in patients with COVID-19 on a global scale.

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 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 (

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

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.

Animal models, human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage and cardiovascular risk in humans. In experimental and small clinical studies both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin (isoLG) scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (secukinumab, tocilizumab, canakinumab, TNF-α inhibitors). In many studies, trial designs have been complicated by a lack of blood pressure related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological antihypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are discussed. Animal model, observational studies, and trial data in humans support the therapeutic potential of immune targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.

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 (

The influence of Viking-Age migrants to the British Isles is obvious in archaeological and place-names evidence, but their demographic impact has been unclear. Autosomal genetic analyses support Norse Viking contributions to parts of Britain, but show no signal corresponding to the Danelaw, the region under Scandinavian administrative control from the ninth to eleventh centuries. Y-chromosome haplogroup R1a1 has been considered as a possible marker for Viking migrations because of its high frequency in peninsular Scandinavia (Norway and Sweden). Here we select ten Y-SNPs to discriminate informatively among hg R1a1 sub-haplogroups in Europe, analyse these in 619 hg R1a1 Y chromosomes including 163 from the British Isles, and also type 23 short-tandem repeats (Y-STRs) to assess internal diversity. We find three specifically Western-European sub-haplogroups, two of which predominate in Norway and Sweden, and are also found in Britain; star-like features in the STR networks of these lineages indicate histories of expansion. We ask whether geographical distributions of hg R1a1 overall, and of the two sub-lineages in particular, correlate with regions of Scandinavian influence within Britain. Neither shows any frequency difference between regions that have higher (≥10%) or lower autosomal contributions from Norway and Sweden, but both are significantly overrepresented in the region corresponding to the Danelaw. These differences between autosomal and Y-chromosomal histories suggest either male-specific contribution, or the influence of patrilocality. Comparison of modern DNA with recently available ancient DNA data supports the interpretation that two sub-lineages of hg R1a1 spread with the Vikings from peninsular Scandinavia. ispartof: European Journal Of Human Genetics vol:29 issue:3 pages:512-523 ispartof: location:England status: published

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., Graphical Abstract Graphical Abstract

ObjectiveTo examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease.DesignConventional observational and Mendelian randomisation study.SettingUK Biobank and international genome-wide association studies.ParticipantsApproximately 300,000 participants of white-British ancestry from UK Biobank and up to 480,000 participants of predominantly European ancestry from genome-wide association studies.Main outcome measuresEstimated glomerular filtration, blood urea nitrogen, kidney health index, chronic kidney disease, hypertensive renal disease, renal failure, acute renal failure, other disorders of kidney and ureters, IgA nephropathy and diabetic nephropathy.ResultsThe Mendelian randomisation analysis indicated that increasing values of genetically predicted body mass index (BMI) and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration and increased blood urea nitrogen in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals. One standard deviation increase in genetically-predicted BMI and waist circumference decreased the relative odds of kidney health index by 14% and 18% (OR=0·86; 95%CI: 0·82-0·92; P=9·18×10-6for BMI and OR=0·82; 95%CI: 0·75-0·90; P=2·12×10-5for waist circumference, respectively). Approximately 13-16% of the causal effect of obesity indices on kidney health was mediated by blood pressure. Obesity increased the risk of both acute and chronic kidney disease of several aetiologies including hypertensive renal disease and diabetic nephropathy.ConclusionsThese findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease.What is already known on this topic-Several previous studies reported associations between increasing adiposity/obesity and either a decline in kidney function or the increased risk of specific kidney disorders.-High blood pressure and diabetes represent the two most common aetiologies of chronic kidney disease and co-exist with obesity.-It is not clear to what extent these associations may reflect cause-effect relationships.What this study adds-Our results show a consistent pattern of causation between obesity and kidney health and disease, across different biochemical parameters of kidney function and a broad spectrum of kidney health/disease.-We further demonstrate that the causal effect of obesity on kidney health is partially mediated by blood pressure and largely independent of type 2 diabetes.-We provide evidence for a causal relationship between two clinical indices of obesity and specific renal disorders including hypertensive renal disease, acute renal failure, chronic kidney disease and diabetic nephropathy.

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

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 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic 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 Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these 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 trans-ethnically 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.

Background and Aims Single mutations in over 620 genes are known as drivers of approximately 330 monogenic disorders of the kidney. These disorders are estimated to account for up to 10% of chronic kidney disease cases. Due to their disease-causing nature, these genes are particularly clinically relevant targets for molecular analysis, but, so far, there has been no systematic analysis of their expression profile and biological functions in the human kidney. We aimed to characterise and compare the genes responsible for monogenic disorders of the kidney with other non-monogenic protein-coding genes. Method We used RNA-sequencing profile of 430 kidneys to explore the characteristics of 530 monogenic genes whose expression was available for analysis in the dataset. The property of genes was characterised using in silico databases such as Genome Reference Consortium Human Build 37 (GRCh37), Drug Gene Interaction database (DGIdb) and the Human Protein Atlas (HPA). The PANTHER (protein analysis through evolutionary relationships) database was used to determine the biological network of interactions between the monogenic genes. A Fast Gene Set Enrichment Analysis (FGSEA) was carried out using single-cell RNA-sequencing data for eight cell types of the kidney from Young et al. Finally, we carried out a two-stage mendelian randomisation to discover a causal link between gene expression and estimated glomerular filtration rate (eGFR) and blood pressure (BP). We used the summary statistics from UK Biobank and the CKDGen consortium for BP and eGFR respectively. Results The expression of monogenic genes was both higher and more specific to the kidney, than other protein-coding kidney genes. The pathway analysis found both fetal and organ development to be overrepresented in this set of genes, when compared to non-monogenic kidney genes. We also found that monogenic genes are significantly overrepresented for cell-type specific expression in the proximal tubule and underrepresented in podocytes. Our Mendelian randomisation analysis identified a causal effect between the expression of 50 monogenic genes and either eGFR, systolic or diastolic blood pressure. Conclusion Our studies revealed differences in the renal expression profile of monogenic genes and protein-coding genes. The proximal tubule segment of the nephron is a particularly enriched segment of the nephron for monogenic disorders. Kidney expression of 50 of the monogenic genes is causally related to changes in eGFR and blood pressure in the general population.

Statement of remit: To align with its mission to reduce the global burden of raised blood pressure (BP), the International Society of Hypertension (ISH) has developed worldwide practice guidelines for the management of hypertension in adults, aged 18 years and older. The ISH Guidelines Committee extracted evidence-based content presented in recently published extensively reviewed guidelines and tailored ESSENTIAL and OPTIMAL standards of care in a practical format that is easy-to-use particularly not only in low-resource settings but also in high-resource settings- by clinicians, but also nurses and community health workers, as appropriate. Although distinction between low-resource and high-resource settings often refers to high (HIC) and low-income and middle-income countries (LMIC), it is well established that in HIC, there are areas with low-resource settings, and vice versa. Herein optimal care refers to evidence-based standard-of-care articulated in recent guidelines [1,2] and summarized here, whereas essential standards recognize that optimal standards would not always be possible. Hence, essential standards refer to minimum standards of care. To allow specification of essential standards of care for low-resource settings, the Committee was often confronted with the limitation or absence in clinical evidence, and thus applied expert opinion. In the Guidelines, differentiation between optimal and essential standards were not always possible, and were made in sections where it was most practical and sensible. The Guidelines Committee is also aware that some recommended essential standards may not be feasible in low-resource settings, for example, out-of-office BP measurements, the requirement of multiple visits for the diagnosis of hypertension, or advising the use of single pill combination therapy. Although challenging to implement, these guidelines may aid in local initiatives to motivate policy changes and serve as an instrument to drive local improvements in standards of care. Every effort should be made to achieve essential standards of care to reduce hypertension-induced cardiovascular morbidity and mortality.

Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2) - the cause of COVID-19 disease. It has been hypothesized that use of renin-angiotensin system (RAS) inhibiting medications in patients with hypertension, increases the expression of ACE2 and thereby increases the risk of COVID-19 infection and severe outcomes or death. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. 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 characterised 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. Collectively, our data indicate that neither hypertension nor antihypertensive treatment are likely to alter individual risk of SARS-CoV-2 infection or influence clinical outcomes in COVID-19 through changes of ACE2 expression. 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.

IntroductionCardiovascular disease (CVD) is a major cause of morbidity and mortality throughout the world. The LIPIDOGRAM2015 study was performed to estimate the prevalence of risk factors for atherosclerotic diseases as well as cardiovascular and related disorders in the primary care setting in Poland. The LIPIDOGEN2015 sub-study was designed to include a random cohort of patients in order to analyse parameters related to lipid metabolism, oxidative stress, inflammatory responses, autoimmune disorders, and gene variants that confer susceptibility to cardiometabolic and atherosclerotic diseases.Material and methodsThe recruitment was carried out by 438 primary care physicians in Poland. The expected number of patients recruited for the LIPIDOGRAM2015 study was 13,000–14,000 with 13–15% (1700–2000) also participating in the LIPIDOGEN2015 sub-study. Each patient had to complete a questionnaire concerning medical and family history, concomitant diseases, and pharmacotherapy. Anthropometric measurements were performed at the doctor’s office. For the LIPIDOGEN2015 sub-study, saliva samples for DNA isolation and blood samples for measurement of glycated haemoglobin, oxidative stress parameters, autoantibody levels, and inflammatory cytokine profile and apolipoprotein profile were collected. Follow-up data will be obtained from the National Health Fund in Poland.ResultsThe LIPIDOGRAM2015 and LIPIDOGEN2015 study cohort reflects the prevalence of cardiovascular risk factors and concomitant diseases, markers of oxidative stress, the presence of autoantibodies, inflammatory cytokine profile, and apolipoprotein profile, as well as genetic variants potentially conferring susceptibility to cardiometabolic and atherosclerotic diseases.ConclusionsThis study presents the prevalence of different CV risk factors, with special emphasis on lipid disorders, and it assesses the relationship between inflammation, oxidative stress, and mutations in genes encoding proteins regulating lipid metabolism, as well as genes conferring susceptibility to cardiovascular, cardiometabolic, and related diseases.

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

BACKGROUND AND AIM: To estimate the prevalence of cardiovascular (CV) disease and CV risk factors among Polish patients.METHODS: A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the 4th quarter of 2015 and 1st and 2nd quarters of 2016; 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices.RESULTS: Nearly 19% of men and approximately 12% of women had cardiovascular disease (CVD). Over 60% of the recruited patients had hypertension (HTN), >80% had dyslipidaemia and CONCLUSIONS: The prevalence of CVD and CV risk factors among patients in Poland is high. CVD is more common in men than in women. The most common CV risk factors are excess waist circumference, dyslipidaemia and HTN. Family physicians should conduct activities to prevent, diagnose early and treat CVD in the primary health care population.

Objective: Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of COVID-19 disease. However, the effect of RAS-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported Design and method: We examined how hypertension, its major metabolic cophenotypes and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterised by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model Results: 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 Conclusions: Our results indicate that neither hypertension nor antihypertensive treatment are likely to alter the expression of the key entry receptor for SARSCoV-2 in the human kidney. Our data further suggest that in the absence of SARSCoV-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.

Postural defect is a set of postural abnormalities defined as minor single deviations from correct posture, which may be repaired with the use of appropriate exercises, passive or active. Studies concerning the evaluation of children and teenagers’ health condition have shown that the incidence of postural defects in the population ranges from 30 to 60%. The greatest threat for the development of incorrect body posture is present in the period of fast growth, namely between the age of 5 and 7 and in the period of adolescence. The most common postural defects in the population of children in Poland include: scoliosis, juvenile kyphosis of the spine (Scheuermann’s disease) and static deformations of lower extremities. Owing to the common nature of the issue and the possibility to apply effective preventive measures, it is necessary to early detect postural defects through appropriate examinations. Preventive healthcare for children is aimed at early diagnosis of irregularities in a child’s development. Screening tests among children detect three types of the motor system disorders: scoliosis, excessive thoracic kyphosis and static deformations of lower extremities and asymmetry in the length of lower extremities. Early detection of the defect prevents against its further development or the development of further abnormalities. The results of a report Health Behaviour in School-aged Children concerning the health of children clearly show that recently, there has been a substantive increase in the number of factors causing the creation of postural defects. School period is the most optimum one to carry out preventive actions in this respect. Postural defects develop in some children, despite preventive measures carried out. In accordance with the recommendations of experts, it is then necessary to perform secondary prophylaxis, which prevents further development of the defect, the creation of muscular contracture and is aimed at the so-called postural re-education. The selection of physical activity should be adequate to the type of postural defect.

