Diabetes Genetic Clusters and Clinical Outcomes in American Indians.

Unlabelled: Diabetes has a large medical and public health impact in American Indians. Studies have used genetic data to distinguish type 1 diabetes (T1D) and type 2 diabetes (T2D) and uncover biologic mechanisms underlying T2D clinical heterogeneity. We applied a T1D polygenic score (PS) to 3,084 American Indians (mean age 56 years, 58% women, 39% diabetes).

Dietary Inflammatory Potential and the Risk of Incident Kidney Failure in the Women's Health Initiative.

Key Points: A pro-inflammatory diet was associated with a higher risk of incident kidney failure. Clinical trials should assess the impact of an anti-inflammatory dietary pattern on CKD risk and progression.

Background: Diet affects inflammation and kidney health, but few studies have investigated dietary inflammatory potential in CKD progression, particularly in women.

Methylation profile of individuals with sickle cell trait.

Sickle cell trait (SCT) is due to heterozygosity for the β-globin sickle cell mutation. SCT recently has been associated with increased risk of various adverse health outcomes. DNA methylation (DNAm) is one potential mechanism by which SCT may impact disease risk.

Protein quantitative trait locus analysis in African American and non-Hispanic White individuals.

Background: Substantial efforts have been dedicated to exploring the link between genetic regulation and the proteome, informing studies of complex trait mechanisms. Most of these efforts have been limited to populations of European ancestry.

Results: We conduct an Olink protein quantitative trait locus (pQTL) analysis on 1245 proteins involving 1033 self-identified African American (AA) and 1764 non-Hispanic White (NHW) participants from the Women's Health Initiative and Framingham Heart Study.

Kidney function is associated with plasma ATN biomarkers among Hispanics/Latinos: SOL-INCA and HCHS/SOL results.

Background: Plasma amyloid-tau-neurodegeneration (ATN) biomarker levels may be influenced by non-brain systems, such as kidney function, which could impact the interpretation of ATN biomarker results, particularly in groups like Hispanic/Latino individuals with higher rates of cardiometabolic health issues. Here, we examine the association between kidney function and plasma ATN markers among a diverse sample of Hispanic/Latino individuals living in the U.S.

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.

Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids.

Old vs. new local ancestry inference in HCHS/SOL: a comparative study.

Hispanic/Latino populations are admixed, with genetic contributions from multiple ancestral populations. To uncover genetic associations in these populations, researchers often turn to admixture mapping, which relies on inferred counts of "local" ancestry, i.e.

Kidney function and cognitive aging and impairment among diverse Hispanic/Latino individuals: Study of Latinos-Investigation of Neurocognitive Aging (HCHS/SOL).

Introduction: The purpose of this study is to examine associations between kidney disease and cognitive impairment among diverse middle-aged and older Hispanic/Latino individuals.

Methods: Between 2016 and 2018, the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) enrolled diverse Hispanic/Latino individuals ages 50 years and older (n = 6377). Cognitive function, cognitive change, and mild cognitive impairment (MCI) were the primary outcomes.

Environmental exposure assessment in the international prospective study of Chronic Kidney Disease of UnceRtain Etiology (CKDu) in Agricultural Communities (CURE) research consortium: Design and protocol development.

Background: Chronic kidney disease of unknown etiology (CKDu) is a major health concern among outdoor manual workers in rural Central America and South Asia. The CURE study is a prospective longitudinal cohort designed to investigate CKDu's environmental risk factors through standardized exposure assessments, questionnaires, and biological and environmental sample collection.

Methods: This manuscript details the development of a standardized exposure assessment protocol within the CKDu CURE Consortium.

Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness.

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS for cIMT involving up to 131,000 individuals.

Improving polygenic risk prediction of renal function by removing biomarker-specific effects.

Biomarkers are frequently used in clinical practice; however, it is essential to consider the genetics that may independently impact their baseline levels in-turn impacting interpretation of results. For example, estimated glomerular filtration rate (eGFR) equations are based on two biomarkers, cystatin C and creatinine, and widely employed in clinical practice. In this work we demonstrate how genetics of the underlying biomarkers impact measurement variability and may explain some of the discrepancies among eGFR equations.

A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes.

Polygenic Scores of Cardiometabolic Risk Factors in American Indian Adults.

Importance: Numerous efforts have been made to include diverse populations in genetic studies, but American Indian populations are still severely underrepresented. Polygenic scores derived from genetic data have been proposed in clinical care, but how polygenic scores perform in American Indian individuals and whether they can predict disease risk in this population remains unknown.

Objective: To study the performance of polygenic scores for cardiometabolic risk factors of lipid traits and C-reactive protein in American Indian adults and to determine whether such scores are helpful in clinical prediction for cardiometabolic diseases.

Genetics of cardiovascular outcomes in individuals with chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study.

Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis.

A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations.

Background: Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance of considering psychosocial factors in gene discovery for blood pressure (BP) but was limited in statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association study (GWAS) of BP accounting for gene-depressive symptomatology (DEPR) interactions in a larger and more diverse sample.

Association of Kidney Function With Incident Heart Failure: An Analysis of the Women's Health Initiative.

Background: Studies have shown an association of chronic kidney disease with heart failure (HF); however, this association has not been adequately examined in postmenopausal women, who are at heightened risk of both chronic kidney disease and HF. Additionally, association with HF subtypes is not well characterized.

Methods And Results: Incident HF was defined as first hospitalization for acute decompensated HF, obtained by self-reported outcomes followed by physician adjudication through review of hospital records.

Old vs. New Local Ancestry Inference in HCHS/SOL: A Comparative Study.

Hispanic/Latino populations are admixed, with genetic contributions from multiple ancestral populations. Studies of genetic association in these admixed populations often use methods such as admixture mapping, which relies on inferred counts of "local" ancestry, i.e.

Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

Background: Genome-wide association studies have identified several hundred susceptibility single nucleotide variants for coronary artery disease (CAD). Despite single nucleotide variant-based genome-wide association studies improving our understanding of the genetics of CAD, the contribution of structural variants (SVs) to the risk of CAD remains largely unclear.

Method And Results: We leveraged SVs detected from high-coverage whole genome sequencing data in a diverse group of participants from the National Heart Lung and Blood Institute's Trans-Omics for Precision Medicine program.

A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data.

Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variants.

Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci.

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup.