Publications by Year: 2023

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and is associated with significant morbidity, mortality, and financial burden. Obstructive sleep apnea (OSA) is more common in individuals with AF and may impair the efficacy of rhythm control strategies including catheter ablation. However, the prevalence of undiagnosed OSA in all-comers with AF is unknown.

DESIGN: This pragmatic, phase IV prospective cohort study will test 250-300 consecutive ambulatory AF patients with all patterns of atrial fibrillation (paroxysmal, persistent, and long-term persistent) and no prior sleep testing for OSA using the WatchPAT system, a disposable home sleep test (HST). The primary outcome of the study is the prevalence of undiagnosed OSA in all-comers with atrial fibrillation.

RESULTS: Preliminary results from the initial pilot enrollment of approximately 15% (N = 38) of the planned sample size demonstrate a 79.0% prevalence of at least mild (AHI≥5) OSA or greater in consecutively enrolled patient with all patterns of AF.

CONCLUSIONS: We report the design, methodology, and preliminary results of our study to define the prevalence of OSA in AF patients. This study will help inform approaches to OSA screening in patients with AF for which there is currently little practical guidance.

CLINICAL TRIAL REGISTRATION: NCT05155813.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

The landmark, multicenter HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is the largest, most comprehensive, longitudinal community-based cohort study to date of diverse Hispanic/Latino persons in the United States. The HCHS/SOL aimed to address the dearth of comprehensive data on risk factors for cardiovascular disease (CVD) and other chronic diseases in this population and has expanded considerably in scope since its inception. This paper describes the aims/objectives and data collection of the HCHS/SOL and its ancillary studies to date and highlights the critical and sizable contributions made by the study to understanding the prevalence of and changes in CVD risk/protective factors and the burden of CVD and related chronic conditions among adults of diverse Hispanic/Latino backgrounds. The continued follow-up of this cohort will allow in-depth investigations on cardiovascular and pulmonary outcomes in this population, and data from the ongoing ancillary studies will facilitate generation of new hypotheses and study questions.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.

STUDY OBJECTIVES: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥ 3%) but not arousal (apnea-hypopnea index [AHI]≥3%Only) vs events with arousals but no desaturation (AHIArOnly) with obstructive sleep apnea-related comorbidities and incident cardiovascular disease across multiple cohorts.

METHODS: In the Sleep Heart Health Study (n = 5,473), the Multi-Ethnic Study of Atherosclerosis (n = 1,904), and the Osteoporotic Fractures in Men Study (n = 2,685), we examined the independent associations of AHI≥3%Only and AHIArOnly with hypertension, diabetes, and daytime sleepiness, and incident cardiovascular disease.

RESULTS: After adjusting for covariates and AHI based on events with electroencephalogram arousal (regardless of desaturation), AHI≥3%Only was associated with hypertension in Sleep Heart Health Study (odds ratio: 1.12; 95% confidence interval: 1.04,1.21), per 1 standard deviation increase). Similar associations were observed in the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study, as well as for associations with diabetes (odds ratio: 1.30; 1.09,1.54, and 1.25; 1.07,1.47, respectively), sleepiness (odds ratio: 1.19; 1.00,1.41; and 1.17; 1.01-1.35), and incident cardiovascular disease (hazard ratio: 1.37; 1.05,1.77 and 1.14; 1.00,1.29). In contrast, after adjusting for events with desaturation (regardless of arousal), AHIArOnly was unassociated with these outcomes. In Sleep Heart Health Study, greater baseline obstructive sleep apnea severity was associated with a reduction in arousal frequency over 5 years (P < .0001).

CONCLUSIONS: In middle-aged and older individuals, addition of events with arousals does not improve the strength of associations with comorbidities or incident cardiovascular disease. Research is needed to understand generalizability to younger individuals and the mechanistic role of arousals in obstructive sleep apnea.

CITATION: Azarbarzin A, Sands SA, Han S, et al. Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis. J Clin Sleep Med. 2023;19(8):1475-1484.

