Toward building a comprehensive human pan-genome: The SEN-GENOME project.

The human reference genome (GRCh38), primarily sourced from individuals of European descent, falls short in capturing the vast genetic diversity across global populations. Efforts to diversify the reference genome face challenges in accessibility and representation, exacerbating the scarcity of African genomic data crucial for studying diseases prevalent in these populations. Sherman et al. proposed constructing reference genomes tailored to distinct human sub-populations. Their African Pan-Genome initiative highlighted substantial genetic variation missing from the GRCh38 human reference genome, emphasizing the necessity for population-specific genomes. In response, local initiatives like the Senegalese Genome project (SEN-GENOME) have emerged to document the genomes of historically overlooked populations. SEN-GENOME embodies community-driven decentralized research. With meticulous recruitment criteria and ethical practices, it aims to sequence 1,000 genomes from 31 ethnolinguistic groups, in the fourteen administrative regions of Senegal, fostering local genomic research tailored to the region. The key to SEN-GENOME's success is its commitment to local governance of data, capacity building, and integration with broader pan-genome projects in Africa. Despite the complexities of data harmonization and sharing, our collaborative efforts are aligned with common goals, ensuring steady progress toward a comprehensive human pan-genome. We invite and welcome collaboration with other research entities to achieve this shared vision. In summary, local initiatives such as SEN-GENOME are pivotal in bridging genomic disparities, offering pathways to equitable and inclusive genomic research. Collaborative endeavors guided by a collective vision for human health will propel us toward a more encompassing understanding of the human genome and better health through genomic medicine.

Relationship between LDL-cholesterol, small and dense LDL particles, and mRNA expression in a cohort of African Americans.

Understanding the characteristics and behavior of low-density lipoprotein (LDL) particles provides insights into the atherogenic risk of elevated LDL cholesterol in hypercholesterolemia, cardiovascular disease risks. Studying LDL particles helps identify specific LDL subtypes [e.g., small dense LDL particles (sdLDL)] that may be atherogenic and, consequently, potential targets for therapeutics. This study cohort consists of African Americans (AAs), a population disproportionately affected by cardiovascular diseases, thereby accentuating the importance of the investigation. Differential expression (DE) analysis was undertaken using a dataset comprising 17,947 protein-coding mRNAs from the whole blood transcriptomes of 416 samples to identify mRNAs associated with low-density lipoprotein cholesterol (LDL-C) and sdLDL plasma levels. Subsequently, mediation analyses were used to investigate the mediating role of sdLDL particles on the relationship between LDL-C levels and mRNA expression. Finally, pathway enrichment analysis was conducted to identify pathways involving mRNAs whose relationship with LDL-C is mediated by sdLDL. DE analysis revealed 1,048 and 284 mRNA transcripts differentially expressed by LDL-C and sdLDL levels, respectively. Mediation analysis revealed that the associations between LDL-C and 33 mRNAs were mediated by sdLDL. Of the 33 mRNAs mediated by sdLDL, 18 were mediated in both males and females. Nine mRNAs were mediated only in females, and six were mediated only in males. Pathway analysis showed that 33 mRNAs are involved in pathways associated with the immune system, inflammatory response, metabolism, and cardiovascular disease (CVD) risk. In conclusion, our study provides valuable insights into the complex interplay between LDL-C, sdLDL, and mRNA expression in a large sample of AAs. The results underscore the importance of incorporating sdLDL measurement alongside LDL-C levels to improve the accuracy of managing hypercholesterolemia and effectively stratify the risk of CVD. This is essential as differences in sdLDL modulate atherogenic properties at the transcriptome level.NEW & NOTEWORTHY The study investigated the interplay between LDL-C and mRNA expression, focusing on the role of small dense LDL (sdLDL) particles and sex differences. Differential expression analysis identified 1,048 and 284 mRNAs associated with LDL-C and sdLDL levels, respectively. Mediation analysis revealed that sdLDL mediates the relationship between LDL-C and 33 mRNAs involved in immune, inflammatory, and metabolic pathways. These findings highlight the significance of sdLDL in cardiovascular disease risk assessment and underscore sex-specific differences in lipid metabolism.

Modifiable mediators associated with the relationship between adiposity and leukocyte telomere length in US adults: The National Health and Nutrition Examination Survey.

