👤 Tamar Sofer

Sleep traits, including sleep apnoea (SA), insomnia, daytime sleepiness, and snoring, frequently co-occur with cardiometabolic diseases (CMDs), with shared genetic factors suspected to underlie these associations. However, the contribution of shared genetic determinants to these associations is not fully understood. We conducted a genome-wide pleiotropic association study applying sequential genetic methods to identify shared genetic variants, genes, pathways and causal associations between the four sleep traits and seven CMDs, including LDSC, high-definition likelihood analysis, colocalisation, gene-based tests, enrichment analysis and Mendelian randomisation. Next, validation of those pleiotropic variants was performed in individuals from the All of Us and MVP studies. Among 28 pairs of sleep traits and CMDs, 25 showed significant genetic correlations. Pleiotropic analysis identified 754 independent SNPs (691 unique) and 102 colocalized loci (85 unique). Among these, 47 SNPs (44 unique) were validated as significantly associated with both traits in the pairs, and notably, rs429358 (19q13.32, APOE) demonstrated pleiotropic effects across SA, insomnia and type 2 diabetes (T2D). Forty-eight annotated genes were validated by gene-based tests. Shared genes were enriched in phenotypes related to mortality and growth. Pathway analysis highlighted Cushing syndrome, hormone secretion, and cGMP-PKG, Ras and calcium signalling pathways. After adjusting for glycaemic traits and blood pressure, genetically predicted T2D increased risk of SA, sleepiness, and snoring. Conversely, SA was positively associated with heart failure and T2D independently. This study of sleep traits and CMDs reveals shared genetic determinants that may partially explain their epidemiologic association and suggests potential treatment targets. Described in Acknowledgements. Show less

Apolipoprotein E (APOE) alleles are well-established genetic risk factors for Alzheimer's disease (AD), but their effects on AD biomarkers (amyloid beta [Aβ]42/40, phosphorylated tau [p-tau]181, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) may vary across populations due to ancestry-, age-, and sex-related differences. We hypothesized that these effects vary across Hispanic/Latino background groups with distinct ancestral admixture. We analyzed ε2 and ε4 allele associations with AD biomarkers using survey-weighted linear regression models, adjusting for demographic covariates. Secondary analyses examined genetic analysis group- and ancestry-specific effects. ε4 was associated with lower Aβ42/40 and higher p-tau181and GFAP levels, but not with NfL, suggesting its role in Aβ and tau deposition and neuroinflammation. ε4 associations were stronger in those with higher European and lower African ancestry. These findings expand on prior studies suggesting that genetic ancestry modifies APOE-associated AD risk in Hispanic/Latino populations and highlight the importance of capturing ancestry-based heterogeneity in AD biomarker research. Show less

Apolipoprotein B (apoB) distribution and its implications as an atherosclerotic cardiovascular disease (ASCVD) risk-enhancing factor among individuals of diverse Hispanic or Latino backgrounds have not been described. To describe the distribution of apoB in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort and to characterize associations of baseline sociodemographic and clinical variables with apoB and self-identified Hispanic or Latino background. The HCHS/SOL was a prospective, population-based cohort study of diverse Hispanic or Latino adults living in the US who were recruited and screened between March 2008 and June 2011. Sampling weights were used to generate a population-based sample of Hispanic or Latino participants aged 18 to 74 years who resided in 4 US metropolitan areas (Bronx, New York; Chicago, Illinois; Miami, Florida; and San Diego, California). ApoB concentration was measured in participants from the HCHS/SOL, and apoB tertiles were compared across demographic groups, including self-identified Hispanic or Latino background. Median percentage continental genetic ancestry (West African, Amerindian, and European) was compared across apoB tertiles. ApoB measured in mg/dL from serum or plasma using an immunoturbidimetric assay. ApoB tertiles were determined, and traditional lipids were evaluated across apoB tertiles. ApoB and traditional lipid measurements were assessed across ASCVD risk categories. Additionally, scatterplots were created to observe correlations between apoB and low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. Overall mean (SD) apoB concentration was 99.8 (0.4) mg/dL, with male participants displaying significantly higher mean levels than female participants (102.4 vs 97.4 mg/dL, respectively). Mean (SD) participant age was 41.1 (0.8) years, and 8376 participants (51.9%) were female. ApoB levels were higher among older age groups. There was significant heterogeneity in mean apoB concentrations across self-identified Hispanic or Latino background groups, ranging from 95.1 mg/dL in Dominican individuals to 104.8 mg/dL in Cuban individuals. The prevalence of elevated apoB (≥130 mg/dL) was greater across higher predicted ASCVD risk categories. Among participants with a 10-year predicted ASCVD risk of 7.5% or higher, 26.5% had an elevated apoB. Median West African ancestry was lower across higher tertiles of apoB. In this cohort study among participants from the HCHS/SOL, elevated apoB was present in one-quarter of a diverse cohort study of Hispanic or Latino individuals who were at intermediate or high predicted ASCVD risk. Differences in apoB distribution among Hispanic or Latino individuals may have important implications for apoB's use in ASCVD risk assessment. Show less

Lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease. An Lp(a) threshold of ≥125 nmol/L is commonly used to identify individuals at higher risk for events, but there is a paucity of data on individuals of Hispanic/Latino descent. The purpose of this study was to provide a comprehensive evaluation of Lp(a) and its association with 10-year cardiovascular disease risk and mortality among Hispanic/Latino adults in the United States. We evaluated the association between Lp(a) and myocardial infarction (MI), ischemic stroke, and all-cause mortality among 16,117 Hispanic Community Health Study/Study of Latinos individuals. Event rates were compared across Lp(a) quintiles. Multivariable Cox proportional hazards models assessed the relationship between events and Lp(a) across increasing quintiles, log-transformed Lp(a), and ≥125 nmol/L vs <125 nmol/L. Sampling weights and survey methods were used to account for the stratified probability sampling of the cohort. Among the Hispanic Community Health Study/Study of Latinos target population (median age 41.1 years, 52.4% women), the median Lp(a) was 19.7 nmol/L (Q1-Q3: 7.3-60.6 nmol/L), with 11.4% having Lp(a) ≥125 nmol/L, and the highest Lp(a) quintile defined as >77 nmol/L. Over a median follow-up of 9.8 years, 883 events (135 MI, 99 stroke, 649 all-cause mortality) occurred. The age-adjusted incidence rate of the composite events (MI, stroke, and all-cause mortality) was 505.2 per 100,000 person-years. After multivariable adjustment, each 1-SD increase in log-transformed Lp(a) was associated with a higher risk of MI (HR: 1.47; 95% CI: 1.14-1.89). Compared with Lp(a) <125 nmol/L, elevated Lp(a) ≥125 nmol/L conferred an increased risk of MI (HR: 2.29; 95% CI: 1.45-3.63), all-cause mortality (HR: 1.43; 95% CI: 1.05-1.93), and composite events (HR: 1.56; 95% CI: 1.22-2.01), but not stroke. Findings were consistent when comparing the highest Lp(a) quintile to the lower 4 quintiles, but the elevated risk was observed only for MI and composite events. Hispanic/Latino individuals with elevated Lp(a) are at an increased risk of MI and all-cause mortality. Although Lp(a) ≥125 nmol/L is a valid risk threshold, Hispanics/Latinos show a continuous relationship between increasing Lp(a) levels and MI risk. Show less

Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk. We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data. By leveraging local ancestry, this study identified significant ancestry-enriched associations for 78 circulating metabolites at 484 independent regions, including 116 novel metabolite-genomic region associations that replicated in an independent sample. Among the main findings, we identified Native American enriched genomic regions at chromosomes 11 and 15, mapping to FADS1/FADS2 and LIPC, respectively, associated with reduced long-chain polyunsaturated fatty acid metabolites implicated in metabolic and inflammatory pathways. An African-derived genomic region at chromosome 2 was associated with N-acetylated amino acid metabolites. This region, mapped to ALMS1, is associated with chronic kidney disease, a disease that disproportionately burdens individuals of African descent. Our findings provide important insights into differences in metabolite quantities related to ancestry in admixed populations including metabolites related to regulation of lipid polyunsaturated fatty acids and N-acetylated amino acids, which may have implications for common diseases in populations. Show less