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Abstract Background The emergence and rapid spread of new severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) variants have challenged the control of the COVID-19 pandemic globally. Burundi was not spared by that pandemic, but the genetic diversity, evolution, and epidemiology of those variants in the country remained poorly understood. The present study sought to investigate the role of different SARS-COV-2 variants in the successive COVID-19 waves experienced in Burundi and the impact of their evolution on the course of that pandemic. We conducted a cross-sectional descriptive study using positive SARS-COV-2 samples for genomic sequencing. Subsequently, we performed statistical and bioinformatics analyses of the genome sequences in light of available metadata. Results In total, we documented 27 PANGO lineages of which BA.1, B.1.617.2, AY.46, AY.122, and BA.1.1, all VOCs, accounted for 83.15% of all the genomes isolated in Burundi from May 2021 to January 2022. Delta (B.1.617.2) and its descendants predominated the peak observed in July–October 2021. It replaced the previously predominant B.1.351 lineage. It was itself subsequently replaced by Omicron (B.1.1.529, BA.1, and BA.1.1). Furthermore, we identified amino acid mutations including E484K, D614G, and L452R known to increase infectivity and immune escape in the spike proteins of Delta and Omicron variants isolated in Burundi. The SARS-COV-2 genomes from imported and community-detected cases were genetically closely related. Conclusion The global emergence of SARS-COV-2 VOCs and their subsequent introductions in Burundi was accompanied by new peaks (waves) of COVID-19. The relaxation of travel restrictions and the mutations occurring in the virus genome played an important role in the introduction and the spread of new SARS-COV-2 variants in the country. It is of utmost importance to strengthen the genomic surveillance of SARS-COV-2, enhance the protection by increasing the SARS-COV-2 vaccine coverage, and adjust the public health and social measures ahead of the emergence or introduction of new SARS-COV-2 VOCs in the country.

