Publications by authors named "Leslie A Lange"

Aims/hypothesis: This is the first study to examine the association between variants of the glucagon-like-peptide-1 receptor gene (GLP-1R) and metabolic characteristics among youth. We explored separate associations of three GLP-1R polymorphisms (rs10305420, rs6923761, and rs1042044) with BMI trajectories and markers of glucose-insulin homeostasis.

Methods: Mixed models examined associations between GLP-1R polymorphisms and trajectories of BMI.

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  • Researchers studied plasma proteomic profiles linked to subclinical mutations in blood cells, particularly focusing on clonal hematopoiesis of indeterminate potential (CHIP) and its connection to various health outcomes, including coronary artery disease (CAD).
  • The study involved a large, diverse group of participants and identified a significant number of unique proteins associated with key driver genes, showing differences based on genetics, sex, and race.
  • Methods like Mendelian randomization and mouse model tests helped clarify the causal effects of these proteins, revealing shared plasma proteins between CHIP and CAD that could inform future clinical insights.
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  • A study explored how different biological factors (like proteins and metabolites) can help identify distinct groups of people with obesity who have varying risks for heart and metabolic diseases.
  • Using data from 243 participants, researchers found two groups: one (iCluster1) with favorable cholesterol levels and another (iCluster2) with higher BMI and inflammation levels.
  • The findings suggest these groups could reflect different stages of obesity-related issues, potentially influenced by factors like diet and behavior, despite similar ages across the groups.
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  • A study investigated how well a polygenic risk score (PRS) for systolic blood pressure (SBP) can predict patients' responses to antihypertensive treatment and the risk of treatment-resistant hypertension.
  • The research focused on participants from the GenHAT study, specifically Black individuals who were assigned to treatment groups involving chlorthalidone or lisinopril.
  • The main outcomes measured were changes in blood pressure after six months and the likelihood of being classified as treatment-resistant hypertension based on defined criteria.
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  • Genome-wide association studies have found numerous genetic loci linked to glycemic traits, but connecting these loci to specific genes and biological pathways remains a challenge.
  • Researchers conducted meta-analyses of exome-array studies across four glycemic traits, analyzing data from over 144,000 participants, which led to the identification of coding variant associations in more than 60 genes.
  • The study revealed significant pathways related to insulin secretion, zinc transport, and fatty acid metabolism, enhancing understanding of glycemic regulation and making data available for further research.
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  • Genetic studies have highlighted the need for more diverse research on plasma fibrinogen levels, as previous studies largely focused on Europeans, leading to gaps in understanding and missing heritability.
  • By analyzing data from whole-genome sequencing and genotype data from large cohorts, researchers identified 18 genetic loci related to fibrinogen levels, some of which are more common in African populations and include variants that may impact protein function.
  • The study's findings indicate a connection between fibrinogen levels and various health conditions, emphasizing the importance of whole-genome sequencing in discovering genetic factors in diverse populations and enhancing knowledge about fibrinogen regulation.
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  • Researchers investigated blood protein networks in chronic obstructive pulmonary disease (COPD) using data from over 3,000 participants to better understand complex interconnections rather than just individual biomarker changes.
  • They applied advanced techniques to analyze 4,776 proteins, identifying significant networks linked to factors like smoking status and emphysema.
  • The study found both known and new proteins associated with COPD, highlighting the importance of these networks in understanding the disease across different ethnic groups, with some results replicating in another study cohort.
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  • Chronic kidney disease (CKD) affects about 1 in 7 adults in the U.S., especially African Americans who are more likely to suffer from it.
  • Scientists discovered that certain changes in DNA can help predict who might get CKD, focusing on specific sites in the DNA.
  • The study created a special score using these DNA changes to see how likely someone is to have CKD and found it works well for African Americans, suggesting it could help in checking kidney health in the future.
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Key Points: The predictive performance of an African ancestry–specific polygenic risk score (PRS) was comparable to a European ancestry–derived PRS for kidney traits. However, multi-ancestry PRSs outperform single-ancestry PRSs in Black American populations. Predictive accuracy of PRSs for CKD was improved with the use of race-free eGFR.

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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).

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  • Coronary artery calcification (CAC) is linked to heart disease and assessed through a genome-wide association study (GWAS) involving 22,400 participants from various backgrounds.
  • The study confirmed connections with four known genetic loci and discovered two new loci related to CAC, with supportive replication findings for both.
  • Functional tests suggest that ARSE promotes calcification in vascular smooth muscle cells and its variants may influence CAC levels, identifying ARSE as a key target for potential treatments in vascular calcific diseases.
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  • The study aimed to find genetic risk factors for cardiovascular disease (CVD) in individuals with type 2 diabetes (T2D) through a genome-wide association approach.
  • Out of 49,230 T2D participants, 8,956 experienced incident CVD events, revealing three new genetic loci associated with increased CVD risk and confirming five known coronary artery disease variants.
  • The findings suggest both novel and established genetic factors contribute to CVD risk in T2D patients, highlighting the importance of genetic screening in this population.
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Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts.

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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.

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Background: Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features.

Methods: Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.

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  • Type 2 diabetes (T2D) is a complex disease influenced by various genetic factors and molecular mechanisms that vary by cell type and ancestry.
  • In a large study involving over 2.5 million individuals, researchers identified 1,289 significant genetic associations linked to T2D, including 145 new loci not previously reported.
  • The study categorized T2D signals into eight distinct clusters based on their connections to cardiometabolic traits and showed that these genetic profiles are linked to vascular complications, emphasizing the role of obesity-related processes across different ancestry groups.
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  • * Discovery of 7 new genetic loci associated with FVIII and 1 new locus for VWF, supporting their roles in thrombotic outcomes via Mendelian randomization.
  • * Functional testing revealed that silencing genes like B3GNT2 and CD36 impacted FVIII and VWF release from endothelial cells, indicating their potential regulatory roles.
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  • X-chromosomal genetic variants can provide important information about differences in human traits and diseases between sexes.
  • A large-scale study analyzed kidney-related traits in nearly 909,000 individuals, finding 23 genetic loci linked to uric acid levels and estimated glomerular filtration rate (eGFR), including four new genes that may play a role in kidney function.
  • The research also discovered five novel sex-specific interactions, with variations showing different effects in males and females, and highlighted genes that are responsive to androgens (male hormones), indicating a complex relationship between sex and kidney-related genetics.
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  • Chronic kidney disease significantly impacts global health, particularly among individuals of African ancestry and those in the Americas, who are often excluded from genetic studies.
  • A comprehensive meta-analysis involving over 145,000 individuals from these groups led to the discovery of 41 significant genetic loci associated with kidney function, two of which hadn't been previously identified across any ancestry group.
  • The study emphasizes the importance of diverse populations in genetic research for better understanding kidney disease and suggests that multi-ancestry polygenic scores can improve predictive capabilities and clinical applications.
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  • The study focuses on apparent treatment-resistant hypertension (aTRH), defined by the need for four or more antihypertensive medications to control blood pressure in individuals.
  • Researchers analyzed genetic data from 12 cohorts using whole-genome sequencing, comparing aTRH cases to normotensive controls and treatment-responsive patients.
  • A significant genetic variant linked to hypertension was identified, and further validation of these results in larger and more diverse populations is necessary to understand its potential role in aTRH.
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African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers.

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Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program.

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Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin's effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts.

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Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population.

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Objective: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

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