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Abstract: Cocaine is the most common stimulant drug that causes death in Connecticut. Unlike opioid intoxication deaths, which largely correlate with dose/concentration, cocaine deaths occur more idiosyncratically, with mechanisms of death often related to underlying cardiovascular disease. We examined 78 sole acute cocaine and 306 sole acute fentanyl intoxication deaths to assess their association with cardiovascular disease. In the cocaine cohort, 87% (68/78) had atherosclerotic and/or hypertensive cardiovascular disease while 40% (122/306) in the fentanyl cohort did. Cocaine was detected in 40% of all accidental drug intoxication deaths, 41% of all accidental drug intoxication deaths involving fentanyl, and 37% of all drug intoxication deaths involving heroin. The relatively low number of sole cocaine deaths compared to the much higher proportion of cocaine/opioid deaths may be explained by the synergistic effects encountered in many mixed drug intoxications, the contributory role of cardiovascular disease in sole cocaine deaths, and/or the increased prevalence and potency of fentanyl. The high number of sole cocaine deaths in which the decedents had co-existing heart disease compared to those from sole fentanyl deaths (P < 0.001) suggests that heart disease plays a mechanistic role in sole cocaine deaths, whereas the potency of fentanyl is the dominant mechanism in fentanyl deaths., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, N case /N control =40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMT max -AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMT mean -AS: HR = 1.39, 95%CI = 1.09-1.78; cIMT min -AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMT max -AS: [Formula: see text]=0.23, P=9.44 × 10 -5 ; cIMT mean -AS: [Formula: see text]=0.21, P=3.00 × 10 -4 ; cIMT min -AS: [Formula: see text]=0.16, P=6.30 × 10 -3 ). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMT max -AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMT mean -AS: OR=1.09, 95%CI=0.93-1.26; cIMT min -AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMT max : beta=0.07, 95%CI = 0.01-0.13; AS-cIMT mean : beta=0.08, 95%CI = 0.01-0.15; AS-cIMT min : beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

No study, to our knowledge, has constructed a polygenic risk score based on clinical blood pressure and investigated the association of genetic and lifestyle risks with home hypertension. We examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. In a cross-sectional study of 7027 Japanese individuals aged ≥20 years, we developed a lifestyle score based on body mass index, alcohol consumption, physical activity, and sodium-to-potassium ratio, categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score was constructed with the target data (n = 1405) using publicly available genome-wide association study summary statistics from BioBank Japan. Using the test data (n = 5622), we evaluated polygenic risk score performance and examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension and home hypertension were defined as blood pressure measured at a community-support center ≥140/90 mmHg or at home ≥135/85 mmHg, respectively, or self-reported treatment for hypertension. In the test data, 2294 and 2322 participants had hypertension and home hypertension, respectively. Both polygenic risk and lifestyle scores were independently associated with hypertension and home hypertension. Compared with those of participants with low genetic risk and an ideal lifestyle, the odds ratios for hypertension and home hypertension in the low genetic risk and poor lifestyle group were 1.94 (95% confidence interval, 1.34-2.80) and 2.15 (1.60-2.90), respectively. In summary, lifestyle is important to prevent hypertension; nevertheless, participants with high genetic risk should carefully monitor their blood pressure despite a healthy lifestyle., (© 2024. The Author(s).)