Obesity is associated with age-related health conditions and telomere attrition - a marker of cellular aging. Obesity is attributable to adverse modifiable lifestyle factors. Little is known about the mediation effect of lifestyle factors associated with the relationship between obesity and telomere length. Our objective was to examine this association in the US. Pack years smoked, drinking level per day, physical activity (PA) per week and diet based on Healthy Eating Index (HEI) were assessed as mediators associated with the relationship between adiposity measures and leukocyte telomere length (LTL); adiposity measures included body mass index (BMI), % total body fat (TBF) and waist circumference (WC). Separate adjusted linear regressions and mediation analysis were conducted on a total of 4919 respondents aged 20-84 years using cross-sectional 1999-2002 data from the US National Health and Nutrition Examination Survey. Inadequate PA correlated with 1.28% shorter LTL and was a factor accounting for 35% of the relationship between BMI and LTL (ß = -0.0128, 95% CI = 0.0259, 0.0004, p = .05). Smoking 30-≥59 pack years correlated with 4% shorter LTL and accounted for 21% of the relationship between %TBF and LTL (ß = -0.0386, 95% CI = -0.0742, -0.0030, p = .03). Improvement in diet correlated with 0.11% longer LTL and contributed 25% of the association between %TBF and LTL (ß = 0.0011, 95%CI =0.0004, 0.0018, p = .01). Diet correlated with 0.11% longer LTL and correspond to 28% of the relationship between WC and LTL (ß = 0.0011, 95%CI = 0.0004, 0.0018, p = .03). Interventions to improve modifiable behaviors may ameliorate cellular aging and aging related health conditions due to obesity among US adults.

Ambient air pollution, traffic noise and adult asthma prevalence: a BioSHaRE approach.

We investigated the effects of both ambient air pollution and traffic noise on adult asthma prevalence, using harmonised data from three European cohort studies established in 2006-2013 (HUNT3, Lifelines and UK Biobank).Residential exposures to ambient air pollution (particulate matter with aerodynamic diameter ≤10 µm (PM10) and nitrogen dioxide (NO2)) were estimated by a pan-European Land Use Regression model for 2007. Traffic noise for 2009 was modelled at home addresses by adapting a standardised noise assessment framework (CNOSSOS-EU). A cross-sectional analysis of 646 731 participants aged ≥20 years was undertaken using DataSHIELD to pool data for individual-level analysis via a "compute to the data" approach. Multivariate logistic regression models were fitted to assess the effects of each exposure on lifetime and current asthma prevalence.PM10 or NO2 higher by 10 µg·m-3 was associated with 12.8% (95% CI 9.5-16.3%) and 1.9% (95% CI 1.1-2.8%) higher lifetime asthma prevalence, respectively, independent of confounders. Effects were larger in those aged ≥50 years, ever-smokers and less educated. Noise exposure was not significantly associated with asthma prevalence.This study suggests that long-term ambient PM10 exposure is associated with asthma prevalence in western European adults. Traffic noise is not associated with asthma prevalence, but its potential to impact on asthma exacerbations needs further investigation.

Circadian CLOCK gene polymorphisms in relation to sleep patterns and obesity in African Americans: findings from the Jackson heart study.

BACKGROUND: Circadian rhythms regulate key biological processes and the dysregulation of the intrinsic clock mechanism affects sleep patterns and obesity onset. The CLOCK (circadian locomotor output cycles protein kaput) gene encodes a core transcription factor of the molecular circadian clock influencing diverse metabolic pathways, including glucose and lipid homeostasis. The primary objective of this study was to evaluate the associations between CLOCK single nucleotide polymorphisms (SNPs) and body mass index (BMI). We also evaluated the association of SNPs with BMI related factors such as sleep duration and quality, adiponectin and leptin, in 2962 participants (1116 men and 1810 women) from the Jackson Heart Study. Genotype data for the selected 23 CLOCK gene SNPS was obtained by imputation with IMPUTE2 software and reference phase data from the 1000 genome project. Genetic analyses were conducted with PLINK RESULTS: We found a significant association between the CLOCK SNP rs2070062 and sleep duration, participants carriers of the T allele showed significantly shorter sleep duration compared to non-carriers after the adjustment for individual proportions of European ancestry (PEA), socio economic status (SES), body mass index (BMI), alcohol consumption and smoking status that reach the significance threshold after multiple testing correction. In addition, we found nominal associations of the CLOCK SNP rs6853192 with longer sleep duration and the rs6820823, rs3792603 and rs11726609 with BMI. However, these associations did not reach the significance threshold after correction for multiple testing. CONCLUSIONS: In this work, CLOCK gene variants were associated with sleep duration and BMI suggesting that the effects of these polymorphisms on circadian rhythmicity may affect sleep duration and body weight regulation in Africans Americans.