Background: Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown., Objectives: This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers., Methods: This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference., Results: The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14)., Conclusions: A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure., Competing Interests: Funding Support and Author Disclosures Dr Arora was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) awards (R01HL160982, R01HL163852, and R01HL163081). Dr Patel was supported by the NIH grant T32HL007457. The TOPMed (Molecular data for the Trans-Omics for Precision Medicine) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Whole genome sequencing (WGS) for NHLBI TOPMed: JHS (phs000964) was performed at the Northwest Genomics Center (HHSN268201100037C). WGS for NHLBI TOPMed: MESA (phs001416) was performed at Broad Genomics (HHSN268201600034I, 3U54HG003067-13S1). WGS for NHLBI TOPMed: CARDIA (phs001612) was performed at Baylor (HHSN268201600033I). WGS for NHLBI TOPMed: CHS (phs001368) was performed at the Broad Institute of MIT and Harvard (HHSN268201600034I) and Baylor (HHSN268201600033I). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). The MESA (Multi-Ethnic Study of Atherosclerosis) projects are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756. The ARIC (Atherosclerosis Risk In Communities) study has been funded in whole or in part with federal funds from the NHLBI, NIH, Department of Health and Human Services (HHS), under contract numbers 5N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. The CARDIA (Coronary Artery Risk Development in Young Adults) Study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). CARDIA was also partially supported by the Intramural Research Program of the NIA (National Institute on Aging) and an intra-agency agreement between the NIA and NHLBI (AG0005). The research for the CHS (Cardiovascular Health Study) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006 and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the NINDS (National Institute of Neurological Disorders and Stroke). Additional support was provided by R01AG023629 from the NIA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The JHS (Jackson Heart Study) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), Mississippi State Department of Health (HHSN268201800015I) and University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. The Women’s Health Initiative program is funded by the NHLBI, NIH, HHS through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. The REGARDS (Reasons for Geographic And Racial Differences in Stroke) study is supported by cooperative agreement U01 NS041588 cofunded by the NINDS and the NIA, NIH, HHS. The genotyping was supported by R01HL13666. Adjudication of heart failure events was supported by R01HL080477. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and its institutes. None of the funding agencies had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Representatives of the NINDS were involved in the review and approval of the manuscript. Dr Arora has received grant support from Merck Sharp and Dohme LLC and Bristol-Myers Squibb; and consulting income from Bristol-Myers Squibb, which are all unrelated to this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: The clinical utility of polygenic risk scores (PRS) for blood pressure (BP) response to antihypertensive treatment (AHT) has not been elucidated., Objective: To investigate the ability of a systolic BP (SBP) PRS to predict AHT response and apparent treatment-resistant hypertension (aTRH)., Design, Setting, and Participants: The Genetics of Hypertension Associated Treatments (GenHAT) study was an ancillary pharmacogenomic study to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT, which enrolled participants aged 55 years or older with hypertension (HTN) starting in February 1994, completed follow-up in March 2002. The current study was conducted from a subset of Black GenHAT participants randomized to the treatment groups of either chlorthalidone (n = 3745) or lisinopril (n = 2294), with genetic data available from a prior genetic association study. The current study's objective was to examine the association of the SBP PRS to AHT response over 6 months, as well as to examine the predictive accuracy of the SBP PRS with aTRH. The current analysis took place in February 2023, with additional analyses conducted in July 2024., Exposure: An SBP PRS (comprising 1 084 157 genetic variants) stratified as quintiles and per SD., Main Outcomes and Measures: The primary outcome was change in SBP (ΔSBP) and diastolic BP (ΔDBP) over 6 months. aTRH was defined as the use of 3 AHTs with uncontrolled HTN at year 3 of follow-up or taking 4 or more AHTs at year 3 of follow-up, regardless of BP. Baseline demographics were compared across PRS quintiles using Kruskal-Wallis or χ2 tests as appropriate. The least-square means of BP response were calculated through multivariable adjusted linear regression, and multivariable adjusted logistic regression was used to calculate the odds ratios and 95% confidence intervals for aTRH., Results: Among 3745 Black GenHAT participants randomized to chlorthalidone treatment, median (IQR) participant age was 65 (60-71) years, and 2064 participants (55.1%) were female. Each increasing quintile of the SBP PRS from 1 to 5 was associated with a reduced BP response to treatment over 6 months. Participants in the lowest quintile experienced a mean ΔSBP of -10.01 mm Hg (95% CI, -11.11 to -8.90) compared to -6.57 mm Hg (95% CI, -7.67 to -5.48) for participants in the median quintile. No associations were observed between the SBP PRS and BP response to lisinopril. Participants in the highest PRS quintile had 67% higher odds of aTRH compared to those in the median quintile (odds ratio, 1.67; 95% CI, 1.19-2.36). These associations were independently validated., Conclusions and Relevance: In this genetic association study, Black individuals with HTN at a lower genetic risk of elevated BP experienced an approximately 3.5 mm Hg-greater response to chlorthalidone compared with those at an intermediate genetic risk of elevated BP. SBP PRS may also identify individuals with HTN harboring a higher risk of treatment-resistant HTN. Overall, SBP PRS demonstrates potential to identify those who may have greater benefit from chlorthalidone, but future research is needed to determine if PRS can inform initiation and choice of treatment among individuals with HTN.

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression., (© 2024. The Author(s).)

The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) is a hybrid of the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, and its association with renal outcomes remains unclear. In the REasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort, diet data were collected at baseline using food frequency questionnaires. Modified Poisson regression was used to examine the association of MIND diet with incident chronic kidney disease (CKD). In the REGARDS stroke case-cohort, 357 metabolites were measured in baseline plasma. Weighted linear regression was used to test associations between MIND diet and metabolites. Weighted logistic regression was used to test associations between MIND-associated metabolites and incident CKD. Mediation analyses were conducted to determine whether metabolites mediated the relationship between MIND diet and CKD. A higher MIND diet score was associated with a decreased risk of incident CKD (risk ratio 0.90, 95% CI (0.86-0.94); p = 2.03 × 10 -7 ). Fifty-seven metabolites were associated with MIND diet ( p < 3 × 10 -4 ). Guanosine was found to mediate the relationship between MIND diet and incident CKD (odds ratio for indirect effects 0.93, 95% CI (0.88-0.97); p < 0.05). These findings suggest a role of the MIND diet in renal outcomes.

