Publications by authors named "Robert C Kaplan"

268 Publications

T-cell immune dysregulation and mortality in women with HIV.

J Infect Dis 2021 Aug 27. Epub 2021 Aug 27.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Dysregulation of adaptive immunity is a hallmark of HIV infection that persists on antiretroviral therapy (ART). Few long-term prospective studies have related adaptive immunity impairments to mortality in HIV, particularly in women.

Methods: Among 606 women with HIV in the Women's Interagency HIV Study, peripheral blood mononuclear cells collected from 2002-2005 underwent multiparameter flow cytometry. Underlying cause of death was ascertained from the National Death Index up to 2018. We examined associations of CD4+ and CD8+ T-cell activation (%CD38+HLADR+), senescence (%CD57+CD28-), exhaustion (%PD-1+), and non-activation/normal function (%CD57-CD28+) with natural-cause, HIV-related, and non-HIV-related mortality.

Results: At baseline, median participant age was 41, and 67% were on ART. Among 100 deaths during median 13.3 years follow-up, 90 were natural-cause (53 non-HIV-related, 37 HIV-related). