Clonal haematopoiesis, ageing and kidney disease.

Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease. Beyond its direct effect on the kidney, CHIP elevates the susceptibility of individuals to various conditions that can detrimentally affect the kidneys, including cardiovascular disease, obesity and insulin resistance, liver disease, gout, osteoporosis and certain autoimmune diseases. Aberrant pro-inflammatory signalling, telomere attrition and epigenetic ageing are potential causal pathophysiological pathways and mediators that underlie CHIP-related disease risk. Experimental animal models have shown that inhibition of inflammatory cytokine signalling can ameliorate many of the pathological effects of CHIP, and assessment of the efficacy and safety of this class of medications for human CHIP-associated pathology is ongoing.

A longitudinal study of polygenic score and cognitive function decline considering baseline cognitive function, lifestyle behaviors, and diabetes among middle-aged and older US adults.

BACKGROUND: Genomic study of cognition decline while considering baseline cognition and lifestyle behaviors is scarce. We aimed to evaluate the impact of a polygenic score for general cognition on cognition decline rate, while considering baseline cognition and lifestyle behaviors, among the general population and people with diabetes, a patient group commonly affected by cognition impairment. METHODS: We tested associations of the polygenic score for general cognition with annual changing rates of cognition measures in 8 years of follow-up among 12,090 White and 3100 Black participants of the Health and Retirement Study (HRS), a nationally representative sample of adults aged 50 years and older in the USA. Cognition measures including word recall, mental status, and total cognitive score were measured biannually. To maximize sample size and length of follow-up, we treated the 2010 wave of survey as baseline, and follow-up data until 2018 were analyzed. Baseline lifestyle behaviors, APOE status, and measured cognition were sequentially adjusted. Given racial differences in polygenic score, all analyses were conducted by race. RESULTS: The polygenic score was significantly associated with annual changing rates of all cognition measures independent of lifestyle behaviors and APOE status. Together with age and sex, the polygenic score explained 29.9%, 15.9%, and 26.5% variances of annual changing rates of word recall, mental status, and total cognitive scores among Whites and explained 17.2%, 13.9%, and 18.7% variance of the three traits among Blacks. Among both White and Black participants, those in the top quartile of polygenic score had the three cognition measures increased annually, while those in the bottom quartile had the three cognition measures decreased annually. After further adjusting for the average cognition assessed in 3 visits around baseline, the polygenic score was still positively associated with annual changing rates of all cognition measures for White (P ≤ 2.89E - 19) but not for Black (P ≥ 0.07) participants. In addition, among participants with diabetes, physical activity offset the genetic susceptibility to decline of mental status (interaction P ≤ 0.01) and total cognitive scores (interaction P = 0.03). CONCLUSIONS: Polygenic score predicted cognition changes in addition to measured cognition. Physical activity offset genetic risk for cognition decline among diabetes patients.

Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Serum Metabolomic Markers of Dairy Consumption: Results from the Atherosclerosis Risk in Communities Study and the Bogalusa Heart Study.

BACKGROUND: Dairy consumption is related to chronic disease risk; however, the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake. OBJECTIVES: We aimed to identify associations between dietary dairy intake (total dairy, low-fat dairy, and high-fat dairy) and serum metabolites in 2 independent study populations of United States adults. METHODS: Dietary intake was assessed with food frequency questionnaires. Multivariable linear regression models were used to estimate cross-sectional associations between dietary intake of dairy and 360 serum metabolites analyzed in 2 subgroups of the Atherosclerosis Risk in Communities study (ARIC; n = 3776). Results from the 2 subgroups were meta-analyzed using fixed effects meta-analysis. Significant meta-analyzed associations in the ARIC study were then tested in the Bogalusa Heart Study (BHS; n = 785). RESULTS: In the ARIC study and BHS, the mean age was 54 and 48 years, 61% and 29% were Black, and the mean dairy intake was 1.7 and 1.3 servings/day, respectively. Twenty-nine significant associations between dietary intake of dairy and serum metabolites were identified in the ARIC study (total dairy, n = 14; low-fat dairy, n = 10; high-fat dairy, n = 5). Three associations were also significant in BHS: myristate (14:0) was associated with high-fat dairy, and pantothenate was associated with total dairy and low-fat dairy, but 23 of the 27 associations significant in the ARIC study and tested in BHS were not associated with dairy in BHS. CONCLUSIONS: We identified metabolomic associations with dietary intake of dairy, including 3 associations found in 2 independent cohort studies. These results suggest that myristate (14:0) and pantothenate (vitamin B5) are candidate biomarkers of dairy consumption.

Examination of Serum Metabolome Altered by Dietary Carbohydrate, Milk Protein, and Soy Protein Interventions Identified Novel Metabolites Associated with Blood Pressure: The ProBP Trial.

SCOPE: This study aims to discover metabolites of dietary carbohydrate, soy and milk protein supplements and evaluate their roles in blood pressure (BP) regulation in the protein and blood pressure (ProBP), a cross-over trial. METHODS AND RESULTS: Plasma metabolites are profiled at pre-trial baseline and after 8 weeks of supplementation with carbohydrate, soy protein, and milk protein, respectively, among 80 ProBP participants. After Bonferroni correction (α = 6.49 × 10-4 ), dietary interventions significantly changed 40 metabolites. Changes of erucate (22:1n9), an omega-9 fatty acid, are positively associated with systolic BP changes (Beta = 1.90, p = 6·27 × 10-4 ). This metabolite is also associated with higher odds of hypertension among 1261 participants of an independent cohort (odds ratio per unit increase = 1.34; 95% confidence interval: 1.07-1.68). High levels of acylcholines dihomo-linolenoyl-choline (p = 4.71E-04) and oleoylcholine (p = 3.48E-04) at baseline predicted larger BP lowering effects of soy protein. Increasing cheese intake during the trial, as reflected by isobutyrylglycine and isovalerylglycine, reduces the BP lowering effect of soy protein. CONCLUSIONS: The study identifies molecular signatures of dietary interventions. Erucate (22:1n9) increases systolic BP. Acylcholine enhances and cheese intake reduces the BP lowering effect of soy protein supplement.

Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

Genomic Innovation in Early Life Cardiovascular Disease Prevention and Treatment.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality globally. Although CVD events do not typically manifest until older adulthood, CVD develops gradually across the life-course, beginning with the elevation of risk factors observed as early as childhood or adolescence and the emergence of subclinical disease that can occur in young adulthood or midlife. Genomic background, which is determined at zygote formation, is among the earliest risk factors for CVD. With major advances in molecular technology, including the emergence of gene-editing techniques, along with deep whole-genome sequencing and high-throughput array-based genotyping, scientists now have the opportunity to not only discover genomic mechanisms underlying CVD but use this knowledge for the life-course prevention and treatment of these conditions. The current review focuses on innovations in the field of genomics and their applications to monogenic and polygenic CVD prevention and treatment. With respect to monogenic CVD, we discuss how the emergence of whole-genome sequencing technology has accelerated the discovery of disease-causing variants, allowing comprehensive screening and early, aggressive CVD mitigation strategies in patients and their families. We further describe advances in gene editing technology, which might soon make possible cures for CVD conditions once thought untreatable. In relation to polygenic CVD, we focus on recent innovations that leverage findings of genome-wide association studies to identify druggable gene targets and develop predictive genomic models of disease, which are already facilitating breakthroughs in the life-course treatment and prevention of CVD. Gaps in current research and future directions of genomics studies are also discussed. In aggregate, we hope to underline the value of leveraging genomics and broader multiomics information for characterizing CVD conditions, work which promises to expand precision approaches for the life-course prevention and treatment of CVD.

Effects of epigenetic age acceleration on kidney function: a Mendelian randomization study.

BACKGROUND: Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function. RESULTS: Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR. CONCLUSION: This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies.

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Novel Genetic Variants Associated with Chronic Kidney Disease Progression.

SIGNIFICANCE STATEMENT: eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD. BACKGROUND: The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. METHODS: We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. RESULTS: SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. CONCLUSIONS: This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Emerging evidence on the role of clonal hematopoiesis of indeterminate potential in chronic kidney disease.

