A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease

Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y2 receptor promoter disrupt multiple transcriptional response motifs

The neuropeptide Y2 G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10 000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter

Genetic Implication of a Novel Thiamine Transporter in Human Hypertension

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

The Influence of Diet and Probiotics on the Response of Solid Tumours to Immunotherapy: Present and Future Perspectives

Currently, various immunotherapeutic treatments are revolutionizing therapies that treat solid neoplasms. For these treatments, within immunotherapy, immune checkpoint inhibitors (ICIs) are the most widely used drugs. Diverse studies have shown the influence of diet and probiotics on the response to ICIs and consequently on the survival rates associated with different neoplasms. The use of various antibiotics, probiotics, and prebiotics has been associated with changes in the gut microbiota, and this, in turn, with resistance to immunotherapy. Together with the above, a lower intake of red meat and greater consumption of a Mediterranean, vegetarian, or vegan diet have led to a new way of understanding the mechanisms of resistance to ICIs. Omega-3 and polyphenol supplements are also powerful regulators of the microbiome whose influence on the immune system. Therefore, this review covers the influence of diet and probiotics on the response to immunotherapy in patients who have solid tumours

Cause-specific death in hospitalized individuals infected with SARS-CoV-2: more than just acute respiratory failure or thromboembolic events

Producción CientíficaInfection with SARS-CoV-2 is becoming the leading cause of death in most countries during the 2020 pandemic. The objective of this study is to assess the association between COVID-19 and cause-specific death. The design is retrospective cohort study. We included data from inpatients diagnosed with COVID-19 between March 18 and April 21, 2020, who died during their hospital stay. Demographic, clinical and management data were collected. Causes of death were ascertained by review of medical records. The sample included 128 individuals. The median age was 84 (IQR 75-89), 57% were men. In 109 patients, the death was caused by SARS-CoV-2 infection, whereas in 19 (14.8%, 95 CI 10-22%), the infection acted only as a precipitating factor to decompensate other pathologies. This second group of patients was older (88y vs 82, p < 0.001). In age-adjusted analysis, they had a greater likelihood of heart failure (OR 3.61 95% CI 1.15-11.32), dependency in activities of daily living (OR 12.07 95% CI 1.40-103.86), frailty (OR 8.73 95% CI 1.37-55.46). The presence of X-ray infiltrates was uncommon (OR 0.07, 95% CI 0.02-0.25). A higher percentage of patient deaths from causes unrelated to COVID-19 complications occurred during the two first weeks of the pandemic. Fifteen percent of patients with COVID-19 infection died from decompensation of other pathologies and the cause of death was unrelated to COVID-19 severe complications. Most of these patients had more comorbidities and were frail and elderly. These findings can partially explain the excess mortality in older people

Genetic implication of a novel thiamine transporter in human hypertension.

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

Author Correction: A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

An amendment to this paper has been published and can be accessed via a link at the top of the paper