Purpose of Review: Hypertension, commonly known as high blood pressure, is a widespread health condition affecting a large number of individuals across the globe. Although lifestyle choices and environmental factors are known to have a significant impact on its development, there is growing recognition of the influence of genetic factors in the pathogenesis of hypertension. This review specifically focuses on the hereditary causes of hypertension that are associated with increased sodium transport through the thiazide-sensitive NaCl cotransporter (NCC) or amiloride-sensitive epithelial sodium channel (ENaC), crucial mechanisms involved in regulating blood pressure in the kidneys. By examining genetic mutations and signaling molecules linked to the dysregulation of sodium transport, this review aims to deepen our understanding of the hereditary causes of hypertension and shed light on potential therapeutic targets., Recent Findings: Liddle syndrome (LS) is a genetic disorder that typically manifests early in life and is characterized by hypertension, hypokalemic metabolic alkalosis, hyporeninemia, and suppressed aldosterone secretion. This condition is primarily caused by gain-of-function mutations in ENaC. In contrast, Pseudohypoaldosteronism type II (PHAII) is marked by hyperkalemia and hypertension, alongside other clinical features such as hyperchloremia, metabolic acidosis, and suppressed plasma renin levels. PHAII results from overactivations of NCC, brought about by gain-of-function mutations in its upstream signaling molecules, including WNK1 (with no lysine (K) 1), WNK4, Kelch-like 3 (KLHL3), and cullin3 (CUL3)., Summary: NCC and ENaC are integral components, and their malfunctions lead to disorders like LS and PHAII, hereditary causes of hypertension. Current treatments for LS involve ENaC blockers (e.g., triamterene and amiloride) in conjunction with low-sodium diets, effectively normalizing blood pressure and potassium levels. In PHAII, thiazide diuretics, which inhibit NCC, are the mainstay treatment, albeit with some limitations and potential side effects. Ongoing research in developing alternative treatments, including small molecules targeting key regulators, holds promise for more effective and tailored hypertension solutions., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Inorganic phosphate (Pi) is an essential component of many biologically important molecules such as DNA, RNA, ATP, phospholipids, or apatite. It is required for intracellular phosphorylation signaling events and acts as pH buffer in intra- and extracellular compartments. Intestinal absorption, uptake into cells, and renal reabsorption depend on a set of different phosphate transporters from the SLC20 (PiT transporters) and SLC34 (NaPi transporters) gene families. The physiological relevance of these transporters is evident from rare monogenic disorders in humans affecting SLC20A2 (Fahr's disease, basal ganglia calcification), SLC34A1 (idiopathic infantile hypercalcemia), SLC34A2 (pulmonary alveolar microlithiasis), and SLC34A3 (hereditary hypophosphatemic rickets with hypercalciuria). SLC34 transporters are inhibited by millimolar concentrations of phosphonoformic acid or arsenate while SLC20 are relatively resistant to these compounds. More recently, a series of more specific and potent drugs have been developed to target SLC34A2 to reduce intestinal Pi absorption and to inhibit SLC34A1 and/or SLC34A3 to increase renal Pi excretion in patients with renal disease and incipient hyperphosphatemia. Also, SLC20 inhibitors have been developed with the same intention. Some of these substances are currently undergoing preclinical and clinical testing. Tenapanor, a non-absorbable Na + /H + -exchanger isoform 3 inhibitor, reduces intestinal Pi absorption likely by indirectly acting on the paracellular pathway for Pi and has been tested in several phase III trials for reducing Pi overload in patients with renal insufficiency and dialysis., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Adrenoceptors are class A G-protein-coupled receptors grouped into three families (α 1 -, α 2 -, and β-adrenoceptors), each one including three members. All nine corresponding adrenoceptor genes display genetic variation in their coding and adjacent non-coding genomic region. Coding variants, i.e., nucleotide exchanges within the transcribed and translated receptor sequence, may result in a difference in amino acid sequence thus altering receptor function and signaling. Such variants have been intensely studied in vitro in overexpression systems and addressed in candidate-gene studies for distinct clinical parameters. In recent years, large cohorts were analyzed in genome-wide association studies (GWAS), where variants are detected as significant in context with specific traits. These studies identified two of the in-depth characterized 18 coding variants in adrenoceptors as repeatedly statistically significant genetic risk factors - p.Arg389Gly in the β 1 - and p.Thr164Ile in the β 2 -adrenoceptor, along with 56 variants in the non-coding regions adjacent to the adrenoceptor gene loci, the functional role of which is largely unknown at present. This chapter summarizes current knowledge on the two coding variants in adrenoceptors that have been consistently validated in GWAS and provides a prospective overview on the numerous non-coding variants more recently attributed to adrenoceptor gene loci., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Introduction: Methadone has shown effectiveness in pain control in patients with cancer who are intolerant to other opioids in China. However, the optimal strategy for methadone conversion from previous high doses of opioids in refractory cancer pain remains debatable. This study aimed to describe the efficacy and safety of a 3-day switch (3DS) strategy for methadone conversion in patients with refractory cancer pain on high doses of opioids. Methods: We retrospectively reviewed 30-day medical records of 70 patients with refractory cancer pain who used a 3DS strategy for methadone conversion from previous high doses of opioids from July 2018 to December 2022. The 3DS strategy indicated that the methadone dose was increased by one third every day for 3 days. Data on the rate of successful conversion, the time to stable analgesia after conversion, the conversion efficiency, the corrected QT (QTc) interval, the actual conversion ratios, adverse events (AEs), and quality of life were analyzed. Results: Seventy patients received 3DS methadone conversion and 64 patients were eligible for analysis. Fifty patients (78%) achieved stable analgesia, and the median time to stable analgesia was 8.14 ± 2.70 (range 6–14) days. The average dose of methadone was 77.94 ± 42.74 mg. The most common AEs (≥ 10%) included constipation, dry mouth, nausea, and cold sweats. The incidence of constipation was reduced post-methadone conversion, and a statistically significant but asymptomatic prolongation of the QTc interval was observed. Additionally, the actual conversion ratios were lower than Ayonrinde's recommended ratios. Conclusions: The 3DS strategy for methadone conversion is applicable in Chinese patients with refractory cancer pain on high doses of opioids. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia plays a pivotal role in the development of diabetes mellitus (DM) and other metabolic disorders. This study aimed to investigate the trends in lipid concentrations among Chinese participants with different blood glucose statuses—ranging from DM and prediabetes mellitus (pre-DM) to normal blood glucose levels—between 2011 and 2015. Additionally, this study sought to provide a comprehensive description of the potential temporal changes in the prevalence of dyslipidemia among these populations in China during this period. Methods: The data for this study were derived from the China Health and Retirement Longitudinal Study (CHARLS), encompassing two time points in 2011 and 2015. The 2011 data sample included 11,408 participants aged 45 years and above, whereas the 2015 data sample included 12,224 participants within the same age range. Results: In this study, a comparative analysis of data from 2011 to 2015 revealed that individuals diagnosed with DM and pre-DM experienced significant decreases in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and a significant increase in high-density lipoprotein cholesterol (HDL-C) (P < 0.05). For participants with pre-DM, the levels of residual cholesterol (RC) significantly increased, whereas the levels of the atherogenic index of plasma (AIP) significantly decreased (P < 0.05). Among participants with normal blood glucose, there was a significant decrease in the levels of TC and LDL-C and a significant increase in the levels of triglycerides (TGs), RCs, and the AIP (P < 0.05). Between 2011 and 2015, the concentrations of TC, TG, LDL-C, RC, and AIP, both unadjusted and adjusted, were significantly higher in individuals with DM than in those with pre-DM and normal blood glucose, with the opposite being true for HDL-C. In 2015, the prevalence of dyslipidemia among participants with DM, pre-DM, and normal blood glucose was 36.56% (95% CI: 34.49%, 38.66%), 15.78% (95% CI: 14.93%, 16.67%), and 11.23% (95% CI: 10.17%, 12.36%), respectively. The results of the present study revealed a significant decrease in the incidence of dyslipidemia in urban areas between 2011 and 2015 (P < 0.05). Conclusion: This study revealed that the prevalence of dyslipidemia is greater among DM patients, particularly those in the 55–64 years age group. Notably, over the four-year observation period, lipid profiles improved among DM patients and pre-DM patients. However, TG levels remained elevated, especially in the 45–54 years age group. [ABSTRACT FROM AUTHOR]