Type 2 diabetes (T2D) is caused by both genetic and environmental factors and is associated with an increased risk of cardiorenal complications and mortality. Though disproportionately affected by the condition, African Americans (AA) are largely underrepresented in genetic studies of T2D, and few estimates of heritability have been calculated in this race group. Using genome-wide association study (GWAS) data paired with phenotypic data from ~ 19,300 AA participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, Genetics of Hypertension Associated Treatments (GenHAT) study, and the Electronic Medical Records and Genomics (eMERGE) network, we estimated narrow-sense heritability using two methods: Linkage-Disequilibrium Adjusted Kinships (LDAK) and Genome-Wide Complex Trait Analysis (GCTA). Study-level heritability estimates adjusting for age, sex, and genetic ancestry ranged from 18% to 34% across both methods. Overall, the current study narrows the expected range for T2D heritability in this race group compared to prior estimates, while providing new insight into the genetic basis of T2D in AAs for ongoing genetic discovery efforts., (© 2024. The Author(s).)

Objective: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D)., Research Design and Methods: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD., Results: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16)., Conclusions: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D., (© 2024 by the American Diabetes Association.)

African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Here, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an AA-focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method. We further tested the score in three independent studies with a total of 7,275 AAs and compared the PRSAA with other published scores. Results show that a 1-SD increase in the PRSAA was associated with 40-60% increase in the odds of T2D (odds ratio [OR] 1.60, 95% CI 1.37-1.88; OR 1.40, 95% CI 1.16-1.70; and OR 1.45, 95% CI 1.30-1.62) across three testing cohorts. These models captured 1.0-2.6% of the variance (R2) in T2D on the liability scale. The positive predictive values for three calculated score thresholds (the top 2%, 5%, and 10%) ranged from 14 to 35%. The PRSAA, in general, performed similarly to existing T2D PRS. The need remains for larger data sets to continue to evaluate the utility of within-ancestry scores in the AA population., (© 2024 by the American Diabetes Association.)

Background: Sex disparities exist in cardiometabolic diseases. Metabolomic profiling offers insight into disease mechanisms, as the metabolome is influenced by environmental and genetic factors. We identified metabolites associated with sex and determined if sex-associated metabolites are associated with incident stoke, incident coronary heart disease, prevalent hypertension, and prevalent chronic kidney disease., Methods and Results: Targeted metabolomics was conducted for 357 metabolites in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) case-cohort substudy for incident stroke. Weighted logistic regression models were used to identify metabolites associated with sex in REGARDS. Sex-associated metabolites were replicated in the HyperGEN (Hypertension Genetic Epidemiology Network) and using the literature. Weighted Cox proportional hazard models were used to evaluate associations between metabolites and incident stroke. Cox proportional hazard models were used to evaluate associations between metabolites and incident coronary heart disease. Weighted logistic regression models were used to evaluate associations between metabolites and hypertension and chronic kidney disease. Fifty-one replicated metabolites were associated with sex. Higher levels of 6 phosphatidylethanolamines were associated with incident stroke. No metabolites were associated with incident coronary heart disease. Higher levels of uric acid and leucine and lower levels of a lysophosphatidylcholine were associated with hypertension. Higher levels of indole-3-lactic acid, 7 phosphatidylethanolamines, and uric acid, and lower levels of betaine and bilirubin were associated with chronic kidney disease., Conclusions: These findings suggest that the sexual dimorphism of the metabolome may contribute to sex differences in stroke, hypertension, and chronic kidney disease.

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., Competing Interests: BP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson and Johnson. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Armstrong, Srinivasasainagendra, Ammous, Assimes, Beitelshees, Brody, Cade, Ida Chen, Chen, de Vries, Floyd, Franceschini, Guo, Hellwege, House, Hwu, Kardia, Lange, Lange, McDonough, Montasser, O’Connell, Shuey, Sun, Tanner, Wang, Zhao, Carson, Edwards, Kelly, Kenny, Kooperberg, Loos, Morrison, Motsinger-Reif, Psaty, Rao, Redline, Rich, Rotter, Smith, Smith, Irvin and Arnett.)