Race-specific associations between health-related quality of life and cellular aging among adults in the United States: evidence from the National Health and Nutrition Examination Survey.

PURPOSE: Poor health-related quality of life (HRQOL) could lead to higher morbidity and mortality through telomere attrition or accelerated cellular aging. We conducted a cross-sectional analysis to examine the relationship between four dimensions of HRQOL and leukocyte telomere length (LTL) among a nationally representative sample of 3547 US adults (≥20 years) using the data from the 2001-2002 National Health and Nutrition Examination Survey. METHOD: We used HRQOL survey information collected on individuals' self-rated general health, recent physical health, recent mental health, and recent activity limitation. Telomere length was assessed using quantitative polymerase chain reaction. Multiple linear regressions were used to estimate the relationship between each dimension of HRQOL and log-transformed values of LTL with adjustment for sample weights and design effects. RESULTS: HRQOL-race interactions were significant, and the results were stratified by race. After controlling for demographic factors, disease conditions, and lifestyle variables, worse general health was significantly associated with shorter LTL for Blacks (coefficient, ß: -0.022, 95% Confidence Interval, 95% CI: -0.03 to -0.01), but not for Whites or Mexican Americans. Unwell physical health was associated with shorter telomere length for Whites (ß: -0.005, 95% CI: -0.01 to -0.001) only. Unwell mental health showed no significant association with LTL in any race. CONCLUSIONS: Although longitudinal studies are needed to prove causality, our findings suggest that HRQOL could be associated with LTL shortening. We also found a possible racial difference in this association and recommend additional multiethnic studies to confirm this and to understand the reasons and consequences of this difference.

ESPRESSO: taking into account assessment errors on outcome and exposures in power analysis for association studies.

MOTIVATION: Very large studies are required to provide sufficiently big sample sizes for adequately powered association analyses. This can be an expensive undertaking and it is important that an accurate sample size is identified. For more realistic sample size calculation and power analysis, the impact of unmeasured aetiological determinants and the quality of measurement of both outcome and explanatory variables should be taken into account. Conventional methods to analyse power use closed-form solutions that are not flexible enough to cater for all of these elements easily. They often result in a potentially substantial overestimation of the actual power. RESULTS: In this article, we describe the Estimating Sample-size and Power in R by Exploring Simulated Study Outcomes tool that allows assessment errors in power calculation under various biomedical scenarios to be incorporated. We also report a real world analysis where we used this tool to answer an important strategic question for an existing cohort. AVAILABILITY AND IMPLEMENTATION: The software is available for online calculation and downloads at http://espresso-research.org. The code is freely available at https://github.com/ESPRESSO-research. CONTACT: louqman@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Data Safe Havens in health research and healthcare.

MOTIVATION: The data that put the 'evidence' into 'evidence-based medicine' are central to developments in public health, primary and hospital care. A fundamental challenge is to site such data in repositories that can easily be accessed under appropriate technical and governance controls which are effectively audited and are viewed as trustworthy by diverse stakeholders. This demands socio-technical solutions that may easily become enmeshed in protracted debate and controversy as they encounter the norms, values, expectations and concerns of diverse stakeholders. In this context, the development of what are called 'Data Safe Havens' has been crucial. Unfortunately, the origins and evolution of the term have led to a range of different definitions being assumed by different groups. There is, however, an intuitively meaningful interpretation that is often assumed by those who have not previously encountered the term: a repository in which useful but potentially sensitive data may be kept securely under governance and informatics systems that are fit-for-purpose and appropriately tailored to the nature of the data being maintained, and may be accessed and utilized by legitimate users undertaking work and research contributing to biomedicine, health and/or to ongoing development of healthcare systems. RESULTS: This review explores a fundamental question: 'what are the specific criteria that ought reasonably to be met by a data repository if it is to be seen as consistent with this interpretation and viewed as worthy of being accorded the status of 'Data Safe Haven' by key stakeholders'? We propose 12 such criteria. CONTACT: paul.burton@bristol.ac.uk.