Despite the identification of numerous genetic variants affecting SBP in European populations, their applicability in admixed populations remains unclear. This study evaluates the predictive efficacy of a systolic blood pressure (SBP) polygenic risk score (PRS), derived from the UK Biobank data, in two Brazilian cohorts. We analyzed 944 K genetic variants consistent across an independent UK Biobank dataset, Brazilian cohorts, and HapMap database. Results show a significant association between increased PRS and SBP, as well as hypertension, in each study groups analyzed. An increase of one standard deviation in the PRS showed a significant association with SBP (β [95% CI] (mmHg) = 5.2 [5.1–5.3], 2.8 [2.1–3.5] and 2.6 [2.2–3.0]) and hypertension (odds ratio (OR) [95% CI] = 1.56 [1.54–1.56], 1.28 [1.2–1.4] and 1.47 [1.3–1.6]) in an independent UKB dataset, Baependi, and Pelotas, respectively. The associations were weaker in the Brazilian samples and the reduced association was noticeable in the Pelotas vs. the UK comparison for hypertension stages 1 and 2 (OR [95% CI] = 2.1 [1.5–3.1] and 3.0 [1.9–4.7] vs. 2.5 [2.2–2.8] and 4.9 [4.4–5.6]), whereas the Baependi data showed no significance for stage 1 hypertension. This trend mirrors findings in homogeneous African and Asian populations with diverse genetic architecture, highlighting the limitations of European-based PRS also in admixed populations. These insights are crucial for developing tailored disease prevention and management strategies in ethnically diverse groups. [ABSTRACT FROM AUTHOR]

Background: Epigenome‐wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. Results: We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p < 0.0001). We examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E−07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E−16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with BP levels, i.e., a one-unit increase in ERS was associated with 0.74 mm Hg (p = 0.002) higher SBP and 0.50 mm Hg (p = 0.0006) higher DBP, but not with HTN. Longitudinal analyses in FHS (n = 3260) and five independent external cohorts (n = 4021) showed that the baseline ERS was not associated with a change in BP over time or with incident HTN. Conclusions: Our findings demonstrate that the ERS has potential clinical utility in assessing lifestyle factors related to cardiovascular risk, especially when self-reported behavioral data (e.g., alcohol consumption) are unreliable or unavailable. [ABSTRACT FROM AUTHOR]

Methadone, a well-known drug used for pain control and as a treatment for opioid addiction, can cause arrhythmias, including torsades de pointes (TdP), which may progress to ventricular fibrillation and sudden death. We present a case of a middle-aged woman with a long history of methadone use who presented to the emergency department after experiencing cardiac arrest at home. During her hospitalization, she experienced multiple episodes of TdP that improved with isoproterenol and potassium correction. The initial diagnosis was methadone-induced prolonged QT. However, even with discontinuation of methadone, her QTc remained prolonged. Congenital long QT syndrome was suspected, and genetic testing was instructed to test in the outpatient setting. She was discharged on nadolol and a LifeVest. [ABSTRACT FROM AUTHOR]

Hypertension is a polygenic disease that affects over 1.2 billion adults aged 30-79 worldwide. It is a major risk factor for renal, cerebrovascular, and cardiovascular diseases. The heritability of hypertension is estimated to be high; nevertheless, our understanding of its underlying mechanisms remains scarce and incomplete. This study covered the entries from European ancestry from the UK-Biobank (UKB), with 74,090 cases diagnosed with essential (primary) hypertension and 200,734 controls. We compared the findings from large-scale genome-wide association studies (GWAS) to the gene-based method of proteome-wide association studies (PWAS). We focused on 70 statistically significant associated genes, most of which failed to reach significance in variant-based GWAS. A total of 30% of the PWAS-associated genes were validated against independent cohorts, including the Finnish Biobank. Furthermore, gene-based analyses that were performed on both sexes revealed sex-dependent genetics with a stronger genetic component associated with females. Analysis of systolic and diastolic blood pressure measurements confirms a strong genetic effect associated with females. We demonstrated that gene-based approaches provide insight into the underlying biology of hypertension. Specifically, the expression profiles of the identified genes exposed the enrichment of endothelial cells from multiple organs. Furthermore, females' top-ranked significant genes are involved in cellular immunity. We conclude that studying hypertension and blood pressure via gene-based association methods improves interpretability and exposes sex-dependent genetic effects, which enhances clinical utility., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of Review: Hypertension (HTN) that can be attributed to a particular source is known as secondary HTN (SH). Often, SH is difficult to control and thus referred to as resistant HTN, although the two terms are not mutually exclusive., Recent Findings: A common theme across several contributors to SH are coactivation of the sympathetic drive and hormonal changes, independent of hormonal axis activation. The key to effective management of SH is early recognition and treatment to avoid catastrophic cardiovascular disease effects and mortality., Summary: This review article provides a contemporary summary of the conditions associated with SH and briefly reviews diagnostics and management., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Genetic studies of blood pressure (BP) traits to date have been performed on conventional measures by brachial cuff sphygmomanometer for systolic BP (SBP) and diastolic BP, integrating several physiologic occurrences. Genetic associations with central SBP (cSBP) have not been well-studied. Genetic discovery studies of BP have been most often performed in European-ancestry samples. Here, we investigated genetic associations with cSBP in a Chinese population and functionally validated the impact of a novel associated coiled-coil domain containing 93 (CCDC93) gene on BP regulation. An exome-wide association study (EWAS) was performed using a mixed linear model of non-invasive cSBP and peripheral BP traits in a Han Chinese population (N = 5,954) from Beijing, China genotyped with a customized Illumina ExomeChip array. We identified four SNP-trait associations with three SNPs, including two novel associations (rs2165468-SBP and rs33975708-cSBP). rs33975708 is a coding variant in the CCDC93 gene, c.535C>T, p.Arg179Cys (MAF = 0.15%), and was associated with increased cSBP (β = 29.3 mmHg, P = 1.23x10-7). CRISPR/Cas9 genome editing was used to model the effect of Ccdc93 loss in mice. Homozygous Ccdc93 deletion was lethal prior to day 10.5 of embryonic development. Ccdc93+/- heterozygous mice were viable and morphologically normal, with 1.3-fold lower aortic Ccdc93 protein expression (P = 0.0041) and elevated SBP as compared to littermate Ccdc93+/+ controls (110±8 mmHg vs 125±10 mmHg, P = 0.016). Wire myography of Ccdc93+/- aortae showed impaired acetylcholine-induced relaxation and enhanced phenylephrine-induced contraction. RNA-Seq transcriptome analysis of Ccdc93+/- mouse thoracic aortae identified significantly enriched pathways altered in fatty acid metabolism and mitochondrial metabolism. Plasma free fatty acid levels were elevated in Ccdc93+/- mice (96±7mM vs 124±13mM, P = 0.0031) and aortic mitochondrial dysfunction was observed through aberrant Parkin and Nix protein expression. Together, our genetic and functional studies support a novel role of CCDC93 in the regulation of BP through its effects on vascular mitochondrial function and endothelial function. Author summary: More than 1000 loci have been reported in previous gene discovery efforts for blood pressure and hypertension. cSBP is a unique blood pressure trait that has not been as extensively studied as peripheral BP, and correlates of cSBP may provide a better indication of future cardiovascular events. In this study we replicated several BP associations in a Han Chinese cohort and found a novel association with a coding variant in CCDC93 (rs33975708, c.535C>T, p.Arg179Cys, MAF 0.15%) which was strongly associated with higher cSBP. To model loss of Ccdc93 and functionally validate the human genetic association, a new transgenic mouse was created. Ccdc93 homozygous deletion was embryonic lethal, and mice with heterozygous loss of Ccdc93 exhibited impaired arterial relaxation and enhanced contractile responses. Aortic RNA-seq analysis of Ccdc93+/- heterozygous mice identified metabolic dysregulation and mitochondrial dysfunction, which was validated by features of elevated plasma free fatty acids and increased aortic Parkin and Nix protein expression. Improved knowledge of the genes involved in BP regulation is needed to develop effective therapies to manage elevated BP, and this study identified the gene CCDC93 as a novel regulator of blood pressure and vascular function. [ABSTRACT FROM AUTHOR]