Protease-activated receptor 4 (PAR4) (gene F2RL3) harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively) and is associated with greater platelet aggregation. The A allele frequency is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than White individuals. However, it is not known whether the A allele is responsible for worse stroke outcomes. To directly test the in vivo effect of this variant on stroke, we generated mice in which F2rl3 was replaced by F2RL3, thereby expressing human PAR4 (hPAR4) with either Thr120 or Ala120. Compared with hPAR4 Ala120 mice, hPAR4 Thr120 mice had worse stroke outcomes, mediated in part by enhanced platelet activation and platelet-neutrophil interactions. Analyses of 7,620 Black subjects with 487 incident ischemic strokes demonstrated the AA genotype was a risk for incident ischemic stroke and worse functional outcomes. In humanized mice, ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice, but not in hPAR4 Thr120 mice. P selectin blockade improved stroke outcomes and reduced platelet-neutrophil interactions in hPAR4 Thr120 mice. Our results may explain some of the racial disparity in stroke and support the need for studies of nonstandard antiplatelet therapies for patients expressing PAR4 Thr120.

Background: Albuminuria is associated with metabolic abnormalities, but these relationships are not well understood. We studied the association of metabolites with albuminuria in Hispanic/Latino people, a population with high risk for metabolic disease., Methods: We used data from 3736 participants from the Hispanic Community Health Study/Study of Latinos, of which 16% had diabetes and 9% had an increased urine albumin-to-creatinine ratio (UACR). Metabolites were quantified in fasting serum through nontargeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Spot UACR was inverse normally transformed and tested for the association with each metabolite or combined, correlated metabolites, in covariate-adjusted models that accounted for the study design. In total, 132 metabolites were available for replication in the Hypertension Genetic Epidemiology Network study ( n =300), and 29 metabolites were available for replication in the Malmö Offspring Study ( n =999)., Results: Among 640 named metabolites, we identified 148 metabolites significantly associated with UACR, including 18 novel associations that replicated in independent samples. These metabolites showed enrichment for D-glutamine and D-glutamate metabolism and arginine biosynthesis, pathways previously reported for diabetes and insulin resistance. In correlated metabolite analyses, we identified two modules significantly associated with UACR, including a module composed of lipid metabolites related to the biosynthesis of unsaturated fatty acids and alpha linolenic acid and linoleic acid metabolism., Conclusions: Our study identified associations of albuminuria with metabolites involved in glucose dysregulation, and essential fatty acids and precursors of arachidonic acid in Hispanic/Latino population., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;02&#95;08&#95;CJN09070822.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries., (© 2022. The Author(s).)

Background: Some but not all African-Americans (AA) who carry APOL1 nephropathy risk variants ( APOL1 ) develop kidney failure (end-stage kidney disease, ESKD). To identify genetic modifiers, we assessed gene-gene interactions in a large prospective cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study., Methods: Genotypes from 8,074 AA participants were obtained from Illumina Infinium Multi-Ethnic AMR/AFR Extended BeadChip. We compared 388 incident ESKD cases with 7,686 non-ESKD controls, using a two-locus interaction approach. Logistic regression was used to examine the effect of APOL1 risk status (using recessive and additive models), single nucleotide polymorphism (SNP), and APOL 1 * SNP interaction on incident ESKD, adjusting for age, sex, and ancestry. APOL1 * SNP interactions that met the threshold of 1.0 × 10 -5 were replicated in the Genetics of Hypertension Associated Treatment (GenHAT) study (626 ESKD cases and 6,165 controls). In a sensitivity analysis, models were additionally adjusted for diabetes status. We conducted additional replication in the BioVU study., Results: Two APOL1 risk alleles prevalence (recessive model) was similar in the REGARDS and GenHAT studies. Only one APOL1 -SNP interaction, for rs7067944 on chromosome 10, ~10 KB from the PCAT5 gene met the genome-wide statistical threshold ( P interaction = 3.4 × 10 -8 ), but this interaction was not replicated in the GenHAT study. Among other relevant top findings (with P interaction < 1.0 × 10 -5 ), a variant ( rs2181251 ) near SMOC2 on chromosome six interacted with APOL1 risk status (additive) on ESKD outcomes (REGARDS study, P interaction =5.3 × 10 -6 ) but the association was not replicated (GenHAT study, P interaction = 0.07, BioVU study, P interaction = 0.53). The association with the locus near SMOC2 persisted further in stratified analyses. Among those who inherited ≥1 alternate allele of rs2181251, APOL1 was associated with an increased risk of incident ESKD (OR [95%CI] = 2.27[1.53, 3.37]) but APOL1 was not associated with ESKD in the absence of the alternate allele (OR [95%CI] = 1.34[0.96, 1.85]) in the REGARDS study. The associations were consistent after adjusting for diabetes., Conclusion: In a large genome-wide association study of AAs, a locus SMOC2 exhibited a significant interaction with the APOL1 locus. SMOC2 contributes to the progression of fibrosis after kidney injury and the interaction with APOL1 variants may contribute to an explanation for why only some APOLI high-risk individuals develop ESKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaudhary, Armstrong, Hidalgo, Gutiérrez, Hellwege, Limdi, Reynolds, Judd, Nadkarni, Lange, Winkler, Kopp, Arnett, Tiwari and Irvin.)

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure., Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants., Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P <5×10 -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P <1×10 -6 and P <1×10 -4 , respectively)., Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

Hypertension is a leading risk factor for cardiovascular disease mortality. African Americans (AAs) have the highest prevalence of hypertension in the United States, and to alleviate the burden of hypertension in this population, better control of blood pressure (BP) is needed. Previous studies have shown considerable interpersonal differences in BP response to antihypertensive treatment, suggesting a genetic component. Utilizing data from 4297 AA participants randomized to chlorthalidone from the Genetics of Hypertension Associated Treatments (GenHAT) study, we aimed to identify variants associated with the efficacy of chlorthalidone. An additional aim was to find variants that contributed to changes in fasting glucose (FG) in these individuals. We performed genome-wide association analyses on the change of systolic and diastolic BP (SBP and DBP) over six months and FG levels over 24 months of treatment. We sought replication in the International Consortia of Pharmacogenomics Studies. We identified eight variants statistically associated with BP response and nine variants associated with FG response. One suggestive LINC02211-CDH9 intergenic variant was marginally replicated with the same direction of effect. Given the impact of hypertension in AAs, this study implies that understanding the genetic background for BP control and glucose changes during chlorthalidone treatment may help prevent adverse cardiovascular events in this population.

Background: Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations., Methods: We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts., Results: The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance., Conclusions: By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare., (© 2022. The Author(s).)

Background Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 [Q568P] and rs75770792 [T555I]) have been previously reported to have a modest association with blood pressure (BP) and hypertension. Methods and Results We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self-identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable-adjusted regression modeling. Multivariable-adjusted genotype-stratified differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and BNP (B-type natriuretic peptide) levels were assessed. Genotype-stratified NPPA and NPPB expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (β±SE, 0.42±0.58; -1.24±0.82), diastolic BP (0.51±0.33; -0.41±0.46), mean arterial pressure (0.48±0.38; -0.68±0.51), and prevalent hypertension (odds ratio [OR], 0.93 [95% CI, 0.80-1.09]; OR, 0.79 [95% CI, 0.61-1.01]) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; -1.26±0.81), diastolic BP (0.52±0.33; -0.33±0.45), mean arterial pressure (0.50±0.38; -0.63±0.50), and prevalent hypertension (OR, 1.02 [95% CI, 0.84-1.23]; OR, 0.87 [95% CI, 0.67-1.13]) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 [95% CI, 0.94-1.93]; OR, 0.95 [95% CI, 0.64-1.39]) in the study cohorts. The NT-proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the NPPA and NPPB expression was similar between the genotype groups. Conclusions Corin gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.