Associations between Vitamin D and Cardiovascular Disease Risk Factors in African Americans Are Partly Explained by Circulating Adipokines and C-Reactive Protein: The Jackson Heart Study.

BACKGROUND: Although it is recognized that vitamin D deficiency is associated with cardiovascular disease (CVD) risk factors, and is more common in African Americans (AAs), the pathologic mechanisms by which vitamin D may influence these risk factors are poorly understood. OBJECTIVES: We explored the association between vitamin D status, as reflected by serum 25-hydroxyvitamin D [25(OH)D] concentrations, and CVD risk factors including mean arterial pressure (MAP), fasting plasma glucose (FPG), plasma HDL cholesterol, and waist circumference (WC) in adult AAs. We also tested whether plasma C-reactive protein (CRP), adipokines (adiponectin and leptin), and aldosterone mediated the associations between 25(OH)D and these risk factors. METHODS: Data on 4010 (63.8% women; mean age: 54.0 y) individuals from the Jackson Heart Study were analyzed. Multivariable linear regression models were used to examine the associations of 25(OH)D with CVD risk factors. We used path analysis and bootstrapping methods to quantify and test the share of these associations that was statistically explained by each of the mediators by decomposing the associations into direct and indirect effects. RESULTS: Serum 25(OH)D concentrations were inversely associated with WC, FPG, and MAP and were positively associated with HDL cholesterol in multivariable analysis. A nearly 20% effect of 25(OH)D on MAP was masked by aldosterone (total indirect effect: ß = 0.01, P < 0.05). Approximately 23% of the effect of 25(OH)D on WC (ß = -0.03, P < 0.05) and ∼9% of the effect of 25(OH)D on FPG (ß = -0.02, P < 0.05) were mediated through CRP, adiponectin, and leptin together. A 23% share of the association between 25(OH)D and HDL cholesterol was mediated by adiponectin alone (ß = 0.03, P < 0.05). CONCLUSIONS: Our findings suggest that the associations between vitamin D status and CVD risk factors in AAs are partially mediated through circulating adipokines and CRP. More evidence, however, is required from longitudinal and randomized controlled studies to validate our findings.

Vitamin D Receptor Gene Polymorphisms Are Associated with Abdominal Visceral Adipose Tissue Volume and Serum Adipokine Concentrations but Not with Body Mass Index or Waist Circumference in African Americans: The Jackson Heart Study.

BACKGROUND: The biological actions of vitamin D are mediated through the vitamin D receptor (VDR). Single-nucleotide polymorphisms (SNPs) in the VDR gene have been previously associated with adiposity traits. However, to our knowledge, few studies have included direct measures of adiposity and adipokine concentrations. OBJECTIVE: We examined the association of tagging SNPs in the VDR gene with multiple adiposity measures, including waist circumference (WC), body mass index (BMI), body fat percentage, subcutaneous and visceral adipose tissue (VAT) volume, and serum adipokine (adiponectin and leptin) concentrations in adult African Americans (AAs). METHODS: Data from 3020 participants (61.9% women; mean age, 54.6 y) from the Jackson Heart Study were used for this analysis. Forty-five tag SNPs were chosen with the use of genotype data from the International HapMap project. We used linear regression to test the associations of imputed VDR SNPs with each of the traits, adjusted for age, sex, educational status, physical activity, smoking, alcohol intake, serum vitamin D concentration, European ancestry, and multiple testing. RESULTS: The G allele of the SNP rs4328262 remained associated with increased VAT volume after multiple testing correction (ß = 45.7; P < 0.001). The A allele of another SNP (rs11574070) was nominally associated with body fat percentage (ß = 0.96; P = 0.002). None of the VDR SNPs analyzed showed any link with WC or BMI. The A allele of rs2228570 (ß = 0.08; P = 0.001) for men and the T allele of rs2853563 (ß = 0.04; P < 0.001) for women remained positively associated with serum adiponectin concentrations after multiple testing correction. CONCLUSION: Although we did not find any association for anthropometric measures, we did observe associations of VDR variants with serum adipokines and with the more metabolically active fat, VAT. Therefore, our findings demonstrate a possible role of VDR variants in regulating adipose tissue activity and adiposity among AAs.

Road traffic noise, blood pressure and heart rate: Pooled analyses of harmonized data from 88,336 participants.