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)-the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value <5 × 10-8) variants associated with MCI-MRS or BAIBA. Variants associated with the MCI-MRS are located in the Alanine-Glyoxylate Aminotransferase 2 (AGXT2 gene), which is known to be associated with BAIBA metabolism. Variants associated with BAIBA are located in the AGXT2 gene and in the SLC6A13 gene. Next, we tested the variants' association with MCI in independent datasets of n = 3178 HCHS/SOL older individuals, n = 3775 European Americans, and n = 1032 African Americans from the Atherosclerosis Risk In Communities (ARIC) study. Variants were considered associated with MCI if their p value <0.05 in the meta-analysis of the three datasets and their direction of association was consistent with expectation. Rs16899972 and rs37369 from the AGXT2 region were associated with MCI. Mediation analysis supported the mediation effect of BAIBA between the two genetic variants and MCI (p value = 0.004 for causal mediated effect). In summary, genetic variants in the AGXT2 region are associated with MCI in Hispanic/Latino, African, and European American populations in the USA, and their effect is likely mediated by changes in BAIBA levels.

IMPORTANCE: Lipoprotein(a) (Lp[a]) is a genetically determined risk-enhancing factor for atherosclerotic cardiovascular disease (ASCVD). The Lp(a) distribution among the diverse Hispanic or Latino community residing in the US has not been previously described, to the authors' knowledge.

OBJECTIVE: To determine the distribution of Lp(a) levels across a large cohort of diverse Hispanic or Latino adults living in the US and by key demographic groups.

DESIGN, SETTING, AND PARTICIPANTS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective, population-based, cohort study of diverse Hispanic or Latino adults living in the US. At screening, participants aged 18 to 74 years were recruited between 2008 and 2011 from 4 US metropolitan areas (Bronx, New York; Chicago, Illinois; Miami, Florida; San Diego, California). HCHS/SOL included 16 415 noninstitutionalized adults recruited through probability sampling of randomly selected households. The study population represents Hispanic or Latino participants from diverse self-identified geographic and cultural backgrounds: Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American. This study evaluated a subset of HCHS/SOL participants who underwent Lp(a) measurement. Sampling weights and surveys methods were used to account for HCHS/SOL sampling design. Data for this study were analyzed from April 2021 to April 2023.

EXPOSURE: Lp(a) molar concentration was measured by a particle-enhanced turbidimetric assay with minimized sensitivity to apolipoprotein(a) size variation.

MAIN OUTCOME AND MEASURE: Lp(a) quintiles were compared using analysis of variance among key demographic groups, including self-identified Hispanic or Latino background. Median percentage genetic ancestry (Amerindian, European, West African) were compared across Lp(a) quintiles.

RESULTS: Lp(a) molar concentration was measured in 16 117 participants (mean [SD] age, 41 [14.8] years; 9680 female [52%]; 1704 Central American [7.7%], 2313 Cuban [21.1%], 1436 Dominican [10.3%], 6395 Mexican [39.1%], 2652 Puerto Rican [16.6%], 1051 South American [5.1%]). Median (IQR) Lp(a) level was 19.7 (7.4-59.7) nmol/L. Across Hispanic or Latino background groups, there was significant heterogeneity in median Lp(a) levels ranging from 12 to 41 nmol/L in those reporting a Mexican vs Dominican background. Median (IQR) West African genetic ancestry was lowest in the first quintile of Lp(a) level and highest in the fifth quintile (5.5% [3.4%-12.9%] and 12.1% [5.0%-32.5%]; respectively; P < .001), whereas the converse was seen for Amerindian ancestry (32.8% [9.9%-53.2%] and 10.7% [4.9%-30.7%], respectively; P < .001).

CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that differences in Lp(a) level distribution across the diverse US Hispanic or Latino population may carry important implications for the use of Lp(a) level in ASCVD risk assessment for this group. Cardiovascular outcomes data are needed to better understand the clinical impact of differences in Lp(a) levels by Hispanic or Latino background.

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.

METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.

RESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10-3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10-5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.

CONCLUSIONS/INTERPRETATION: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation.

DATA AVAILABILITY: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal ( https://hugeamp.org ) and the GWAS Catalog ( www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899).

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.