Background: This study aims to identify a novel gene signature for coronary artery disease (CAD), explore the role of immune cell infiltration in CAD pathogenesis, and assess the cell function of mast cell-expressed membrane protein 1 (MCEMP1) in human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL). Methods: To identify differentially expressed genes (DEGs) of CAD, datasets GSE24519 and GSE61145 were downloaded from the Gene Expression Omnibus (GEO) database using the R "limma" package with p < 0.05 and |log2 FC| > 1. Gene ontology (GO) and pathway analyses were conducted to determine the biological functions of DEGs. Hub genes were identified using support vector machine-recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO). The expression levels of these hub genes in CAD were validated using the GSE113079 dataset. CIBERSORT program was used to quantify the proportion of immune cell infiltration. Western blot assay and qRT‐PCR were used to detect the expression of hub genes in ox-LDL-treated HUVECs to validate the bioinformatics results. Knockdown interference sequences for MCEMP1 were synthesized, and cell proliferation and apoptosis were examined using a CCK8 kit and Muse® Cell Analyzer, respectively. The concentrations of IL-1β, IL-6, and TNF-α were measured with respective enzyme-linked immunosorbent assay (ELISA) kits. Results: A total of 73 DEGs (four down-regulated genes and 69 up-regulated genes) were identified in the metadata (GSE24519 and GSE61145) cohort. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results indicated that these DEGs might be associated with the regulation of platelet aggregation, defense response or response to bacterium, NF-kappa B signaling pathway, and lipid and atherosclerosis. Using SVM-RFE and LASSO, seven hub genes were obtained from the metadata. The upregulated expression of DIRC2 and MCEMP1 in CAD was confirmed in the GSE113079 dataset and in ox-LDL-treated HUVECs. The associations between the two hub genes (DIRC2 and MCEMP1) and the 22 types of immune cell infiltrates in CAD were found. MCEMP1 knockdown accelerated cell proliferation and suppressed cell apoptosis for ox-LDL-treated HUVECs. Additionally, MCEMP1 knockdown appeared to decrease the expression of inflammatory factors IL-1β, IL-6, and TNF-α. Conclusions: The results of this study indicate that MCEMP1 may play an important role in CAD pathophysiology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Vitiligo is an auto-immune progressive depigmentation disorder of the skin due to loss of melanocytes. Genetic risk is one of the important factors for development of vitiligo. Preponderance of vitiligo in certain ethnicities is known which can be analysed by understanding the distribution of allele frequencies across normal populations. Earlier GWAS identified 108 risk alleles for vitiligo in Europeans and East Asians. In this study, 64 of these risk alleles were used for analysing their enrichment and depletion across populations (1000 Genomes Project and IndiGen) with reference to 1000 Genomes dataset. Genetic risk scores were calculated and Fisher's exact test was performed to understand statistical significance of their variation in each population with respect to 1000 Genomes dataset as reference. In addition to SNPs reported in GWAS, significant variation in allele frequencies of 1079 vitiligo-related genes were also analysed. Two-tailed Chi-square test and Bonferroni's multiple adjustment values along with fixation index (≥ 0.5) and minimum allele frequency (≥ 0.05) were calculated and used to prioritise the variants based on pairwise comparison across populations. Results: Risk alleles rs1043101 and rs10768122 belong to 3 prime UTR of glutamate receptor gene SLC1A2 are found to be highly enriched in the South Asian population when compared with the 'global normal' population. Intron variant rs4766578 (ATXN2) was found to be deleted in SAS, EAS and AFR and enriched in EUR and AMR1. This risk allele is found to be under positive selection in SAS, AMR1 and EUR. From the ancillary vitiligo gene list, nonsynonymous variant rs16891982 was found to be enriched in the European and the Admixed American populations and depleted in all others. rs2279238 and rs11039155 belonging to the LXR-α gene involved in regulation of metalloproteinase 2 and 9 (melanocyte precursors) were found to be associated with vitiligo in the North Indian population (in earlier study). Conclusion: The differential enrichment/depletion profile of the risk alleles provides insight into the underlying inter-population variations. This would provide clues towards prioritisation of SNPs associated with vitiligo thereby elucidating its preponderance in different ethnic groups. [ABSTRACT FROM AUTHOR]