Telomere length (TL) is widely studied as a possible biomarker for stress-related cellular aging and decreased longevity. There have been conflicting findings about the relationship between family caregiving stress and TL. Several initial cross-sectional studies have found associations between longer duration of caregiving or perceived stressfulness of caregiving and shortened TL, suggesting that caregiving poses grave risks to health. Previous reviews have suggested the need for longitudinal methods to investigate this topic. This study examined the association between the transition to family caregiving and change in TL across ~9 years. Data was utilized from the Caregiving Transitions Study, an ancillary study to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. TL was assayed using qPCR and analyzed as the telomere-to-single copy gene ratio for each participant at baseline and follow-up. General linear models examined the association between caregiving status and the change in TL for 208 incident caregivers and 205 controls, as well as associations between perceived stress and TL among caregivers. No association was found between TL change and caregiving (p = 0.494), and fully adjusted models controlling for health and socioeconomic factors did not change the null relationship (p = 0.305). Among caregivers, no association was found between perceived caregiving stress and change in TL (p = 0.336). In contrast to earlier cross-sectional studies, this longitudinal, population-based study did not detect a significant relationship between the transition into a family caregiving role and changes in TL over time. Given the widespread citation of previous findings suggesting that caregiving shortens telomeres and places caregivers at risk of early mortality, these results demonstrate the potential need of a more balanced narrative about caregiving., Competing Interests: The authors have declared that no competing interests exist.

Importance: A genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis., Objective: To estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals., Design, Setting, and Participants: Retrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020., Exposures: TTR Val122Ile (rs76992529) genotype., Main Outcome and Measures: The primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors., Results: Among 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes., Conclusions and Relevance: Among a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.

Aims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA 1c , that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA 1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study., Methods: We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA 1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci., Results: Four novel associations were identified (p < 5 × 10 -9 ), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis., Conclusions/interpretation: Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations., Data Availability: Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics )., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant ( p < 5.00E-08) and 90 additional suggestive ( p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 ( LINC01443-LOC644669 ). Additional variants of interest were located in or near the COL12A1, SNTG1 , PCDH7 , TMTC1 , and NTM genes . Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p -value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Armstrong, Srinivasasainagendra, Patki, Tanner, Hidalgo, Tiwari, Limdi, Lange, Lange, Arnett and Irvin.)

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10 -8 /132 = 4 × 10 -10 ), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/ FADS1 and FADS2 ) on chromosome 11 had p < 8.0 × 10 -7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10 -3 . CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG ( p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Objective: To determine the association of serum urate (SU) levels with sudden cardiac death and incident coronary heart disease (CHD), separately, among adults without a history of CHD., Methods: We conducted a case-cohort analysis of Black and White participants aged ≥ 45 years enrolled in the REason for Geographic And Racial Differences in Stroke (REGARDS) study without a history of CHD at baseline between 2003 and 2007. Participants were followed for sudden cardiac death or incident CHD (i.e., myocardial infarction [MI] or death from CHD excluding sudden cardiac death) through December 31, 2013. Baseline SU was measured in a random sample of participants (n = 840) and among participants who experienced sudden cardiac death (n = 235) or incident CHD (n = 851) during follow-up., Results: Participants with higher SU levels were older and more likely to be male or Black. The crude HR (95% CI) per 1 mg/dL higher SU level was 1.26 (1.14-1.40) for sudden cardiac death and 1.17 (1.09-1.26) for incident CHD. After adjustment for age, sex, race, and cardiovascular risk factors, the HR (95% CI) per 1 mg/dL higher SU level was 1.19 (1.03-1.37) for sudden cardiac death and 1.05 (0.96-1.15) for incident CHD. HRs for sudden cardiac death were numerically higher among participants aged 45-64 vs ≥ 65 years, without vs with diabetes, and among those of White vs Black race, although P values for effect modification were all ≥ 0.05., Conclusion: Higher SU levels were associated with an increased risk for sudden cardiac death but not with incident CHD., (Copyright © 2021 by the Journal of Rheumatology.)

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10 -8 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10 -4 , Beta = 3.09, diastolic BP response P = 5 × 10 -3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients' subgroup (P = 2.35 × 10 -4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)