We thank Dr Spence for his interest in the 2020 International Society of Hypertension (ISH) Global Hypertension Practice Guidelines and highlighting what he considers blind spots in the new guidelines. Specifically, the author is concerned that Liddle syndrome, one of the rare monogenic causes of hypertension is not mentioned and its treatment not appropriately addressed in the 2020 ISH guidelines. Dr Spence provides insightful comments describing the central role of the epithelial sodium channel (ENaC) in Liddle syndrome which is responsible for its clinical features including early onset of salt-sensitive hypertension, hypokalemic metabolic alkalosis, and suppression of both renin and aldosterone secretion. Importantly, Liddle syndrome is associated with increased incidence of premature cardiovascular and cerebrovascular events and usually unresponsive to mineralocorticoid receptor antagonists.

Introduction Suboptimal drug adherence in hypertension is pandemic and traditional diagnostic tools to detect non-adherence have lacked accuracy and robustness. The inability to identify non-adherence has therefore driven the development of biochemical drug screening by liquid chromatography tandem mass spectrometry (LC- MS/MS) in urine and blood, which are the most accurate metrics presently available. Urinary antihypertensive testing is evidenced to improve non-adherence rates, significantly decrease blood pressure after physician intervention, and be cost effective. The European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 guidelines have recommended the use of biochemical testing for non-adherence diagnosis. However, it has been argued that the variable pharmacokinetic parameters of the medication (such as their half-lives and clearance rates) may affect the detection of medications in urine and hence the determination of adherence. We hypothesized that pharmacokinetic parameters do not affect the detection of antihypertensive medications in urine. Aim This study compared the pharmacokinetic parameters of the most commonly prescribed antihypertensive medications against their detection in urine by LC-MS/MS. Methods Results of urinary drug screens from 463 hypertensive patients (total prescribed medications N=1709) were collated. An adherence score termed as the C score (number of detected vs. prescribed medication) was generated for each of the 27 common antihypertensive medications. Pharmacokinetic parameters such as bioavailability, plasma concentration, volume of distribution, half-life, plasma clearance and urinary excretion values for each drug were obtained from published literature. Partial linear correlation was conducted between the C score of all the medications and each pharmacokinetic parameter studied. Results 40% of patients were non-adherent. The average number of prescribed medications was high (N=3.7, SD: 1.5), and the average number of drugs detected was lower (N=2.5, SD: 1.6). Amlodipine was the most prescribed (N=224), and clonidine was the least (N=10). The half-lives ranged from 0.87 to 39 hours for bumetanide and amlodipine respectively. The urinary excretion percentage varied from Half-life versus adherence score Conclusion This study reports no significant correlation between drug pharmacokinetics and adherence. To the best of our knowledge this is the first study of its kind. Urinary biochemical testing by LC-MS/MS for non-adherence remains a valid tool for diagnosis although further detailed pharmacokinetic studies are needed to confirm this finding. Acknowledgement/Funding None

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 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.

Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (BP; P =0.403). Measurement of urinary drug and drug metabolite levels demonstrates a similarly high level of antihypertensive medication adherence in both MUCH and truly controlled hypertensive patients. These findings indicate that MUCH is not attributable to antihypertensive medication nonadherence.

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.

Endurance exercise improves cardiovascular health and reduces mortality risk. Augmentation index (AIx) reflects adverse loading exerted on the heart and large arteries and predicts future cardiovascular disease. The purpose of this study was to establish whether endurance athletes possess lower AIx and aortic blood pressure compared to healthy controls, and to determine the association between AIx and cardiorespiratory fitness. Forty-six endurance athletes and 43 healthy controls underwent central BP and AIx measurements by non-invasive applanation tonometry before a maximal exercise test. Peak oxygen uptake ( $$\dot{V}{\text{O}}_{{ 2 {\text{peak}}}}$$ ) was assessed by pulmonary analysis. Relative to controls, athletes had significantly lower brachial diastolic blood pressure (BP, −4.8 mmHg, p

Hypertension is a leading cause of cardiovascular morbidity and mortality worldwide, yet the molecular mechanisms underpinning the development of high blood pressure remain incompletely understood. MicroRNAs are small, non-coding RNA molecules approximately 22 nucleotides in length that act as post-transcriptional regulators of gene expression. We highlight, through a review of recent literature, that studies on circulating microRNAs have provided novel insights into blood pressure regulation. They have also complemented tissue-based and animal-based experiments in shedding new light on our understanding of established pathways in hypertension, such as the renin-angiotensin system. Despite a number of challenges, we believe microRNAs herald particular potential in becoming effective biomarkers of target-organ damage in hypertension.