Background: Peripheral arterial disease (PAD) generally occurs as a result of progressive narrowing of arteries within the lower extremities and is a manifestation of systemic atherosclerosis. We define PAD with the aid of using the dimension ankle-brachial index (ABI) which is the most accurate tool and determination of ABI is a simple non-invasive procedure that can be easily performed on an outpatient basis. The cut-off point for diagnosis of peripheral arterial disease (PAD) & cardiovascular risk is ABI ≤ 0.90 or ≥ 1.30. Materials and Methods: This cross sectional study involves 47 newly diagnosed hypertensive patients of age between 30-50 years. Anthropometric measurements and ABI of all the patients were done in the research lab of the Physiology department. The ABI measurements were performed by using an automated oscillometric device (Watch BP Office, Microlife, Widnau, Switzerland). In this procedure, the blood pressure was measured simultaneously on both arms followed by both ankles in the supine position. Results: In our study out of 47 patients, 31 (66.0%) were male and 16 (34.0%) were female of mean age 43.79±6.82 years. The prevalence of deranged ABI in the present study was 10.64% according to Right ABI, while it was 6.38% according to Left ABI. A significant correlation was found for ABI in the Right ankle with SBP in the right upper limb (P=0.013) & both right and left lower limb (P˂0.001 & P=0.028 respectively), while a significant correlation was also found for Left ABI with SBP in both right and left upper limbs (P=0.007 & P=0.003 respectively). We also found that 29.8% of the subjects have a low normal value of ABI (i.e., between 0.9-1.1), this is significant, even in asymptomatic patients, for Peripheral Arterial Disease (PAD). Conclusion: So we can conclude that in newly diagnosed hypertensive patients, ABI are valuable tools for early detection of cardiovascular damage. By identifying subclinical changes before symptoms arise, healthcare providers can implement early, targeted interventions to manage hypertension more effectively and reduce the risk of long-term complications. [ABSTRACT FROM AUTHOR]

Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (∼39.7%), West Asian (∼28.6%), Siberian (∼23.6%), and South Asian (∼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5 , OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR , SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road. [ABSTRACT FROM AUTHOR]

The Na+-Cl− cotransporter (NCC; SLC12A3) is a highly regulated integral membrane protein that is known to exist as three splice variants in primates. Its primary role in the kidney is to mediate the cosymport of Na+ and Cl− across the apical membrane of the distal convoluted tubule. Through this role and the involvement of other ion transport systems, NCC allows the systemic circulation to reclaim a fraction of the ultrafiltered Na+, K+, Cl−, and Mg+ loads in exchange for Ca2+ and HC O 3 − . The physiological relevance of the Na+-Cl− cotransport mechanism in humans is illustrated by several abnormalities that result from NCC inactivation through the administration of thiazides or in the setting of hereditary disorders. The purpose of the present review is to discuss the molecular mechanisms and overall roles of Na+-Cl− cotransport as the main topics of interest. On reading the narrative proposed, one will realize that the knowledge gained in regard to these themes will continue to progress unrelentingly no matter how refined it has now become. [ABSTRACT FROM AUTHOR]

Objective: Blood pressure is a complex, polygenic trait, and the need to identify prehypertensive risks and new gene targets for blood pressure control therapies or prevention continues. We hypothesize a developmental origins model of blood pressure traits through the life course where the placenta is a conduit mediating genomic and nongenomic transmission of disease risk. Genetic control of placental gene expression has recently been described through expression quantitative trait loci (eQTL) studies which have identified associations with childhood phenotypes., Methods: We conducted a transcriptome-wide gene expression analysis estimating the predicted gene expression of placental tissue in adult individuals with genome-wide association study (GWAS) blood pressure summary statistics. We constructed predicted expression models of 15 154 genes from reference placenta eQTL data and investigated whether genetically-predicted gene expression in placental tissue is associated with blood pressure traits using published GWAS summary statistics. Functional annotation of significant genes was generated using FUMA., Results: We identified 18, 9, and 21 genes where predicted expression in placenta was significantly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), respectively. There were 14 gene-tissue associations (13 unique genes) significant only in placenta., Conclusions: In this meta-analysis using S-PrediXcan and GWAS summary statistics, the predicted expression in placenta of 48 genes was statistically significantly associated with blood pressure traits. Notable findings included the association of FGFR1 expression with increased SBP and PP. This evidence of gene expression variation in placenta preceding the onset of adult blood pressure phenotypes is an example of extreme preclinical biological changes which may benefit from intervention., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Pharmacogenetics play an important role in determining the anti-hypertensive effects of blood pressure-lowering medications and have the potential to improve future patient care. Current literature on the topic, however, has a heavy focus on Caucasians and may not be generalisable to the Asian populations. Therefore, we have conducted this systematic review to summarise and evaluate the literature of the past decade. PubMed, Embase, and the Cochrane Register of Controlled Trials were searched for relevant studies from 1 January 2011 to 23 July 2021. The outcome of interest was the response to anti-hypertensive treatment in Asians according to each genetic polymorphism. A total of 26 studies with a total of 8837 patients were included in our review, covering five classes of anti-hypertensive agents-namely, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta-blockers (BB), calcium channel blockers (CCB), and thiazide-like diuretics. Response to ACEI therapy was most susceptible to genotypic variations, while the efficacy of ARB and CCB were affected by pharmacogenetic differences to varying extent. For BB, only variations in the ADRB1 genotype significantly affects therapeutic response, while the therapeutic efficacy of thiazide-like diuretics was correlated with genotypic variations in the REN and ACE. This systematic review evaluated the impact of pharmacogenetic variations on the therapeutic efficacy of anti-hypertensive treatment in Asians and has described numerous drug-gene pairs that are potentially clinically important. Future prospective studies with larger sample sizes and longer follow-up periods are needed to better elucidate the impact of these drug-gene pairs., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite successive advancement of genome editing technology with zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), the recent breakthrough in the field has been related to clustered regularly interspaced short palindromic repeats/associated proteins (CRISPR/Cas). The high efficiency and convenience of CRIPSR/Cas systems dramatically accelerate pre- and clinical experimentations of dyslipidemia and atherosclerosis. In this chapter, we review the latest state of genome editing in translational research of dyslipidemia and atherosclerosis. We highlight recent progress in therapeutic development for familial dyslipidemia by genome editing. We point to the challenges in maximizing efficacy and minimizing safety issues related to the once-and-done therapy focusing on CRISPR/Cas systems. We give an outlook on the potential gene targets prioritized by large-scale genetic studies of cardiovascular diseases and genome editing in precision medicine of dyslipidemia and atherosclerosis., (© 2023. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans. Author summary: A previous study discovered that a genomic region close to the Endothelin3 gene was associated with harness racing performance. Here, careful phenotypic documentation of athletic performance and blood pressure measurements in horses, followed by state-of-the-art genomics, allowed us to identify a 5.5 kb regulatory region located approximately 50 kb 3' of the EDN3 gene. A comparative analysis of the region using human HiCap data supported a regulatory role as, in endothelial cells, interaction was observed between the region and multiple genes relevant to blood pressure regulation and athletic performance. Long range cis-regulatory modules are critical for cooperatively controlling multiple genes located within transcriptionally active domains. We measured blood pressure in Coldblooded trotters during exercise and demonstrated that horses with two copies of the elite-performing haplotype had lower blood pressure during exercise and better racing performance results, compared to horses with two copies of the sub-elite performing haplotype. In addition, horses with the elite-performing haplotype also had higher levels of Endothelin3 in plasma. The results reported here are important for understanding the biological mechanisms behind blood pressure regulation in relation to racing performance in both horses and humans. [ABSTRACT FROM AUTHOR]