INTRODUCTION: Exposure to road traffic noise may increase blood pressure and heart rate. It is unclear to what extent exposure to air pollution may influence this relationship. We investigated associations between noise, blood pressure and heart rate, with harmonized data from three European cohorts, while taking into account exposure to air pollution. METHODS: Road traffic noise exposure was assessed using a European noise model based on the Common Noise Assessment Methods in Europe framework (CNOSSOS-EU). Exposure to air pollution was estimated using a European-wide land use regression model. Blood pressure and heart rate were obtained by trained clinical professionals. Pooled cross-sectional analyses of harmonized data were conducted at the individual level and with random-effects meta-analyses. RESULTS: We analyzed data from 88,336 participants, across the three participating cohorts (mean age 47.0 (±13.9) years). Each 10dB(A) increase in noise was associated with a 0.93 (95% CI 0.76;1.11) bpm increase in heart rate, but with a decrease in blood pressure of 0.01 (95% CI -0.24;0.23) mmHg for systolic and 0.38 (95% CI -0.53; -0.24) mmHg for diastolic blood pressure. Adjustments for PM10 or NO2 attenuated the associations, but remained significant for DBP and HR. Results for BP differed by cohort, with negative associations with noise in LifeLines, no significant associations in EPIC-Oxford, and positive associations with noise >60dB(A) in HUNT3. CONCLUSIONS: Our study suggests that road traffic noise may be related to increased heart rate. No consistent evidence for a relation between noise and blood pressure was found.

Association of adiponectin and socioeconomic status in African American men and women: the Jackson heart study.

BACKGROUND: Recent emphasis has been placed on elucidating the biologic mechanism linking socioeconomic status (SES) to cardiovascular disease (CVD). Positive associations of inflammatory biomarkers provide evidence suggestive of a biologic pathway by which SES may predispose to CVD. African Americans have disproportionately lower SES and have a higher prevalence of CVD risk factors compared to most ethnic/racial groups. Adiponectin (an anti-inflammatory marker) is also lower. The objective of this study was to assess the association of adiponectin with SES among African American men and women using the Jackson Heart Study. METHODS: Study sample included 4340 participants. Linear regression was performed separately by SES and stratified by sex. Annual household income and level of education was used as proxies for SES. Crude, age, health behavior and health status adjusted models were analyzed. The main outcome was log-transformed adiponectin. RESULTS: Men in the lowest income group had significantly higher adiponectin than those in the highest income group in the fully adjusted model (ß/standard error [se], p value = .16/.08, p = .0008. Men with < high school level of education had significantly higher adiponectin in the crude and age adjusted models than those with ≥ college degree (.25/.05, p < .0001; .14/.05/ p = .005, respectively). Women with some college or vocational training in the crude and age adjusted models had lower adiponectin compared to women with ≥ college degree (-.09/.03, p = .004; -.06/.03, p = .04, respectively). CONCLUSION: Findings suggest a potential inverse biologic pathway between annual household income and adiponectin among African American men. There was no such finding among women. Findings suggest interventions should be targeted for higher SES African American men to improve adiponectin levels.

Association of ADIPOQ gene with type 2 diabetes and related phenotypes in African American men and women: the Jackson Heart Study.

BACKGROUND: African Americans experience disproportionately higher prevalence of type 2 diabetes and related risk factors. Little research has been done on the association of ADIPOQ gene on type 2 diabetes, plasma adiponectin, blood glucose, HOMA-IR and body mass index (BMI) in African Americans. The objective of our research was to assess such associations with selected SNPs. The study included a sample of 3,020 men and women from the Jackson Heart Study who had ADIPOQ genotyping information. Unadjusted and adjusted regression models with covariates were used with type 2 diabetes and related phenotypes as the outcome stratified by sex. RESULTS: There was no association between selected ADIPOQ SNPs with type 2 diabetes, blood glucose, or BMI in men or women. There was a significant association between variant rs16861205 and lower adiponectin in women with minor allele A in the fully adjusted model (ß(SE) p = -.13(0.05), 0.003). There was also a significant association with variant rs7627128 and lower HOMA-IR among men with minor allele A in the fully adjusted model (ß(SE) p = -0.74(0.20), 0.0002). CONCLUSIONS: These findings represent new insights regarding the association of ADIPOQ gene and type 2 diabetes and related phenotypes in African American men and women.

The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies.