Blunted day–night difference in blood pressure (BP) is an independent cardiovascular risk factor, although there is limited information on determinants of diurnal variation in BP. We investigated determinants of day–night difference in systolic (SBP) and diastolic (DBP) BP and how these compared with determinants of daytime and night-time SBP and DBP. We analysed the association of mean daytime, mean night-time and mean day–night difference (defined as (mean daytime−mean night-time)/mean daytime) in SBP and DBP with clinical, lifestyle and biochemical parameters from 1562 adult individuals (mean age 38.6) from 509 nuclear families recruited in the GRAPHIC Study. We estimated the heritability of the various BP phenotypes. In multivariate analysis, there were significant associations of age, sex, markers of adiposity (body mass index and waist–hip ratio), plasma lipids (total and low-density lipoprotein cholesterol and triglycerides), serum uric acid, alcohol intake and current smoking status on daytime or night-time SBP and/or DBP. Of these, only age (P=4.7 × 10−5), total cholesterol (P=0.002), plasma triglycerides (P=0.006) and current smoking (P=3.8 × 10−9) associated with day–night difference in SBP, and age (P=0.001), plasma triglyceride (P=2.2 × 10−5) and current smoking (3.8 × 10−4) associated with day–night difference in DBP. 24-h, daytime and night-time SBP and DBP showed substantial heritability (ranging from 18–43%). In contrast day–night difference in SBP showed a lower heritability (13%) while heritability of day–night difference in DBP was not significant. These data suggest that specific clinical, lifestyle and biochemical factors contribute to inter-individual variation in daytime, night-time and day–night differences in SBP and DBP. Variation in day–night differences in BP is largely non-genetic.

Chronic kidney disease (CKD) is an important challange for healthcare systems wordwide because of its high prevalence and serious late complications. The results of recent studies suggest an association between CKD development and genetic variation within the uromodulin gene (UMOD). The aim of this study was to investigate associations between two common single nucleotide polymorphisms – rs12917707 and rs11864909, located in the region of UMOD and chronic renal disease. The study group consisted of 109 patients with chronic kidney disease, caused by chronic renal glomerulonephritis or chronic tubulointerstitial nephritis, and 109 pairs of their biological parents. Genotyping for rs12917707 and rs11864909 was carried out using the TaqMan Pre-designed SNP Genotyping Assay. In the transsmission disequilibrium test, allele C of rs11864909 was preferentialy transmitted from parents to the children with chronic tubulointerstinal nephritis. The rs12917707 was not associated with CKD. Neither of the investigated polymorphisms was associated with the progression of chronic kidney disease. The obtained results suggest an association of rs11864909 with chronic kidney disease secondary to chronic tubulointerstinal nephritis.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectionalmeta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Studyspecific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a-3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI:-10.03,-5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10-3 unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10-3, -1.01 × 10-3) difference in ageand sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10-3 unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10-3, -1.25 × 10-3). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL arewarranted.

Chronic kidney disease (CKD) affects ∼10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

In 2017, the American College of Cardiology (ACC), the American Heart Association (AHA), and 9 other American societies released guidelines for the prevention, detection, evaluation, and management of high blood pressure (BP) in adults.1 These guidelines are perhaps the most controversial set of US guidelines—even more so than those attributed to some of the committee set up to produce the guidelines of the Eighth Joint National Committee in 2014.2 Before discussing the various controversial aspects of the ACC/AHA guidelines, the International Society of Hypertension would like to congratulate the authors on 3 counts. First, emphasis was placed on the appropriate technique of BP measurements and the increased need for out-of-office BP measurement. Second, the value of risk assessment was recognized and introduced for the first time in US guidelines and finally, perhaps in part because of the controversial nature of the document, awareness of the importance of BP as a global cause of morbidity and mortality has been raised. The central controversy around which several others arise is the redefining of hypertension—as a systolic BP ≥130 mm Hg or a diastolic BP ≥80 mm Hg. Although there is a clear dose-response relationship between increasing BP levels and adverse cardiovascular outcomes,3 this preempts the ability, based on predicting cardiovascular events, of precisely defining hypertension. However, the pragmatic definition proposed by Geoffrey Rose decades ago should perhaps be considered—viz: “that level of BP above which investigation and management does more good than harm.”4 Does the new BP level proposed in the ACC/AHA guidelines fully satisfy that criterion? Perhaps not. To date, the relevant data are inconsistent and hence controversial. The problem arises because the definition of hypertension, treatment thresholds, and BP targets should …