Aims APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidaemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation. Methods and results We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) [odds ratio, 0.57 per s.d. protein (95% CI 0.47–0.70)] and Type 2 diabetes (T2D) [odds ratio, 0.73 per s.d. protein (95% CI 0.57–0.94)]. Genetically lowering circulating APOC3 levels also reduced the odds of CAD [odds ratio, 0.90 per s.d. protein (95% CI 0.82–0.99)]. Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of protein-truncating variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI, 0.58–0.85]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns. Conclusion Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D. [ABSTRACT FROM AUTHOR]

This cohort study investigates the patterns of morphological brain changes that are reproducibly detectable with artificial intelligence (AI) in cognitively unimpaired populations and their genetic, clinical, lifestyle, and cognitive features. Key Points: Question: What patterns of morphological brain changes are reproducibly detectable in cognitively unimpaired populations, and what are their genetic, clinical, lifestyle, and cognitive features? Findings: In this multistudy harmonized cohort of 27 402 individuals aged 45 to 85 years without diagnosed cognitive impairment, 3 subgroups of structural brain measures in decade-spanning groups in a data-driven manner were found: 1 typical and 2 accelerated aging subgroups, displaying distinct associations with genetics, cognitive decline, cardiovascular risk factors, and amyloid pathology. Meaning: Three genetically distinct and longitudinally stable subgroups display brain changes reflecting differential susceptibility to Alzheimer disease and other neurodegenerative diseases, cognitive decline, and clinical progression. Importance: Brain aging elicits complex neuroanatomical changes influenced by multiple age-related pathologies. Understanding the heterogeneity of structural brain changes in aging may provide insights into preclinical stages of neurodegenerative diseases. Objective: To derive subgroups with common patterns of variation in participants without diagnosed cognitive impairment (WODCI) in a data-driven manner and relate them to genetics, biomedical measures, and cognitive decline trajectories. Design, Setting, and Participants: Data acquisition for this cohort study was performed from 1999 to 2020. Data consolidation and harmonization were conducted from July 2017 to July 2021. Age-specific subgroups of structural brain measures were modeled in 4 decade-long intervals spanning ages 45 to 85 years using a deep learning, semisupervised clustering method leveraging generative adversarial networks. Data were analyzed from July 2021 to February 2023 and were drawn from the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) international consortium. Individuals WODCI at baseline spanning ages 45 to 85 years were included, with greater than 50 000 data time points. Exposures: Individuals WODCI at baseline scan. Main Outcomes and Measures: Three subgroups, consistent across decades, were identified within the WODCI population. Associations with genetics, cardiovascular risk factors (CVRFs), amyloid β (Aβ), and future cognitive decline were assessed. Results: In a sample of 27 402 individuals (mean [SD] age, 63.0 [8.3] years; 15 146 female [55%]) WODCI, 3 subgroups were identified in contrast with the reference group: a typical aging subgroup, A1, with a specific pattern of modest atrophy and white matter hyperintensity (WMH) load, and 2 accelerated aging subgroups, A2 and A3, with characteristics that were more distinct at age 65 years and older. A2 was associated with hypertension, WMH, and vascular disease–related genetic variants and was enriched for Aβ positivity (ages ≥65 years) and apolipoprotein E (APOE) ε4 carriers. A3 showed severe, widespread atrophy, moderate presence of CVRFs, and greater cognitive decline. Genetic variants associated with A1 were protective for WMH (rs7209235: mean [SD] B = −0.07 [0.01]; P value = 2.31 × 10−9) and Alzheimer disease (rs72932727: mean [SD] B = 0.1 [0.02]; P value = 6.49 × 10−9), whereas the converse was observed for A2 (rs7209235: mean [SD] B = 0.1 [0.01]; P value = 1.73 × 10−15 and rs72932727: mean [SD] B = −0.09 [0.02]; P value = 4.05 × 10−7, respectively); variants in A3 were associated with regional atrophy (rs167684: mean [SD] B = 0.08 [0.01]; P value = 7.22 × 10−12) and white matter integrity measures (rs1636250: mean [SD] B = 0.06 [0.01]; P value = 4.90 × 10−7). Conclusions and Relevance: The 3 subgroups showed distinct associations with CVRFs, genetics, and subsequent cognitive decline. These subgroups likely reflect multiple underlying neuropathologic processes and affect susceptibility to Alzheimer disease, paving pathways toward patient stratification at early asymptomatic stages and promoting precision medicine in clinical trials and health care. [ABSTRACT FROM AUTHOR]

Background: The present study aimed to estimate the additive interaction of family history of diabetes and hypertension on the diagnosis of diabetes among individuals aged 45 years and above in India. The coexistence of these two exposures may act synergistically on the risk of diabetes, leading to adverse health outcomes. Methods: The study utilized the data from the Longitudinal Ageing Study in India (LASI) Wave 1 (2017–2018). The total sample size for the current study was 58,612 individuals aged 45 years and above. Multivariable logistic regression models were employed to determine the individual and joint effect of a family history of diabetes with hypertension on diabetes. An additive model was applied to assess the interaction effect of the family medical history of diabetes with hypertension on the diagnosis of diabetes by calculating three different measures of additive interaction such as the relative excess risk due to interaction (RERI), attribution proportion due to interaction (AP), and synergy index (S). Results: The prevalence of diabetes was three times higher among individuals with family history of diabetes (27.8% vs. 9.2%) than those without family history. Individuals with family history of diabetes (AOR: 2.47, CI: 2.11 2.89) had 2.47 times higher odds of having diabetes than those without family history. The prevalence of diabetes was significantly higher among individuals with hypertension and family history of diabetes (46.6%, 95% CI: 39.7–53.6) than those without the coexistence of family history of diabetes and hypertension (9.9%, 95% CI: 9.5–10.4), individuals with hypertension and without a family history of diabetes (22.7%, 95% CI: 21.2–24.2), and individuals with family history of diabetes and without hypertension (16.5%, 95% CI: 14.5–18.7). Moreover, the adjusted odds ratio (AOR) of the joint effect between family medical history of diabetes and hypertension on diabetes was 9.28 (95% CI: 7.51–11.46). In the adjusted model, the RERI, AP, and S for diabetes were 3.5 (95% CI: 1.52–5.47), 37% (0.37; 95% CI: 0.22–0.51), and 1.69 (95% CI: 1.31–2.18) respectively, which indicates that there is a significant positive interaction between family history of diabetes and hypertension on the diagnosis of diabetes. The study findings on interaction effects further demonstrate consistent results for two models of hypertension (self-reported hypertension and hypertensive individuals receiving medication) even after adjustment with potential confounding factors on diabetes (self-reported diabetes and individuals with diabetes receiving medication). Conclusions: The study findings strongly suggest that the interaction of family history of diabetes with hypertension has a positive and significant effect on the risk of diabetes even after adjustment with potential confounding factors. Furthermore, the findings indicate a synergistic effect, emphasizing the importance of considering both family medical history of diabetes and hypertension when assessing diabetes risk and designing preventive strategies or interventions. [ABSTRACT FROM AUTHOR]

Single‐nucleotide polymorphisms (SNP) of ATP2B1 gene are associated with essential hypertension but their association with resistant hypertension (RHT) remains unexplored. The authors examined the relationship between ATP2B1 SNPs and RHT by genotyping 12 SNPs in ATP2B1 gene of 1124 Japanese individuals with lifestyle‐related diseases. Patients with RHT had inadequate blood pressure (BP) control using three antihypertensive drugs or used ≥4 antihypertensive drugs. Patients with controlled hypertension had BP controlled using ≤3 antihypertensive drugs. The association between each SNP and RHT was analyzed by logistic regression. The final cohort had 888 (79.0%) and 43 (3.8%) patients with controlled hypertension and RHT, respectively. Compared with patients homozygous for the minor allele of each SNP in ATP2B1, a significantly higher number of patients carrying the major allele at 10 SNPs exhibited RHT (most significant at rs1401982: 5.8% vs. 0.8%, p =.014; least significant at rs11105378: 5.7% vs. 0.9%, p =.035; most nonsignificant at rs12817819: 5.1% vs. 10%, p =.413). After multivariate adjustment for age, sex, systolic BP, and other confounders, the association remained significant for rs2681472 and rs1401982 (OR: 7.60, p <.05 and OR: 7.62, p =.049, respectively). Additionally, rs2681472 and rs1401982 were in linkage disequilibrium with rs11105378. This study identified two ATP2B1 SNPs associated with RHT in the Japanese population. rs1401982 was most closely associated with RHT, and major allele carriers of rs1401982 required significantly more antihypertensive medications. Analysis of ATP2B1 SNPs in patients with hypertension can help in early prediction of RHT and identification of high‐risk patients who are more likely to require more antihypertensive medications. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the association between nine tag single nucleotide polymorphisms (SNPs) in the C3 gene locus and the risk of coronary artery disease (CAD) as well as lipid levels in the Chinese population, and to further explore the interactions between SNPs and environmental factors that may be associated with CAD risk. Methods: A case-control study was conducted to investigate the association between CAD and C3 gene polymorphisms in a hospital setting. The study consisted of 944 CAD patients with a mean age of 55.97 ± 10.182 years and 897 non-CAD controls with a mean age of 55.94 ± 9.162 years. There were 565 males and 288 females in the CAD group and 583 males and 314 females in the control group. TagSNPs in the C3 gene were identified by employing the improved multiplex ligation detection reaction (iMLDR) technique, and multifactor dimensionality reduction (MDR) analysis was utilized to investigate the C3 gene–environment and gene-gene interactions in relation to the risk of CAD. Results: Results of the polymorphism study indicated that the CC genotype of rs7257062 was more frequent in the CAD group compared to the control group (10.9% vs 7.7%), with a statistically significant difference (p = 0.009). Moreover, the TT and CC + CT genotype groups of rs7257062 in the CAD subgroup showed a significant difference in terms of serum triglyceride levels (2.326 ± 1.889 vs 2.059 ± 1.447, p = 0.019). Analysis of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (ApoA), and apolipoprotein B (ApoB) levels revealed no significant differences between the TT and CC + CT genotypes. Furthermore, no significant differences in serum lipid levels were observed between genotypes of the other SNPs. Multivariable logistic analysis, controlling for gender, age, body mass index (BMI), triglycerides (TG), TC, HDL-C, LDL-C, ApoA and ApoB, demonstrated that rs7257062 was still an independent risk factor of CAD (OR = 1.499, 95% CI: 1.036-2.168, p = 0.032). MDR analysis revealed that the rs7257062 interacted significantly with environmental factors such as smoking, diabetes, hypertension, BMI, and TG (p < 0.05). Conclusions: The rs7257062 variation of the C3 gene could be linked to both lipid balance and the risk of CAD. It is conceivable that the interplay between C3 polymorphisms and environmental elements could account for the etiology of CAD. [ABSTRACT FROM AUTHOR]