BACKGROUND: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. METHODS: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. RESULTS: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes. CONCLUSIONS: Through a rigorous harmonization process, the BioSHaRE-EU consortium was able to compare key characteristics defining the metabolically healthy obese phenotype across ten cohort studies. There is considerable variability in the prevalence of healthy obesity across the different European populations studied, even when unified criteria were used to classify this phenotype.

Transcriptome Study of 2 Black Cohorts Reveals cis Long Noncoding RNAs Associated With Hypertension-Related mRNAs.

BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged as critical regulators of the expression of genes involved in cardiovascular diseases. This project aims to identify circulating lncRNAs associated with protein-coding mRNAs differentially expressed between hypertensive and normotensive individuals and establish their link with hypertension. METHODS AND RESULTS: The analyses were conducted in 3 main steps: (1) an unbiased whole blood transcriptome-wide analysis was conducted to identify and replicate protein-coding genes differentially expressed by hypertension status in 497 and 179 Black individuals from the GENE-FORECAST (Genomics, Environmental Factors and the Social Determinants of Cardiovascular Disease in African-Americans Study) and MH-GRID (Minority Health Genomics and Translational Research Bio-Repository Database) studies, respectively. Subsequently, (2) proximal lncRNAs, termed cis lncRNA quantitative trait loci, associated with each mRNA were identified in the GENE-FORECAST study and replicated in the MH-GRID study. Finally, (3) the lncRNA quantitative trait loci were used as predictors in a random forest model to predict hypertension in both data sets. A total of 129 mRNAs were significantly differentially expressed between normotensive and hypertensive individuals in both data sets. The lncRNA-mRNA association analysis revealed 249 cis lncRNA quantitative trait loci associated with 102 mRNAs, including VAMP2 (vesicle-associated membrane protein 2), mitogen-activated protein kinase kinase 3, CCAAT enhancer binding protein beta, and lymphocyte antigen 6 complex, locus E. The 249 lncRNA quantitative trait loci predicted hypertension with an area under the curve of 0.79 and 0.71 in GENE-FORECAST and MH-GRID studies, respectively. CONCLUSIONS: This study leveraged a significant sample of Black individuals, a population facing a disproportionate burden of hypertension. The analyses unveiled a total of 271 lncRNA-mRNA relationships involving mRNAs that play critical roles in vascular pathways relevant to blood pressure regulation. The compelling findings, consistent across 2 independent data sets, establish a reliable foundation for designing in vitro/in vivo experiments.

Regulatory Roles of Long Non-Coding RNAs in Arterial Stiffness and Hypertension: Insights from Two African American Studies.

Background: Arterial stiffness, commonly assessed via pulse wave velocity (PWV), is marked by reduced arterial elasticity and serves as a significant risk factor for cardiovascular disease and an early indicator of hypertension. This study investigated the regulatory roles of long non-coding RNAs (lncRNAs) in modulating mRNAs associated with arterial stiffness and hypertension, with a particular focus on African Americans, a population disproportionately impacted by hypertension. Methods: We utilized whole-blood transcriptome sequencing data from two African American (AA) cohorts with high hypertension prevalence: the GENE-FORECAST study (436 subjects) and the MH-GRID study (179 subjects). Our objectives were to: (1) identify lncRNAs and mRNAs differentially expressed (DE) between the upper and lower tertiles of PWV, (2) determine DE lncRNAs associated with the expression levels of each DE mRNA, and (3) link the lncRNA-modulated mRNAs to hypertension across both datasets. Results: Differential expression analysis revealed 1,035 DE mRNAs and 31 DE lncRNAs between upper and lower PWV groups. Then lncRNA-mRNA pairs significantly associated were identified, involving 31 unique lncRNAs and 1,034 unique mRNAs. Finally, 22 of the lncRNA-modulated mRNAs initially linked to PWV were found associated with hypertension, in both datasets. Interestingly, 30 lncRNAs were linked to the expression of UCP2 (Uncoupling Protein 2), a gene implicated in oxidative stress and endothelial function. Conclusions: Our findings underscore the significant roles of lncRNAs in regulating gene expression associated with arterial stiffness and hypertension. The differential expression of UCP2 in relation to PWV and hypertension, along with its potential regulation by lncRNAs, offers valuable insights into the molecular mechanisms underlying arterial stiffness and its connection with hypertension.

Leveraging the transcriptome to further our understanding of GWAS findings: eQTLs associated with genes related to LDL and LDL subclasses, in a cohort of African Americans.