Chronic kidney disease (CKD) was responsible for 1.2 million deaths globally in 2016. Despite the large and growing burden of CKD, treatment options are limited and generally only preserve kidney function. Characterizing molecular precursors to incident and progressive CKD could point to critically needed prevention and treatment strategies. Clonal hematopoiesis of indeterminate potential (CHIP) is typically characterized by the clonal expansion of blood cells carrying somatic mutations in specific driver genes. An age-related disorder, CHIP is rare in the young but common in older adults. Recent studies have identified causal associations between CHIP and atherosclerotic cardiovascular disease which are most likely mediated by inflammation, a hallmark of CKD. Animal evidence has supported causal effects of CHIP on kidney injury, inflammation, and fibrosis, providing impetus for human research. Although prospective epidemiologic studies investigating associations of CHIP with development and progression of CKD are few, intriguing findings have been reported. CHIP was significantly associated with kidney function decline and end stage kidney disease in the general population, although effect sizes were modest. Recent work suggests larger associations of CHIP with kidney disease progression in CKD patients, but further investigations in this area are needed. In addition, the accumulating literature has identified some heterogeneity in associations between CHIP and kidney endpoints across study populations, but reasons for these differences remain unclear. The current review provides an in-depth exploration into this nascent area of research, develops a conceptual framework linking CHIP to CKD, and discusses the clinical and public health implications of this work.

Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3. Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

Whole genome sequence analysis of blood lipid levels in >66,000 individuals.

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Rare Variants in Genes Encoding Subunits of the Epithelial Na+ Channel Are Associated With Blood Pressure and Kidney Function.

BACKGROUND: The epithelial Na+ channel (ENaC) is intrinsically linked to fluid volume homeostasis and blood pressure. Specific rare mutations in SCNN1A, SCNN1B, and SCNN1G, genes encoding the α, ß, and γ subunits of ENaC, respectively, are associated with extreme blood pressure phenotypes. No associations between blood pressure and SCNN1D, which encodes the δ subunit of ENaC, have been reported. A small number of sequence variants in ENaC subunits have been reported to affect functional transport in vitro or blood pressure. The effects of the vast majority of rare and low-frequency ENaC variants on blood pressure are not known. METHODS: We explored the association of low frequency and rare variants in the genes encoding ENaC subunits, with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure. Using whole-genome sequencing data from 14 studies participating in the Trans-Omics in Precision Medicine Whole-Genome Sequencing Program, and sequence kernel association tests. RESULTS: We found that variants in SCNN1A and SCNN1B were associated with diastolic blood pressure and mean arterial pressure (P<0.00625). Although SCNN1D is poorly expressed in human kidney tissue, SCNN1D variants were associated with systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure (P<0.00625). ENaC variants in 2 of the 4 subunits (SCNN1B and SCNN1D) were also associated with estimated glomerular filtration rate (P<0.00625), but not with stroke. CONCLUSIONS: Our results suggest that variants in extrarenal ENaCs, in addition to ENaCs expressed in kidneys, influence blood pressure and kidney function.

Large-Scale Targeted Sequencing Study of Ischemic Stroke in the Han Chinese Population.

Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previously identified genes associated with atherosclerotic disease among 999 ischemic stroke cases and 1001 controls of Chinese ancestry. Multiple logistic regression models were used to examine the associations between variants and ischemic stroke and test interactions between variants and clinical and lifestyle risk factors. Functional variants achieving suggestive significance were replicated in an independent sample of 4724 ischemic stroke cases and 5029 controls. Driven by variant main effects, each minor allele of the correlated rs174535, rs174545, and rs3834458 variants at MYRF-FADS1-FADS2 conferred an average 0.83-fold (95% CI, 0.78-0.88) decreased odds of stroke. Significant main effects of MTHFR rs1801133 missense variant were also observed, with each copy of the A allele associated with a 1.20-fold (95% CI, 1.13-1.27) higher odds of ischemic stroke. The functional ALDH2 rs671 variant was identified in interaction analyses with alcohol drinking (Meta-P=3.39×10-17). Each minor allele conferred a 0.54-fold (95% CI, 0.45-0.64) decreased odds of stroke among drinkers and a 0.89-fold (95% CI, 0.83-0.97) decreased odds among nondrinkers. Conclusions Significant associations at MYRF-FADS1-FADS2 indicate that genetically elevated polyunsaturated fatty acids may decrease ischemic stroke risk in East Asians. Significant associations at MTHFR and ALDH2 robustly confirm deleterious effects of genetically elevated homocysteine and alcohol intake, respectively, on ischemic stroke.

Life-Course Associations between Blood Pressure-Related Polygenic Risk Scores and Hypertension in the Bogalusa Heart Study.

Genetic information may help to identify individuals at increased risk for hypertension in early life, prior to the manifestation of elevated blood pressure (BP) values. We examined 369 Black and 832 White Bogalusa Heart Study (BHS) participants recruited in childhood and followed for approximately 37 years. The multi-ancestry genome-wide polygenic risk scores (PRSs) for systolic BP (SBP), diastolic BP (DBP), and hypertension were tested for an association with incident hypertension and stage 2 hypertension using Cox proportional hazards models. Race-stratified analyses were adjusted for baseline age, age2, sex, body mass index, genetic principal components, and BP. In Black participants, each standard deviation increase in SBP and DBP PRS conferred a 38% (p = 0.009) and 22% (p = 0.02) increased risk of hypertension and a 74% (p < 0.001) and 50% (p < 0.001) increased risk of stage 2 hypertension, respectively, while no association was observed with the hypertension PRSs. In Whites, each standard deviation increase in SBP, DBP, and hypertension PRS conferred a 24% (p < 0.05), 29% (p = 0.01), and 25% (p < 0.001) increased risk of hypertension, and a 27% (p = 0.08), 29% (0.01), and 42% (p < 0.001) increased risk of stage 2 hypertension, respectively. The addition of BP PRSs to the covariable-only models generally improved the C-statistics (p < 0.05). Multi-ancestry BP PRSs demonstrate the utility of genomic information in the early life prediction of hypertension.

Association of Mitochondrial DNA Copy Number with Risk of Progression of Kidney Disease.

BACKGROUND AND OBJECTIVES: Mitochondrial DNA copy number is a biomarker of mitochondrial function, which has been hypothesized to contribute to pathogenesis of CKD through podocyte injury, tubular epithelial cell damage, and endothelial dysfunction. The prospective association of mitochondrial DNA copy number with CKD progression has not been previously evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Chronic Renal Insufficiency Cohort study participants had serum levels of mitochondrial DNA copy number calculated from probe intensities of mitochondrial single nucleotide polymorphisms genotyped on the Illumina HumanOmni 1-Quad Array. CKD progression was defined as kidney failure or halving of eGFR from baseline. Cox proportional hazards models were used to calculate hazard ratios for mitochondrial DNA copy number and risk of CKD progression. RESULTS: Among 2943 participants, mean age was 58 years, 45% were women, and 48% self-identified as Black. There were 1077 patients who experienced CKD progression over a median follow-up of 6.5 years. The incidence rate of CKD progression was highest for those in the lowest tertile of mitochondrial DNA copy number (tertile 1, 58.1; tertile 2, 50.8; tertile 3, 46.3 per 1000 person-years). Risk for CKD progression was higher for participants with lower levels of mitochondrial DNA copy number after adjustment for established risk factors (for tertile 1 versus 3, hazard ratio, 1.28 [95% confidence interval, 1.10 to 1.50]; for tertile 2 versus 3, hazard ratio, 0.99 [95% confidence interval, 0.85 to 1.16]; trend P=0.002). Similar results were seen among those with albuminuria (for tertile 1 versus 3, hazard ratio, 1.24; 95% confidence interval, 1.05 to 1.47), but there were no statistically significant associations among individuals without albuminuria (for tertile 1 versus 3, hazard ratio, 1.04; 95% confidence interval, 0.70 to 1.53; interaction P<0.001). CONCLUSIONS: These findings suggest lower mitochondrial DNA copy number is associated with higher risk of CKD progression, independent of established risk factors among patients with CKD.

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.