Objective: Hypertension is associated with vascular injury, which contributes to end-organ damage. MicroRNAs regulating mRNAs have been shown to play a role in vascular injury in hypertensive mice. We aimed to identify differentially expressed microRNAs and their mRNA targets in small arteries of hypertensive patients with/without chronic kidney disease (CKD) to shed light on the pathophysiological molecular mechanisms of vascular remodeling., Methods and Results: Normotensive individuals and hypertensive patients with/without CKD were recruited ( n  = 15-16 per group). Differentially expressed microRNAs and mRNAs were identified uniquely associated with hypertension (microRNAs: 10, mRNAs: 68) or CKD (microRNAs: 68, mRNAs: 395), and in both groups (microRNAs: 2, mRNAs: 32) with a P less than 0.05 and a fold change less than or greater than 1.3 in subcutaneous small arteries ( n  = 14-15). One of the top three differentially expressed microRNAs, miR-338-3p that was down-regulated in CKD, presented the best correlation between RNA sequencing and reverse transcription-quantitative PCR (RT-qPCR, R2  = 0.328, P  < 0.001). Profiling of human aortic vascular cells showed that miR-338-3p was mostly expressed in endothelial cells. Two of the selected top nine up-regulated miR-338-3p predicted targets, glutathione peroxidase 3 ( GPX3 ) and protein tyrosine phosphatase receptor type S ( PTPRS ), were validated with mimics by RT-qPCR in human aortic endothelial cells ( P  < 0.05) and by a luciferase assay in HEK293T cells ( P  < 0.05)., Conclusion: A distinct transcriptomic profile was observed in gluteal subcutaneous small arteries of hypertensive patients with CKD. Down-regulated miR-338-3p could contribute to GPX3 and PTPRS up-regulation via the canonical microRNA targeting machinery in hypertensive patients with CKD., http://links.lww.com/HJH/C27., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Polycystic ovary syndrome (PCOS) affects many women and is linked to nutrient intake, but the causal role of nutrients is unclear. Our study used Mendelian randomization (MR) to explore this relationship., Methods: We employed two-sample MR to investigate the causal effects of four macronutrients (carbohydrates, fats, sugars, proteins) and 12 micronutrients (vitamin A [retinol], folate, vitamin B6, vitamin B12, vitamin C [ascorbic acid], vitamin D, vitamin E [alpha-tocopherol], magnesium, calcium, iron, selenium, and zinc) on the risk of PCOS based on their circulating levels. We conducted analyses using the inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, and simple model approach, with IVW as the primary method. To correct for multiple testing, the false discovery rate (FDR) method was applied. The reliability and potential bias of the results were assessed by sensitivity analysis and F-statistics., Results: From a genetic standpoint, higher circulating vitamin A (retinol) levels were found to be a protective factor for PCOS and closely associated with the risk of PCOS, consistent with recent research findings. The inverse variance-weighted (IVW) estimation indicated a protective effect of vitamin A (retinol) on PCOS (IVWOR = 0.97, 95% CI: 0.95-0.99, P = 0.002, FDR&#95;P = 0.03). However, no causal relationship was found between other nutrients and PCOS. In addition, MR-PRESSO and MR-Egger regression showed that our results were not affected by horizontal pleiotropy (P > 0.05). Finally, leave-one-out sensitivity analysis confirmed the robustness of MR Results., Conclusion: Our findings suggest that circulating vitamin A (retinol) levels influence the risk of PCOS, but further research is needed., (© 2024 International Federation of Gynecology and Obstetrics.)

Background: Genome-wide association studies have identified dozens of genomic loci for obesity. However, functional genes and their detailed genetic mechanisms underlying these loci are mainly unknown. In this study, we conducted an integrative study to prioritize plausibly functional genes by combining information from genome-, transcriptome- and proteome-wide association analyses., Methods: We first conducted proteome-wide association analyses and transcriptome-wide association analyses for the six obesity-related traits. We then performed colocalization analysis on the identified loci shared between the proteome- and transcriptome-association analyses. Finally, we validated the identified genes with other plasma/blood reference panels. The highlighted genes were assessed for expression of other tissues, single-cell and tissue specificity, and druggability., Results: We prioritized 4 high-confidence genes (FASN, ICAM1, PDCD6IP, and YWHAB) by proteome-wide association studies, transcriptome-wide association studies, and colocalization analyses, which consistently influenced the variation of obesity traits at both mRNA and protein levels. These 4 genes were successfully validated using other plasma/blood reference panels. These 4 genes shared regulatory structures in obesity-related tissues. Single-cell and tissue-specific analyses showed that FASN and ICAM1 were explicitly expressed in metabolism- and immunity-related tissues and cells. Furthermore, FASN and ICAM1 had been developed as drug targets., Conclusion: Our study provided novel promising protein targets for further mechanistic and therapeutic studies of obesity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context. Methods and results: Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders. Conclusion: The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care. [ABSTRACT FROM AUTHOR]

Clinical genetics is increasingly recognized as an important area within nephrology care. Clinicians require awareness of genetic kidney disease to recognize clinical phenotypes, consider use of genomics to aid diagnosis, and inform treatment decisions. Understanding the broad spectrum of clinical phenotypes and principles of genomic sequencing is becoming increasingly required in clinical nephrology, with nephrologists requiring education and support to achieve meaningful patient outcomes. Establishment of effective clinical resources, multi-disciplinary teams and education is important to increase application of genomics in clinical care, for the benefit of patients and their families. Novel applications of genomics in chronic kidney disease include pharmacogenomics and clinical translation of polygenic risk scores. This review explores established and emerging impacts and utility of genomics in kidney disease. [ABSTRACT FROM AUTHOR]