Background: GWAS discoveries often pose a significant challenge in terms of understanding their underlying mechanisms. Further research, such as an integration with expression quantitative trait locus (eQTL) analyses, are required to decipher the mechanisms connecting GWAS variants to phenotypes. An eQTL analysis was conducted on genes associated with low-density lipoprotein (LDL) cholesterol and its subclasses, with the aim of pinpointing genetic variants previously implicated in GWAS studies focused on lipid-related traits. Notably, the study cohort consisted of African Americans, a population characterized by a heightened prevalence of hypercholesterolemia. Methods: A comprehensive differential expression (DE) analysis was undertaken, with a dataset of 17,948 protein-coding mRNA transcripts extracted from the whole-blood transcriptomes of 416 samples to identify mRNA transcripts associated with LDL, with further granularity delineated between small LDL and large LDL subclasses. Subsequently, eQTL analysis was conducted with a subset of 242 samples for which whole-genome sequencing data were available to identify single-nucleotide polymorphisms (SNPs) associated with the LDL-related mRNA transcripts. Lastly, plausible functional connections were established between the identified eQTLs and genetic variants reported in the GWAS catalogue. Results: DE analysis revealed 1,048, 284, and 94 mRNA transcripts that exhibited differential expression in response to LDL, small LDL, and large LDL, respectively. The eQTL analysis identified a total of 9,950 significant SNP-mRNA associations involving 6,955 SNPs including a subset 101 SNPs previously documented in GWAS of LDL and LDL-related traits. Conclusion: Through comprehensive differential expression analysis, we identified numerous mRNA transcripts responsive to LDL, small LDL, and large LDL. Subsequent eQTL analysis revealed a rich landscape of eQTL-mRNA associations, including a subset of eQTL reported in GWAS studies of LDL and related traits. The study serves as a testament to the important role of integrative genomics in unraveling the enigmatic GWAS relationships between genetic variants and the complex fabric of human traits and diseases.

Genomic study of taste perception genes in African Americans reveals SNPs linked to Alzheimer's disease.

While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer's disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer's disease. This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer's Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.

Genomic Study of Taste Perception Genes in African Americans Reveals SNPs Linked to Alzheimer's Disease.

Background: While previous research has shown the potential links between taste perception pathways and brain-related conditions, the area involving Alzheimer's disease remains incompletely understood. Taste perception involves neurotransmitter signaling, including serotonin, glutamate, and dopamine. Disruptions in these pathways are implicated in neurodegenerative diseases. The integration of olfactory and taste signals in flavor perception may impact brain health, evident in olfactory dysfunction as an early symptom in neurodegenerative conditions. Shared immune response and inflammatory pathways may contribute to the association between altered taste perception and conditions like neurodegeneration, present in Alzheimer's disease. Methods: This study consists of an exploration of expression-quantitative trait loci (eQTL), utilizing whole-blood transcriptome profiles, of 28 taste perception genes, from a combined cohort of 475 African American subjects. This comprehensive dataset was subsequently intersected with single-nucleotide polymorphisms (SNPs) identified in Genome-Wide Association Studies (GWAS) of Alzheimer's Disease (AD). Finally, the investigation delved into assessing the association between eQTLs reported in GWAS of AD and the profiles of 741 proteins from the Olink Neurological Panel. Results: The eQTL analysis unveiled 3,547 statistically significant SNP-Gene associations, involving 412 distinct SNPs that spanned all 28 taste genes. In 17 GWAS studies encompassing various traits, a total of 14 SNPs associated with 12 genes were identified, with three SNPs consistently linked to Alzheimer's disease across four GWAS studies. All three SNPs demonstrated significant associations with the down-regulation of TAS2R41, and two of them were additionally associated with the down-regulation of TAS2R60. In the subsequent pQTL analysis, two of the SNPs linked to TAS2R41 and TAS2R60 genes (rs117771145 and rs10228407) were correlated with the upregulation of two proteins, namely EPHB6 and ADGRB3. Conclusions: Our investigation introduces a new perspective to the understanding of Alzheimer's disease, emphasizing the significance of bitter taste receptor genes in its pathogenesis. These discoveries set the stage for subsequent research to delve into these receptors as promising avenues for both intervention and diagnosis. Nevertheless, the translation of these genetic insights into clinical practice requires a more profound understanding of the implicated pathways and their pertinence to the disease's progression across diverse populations.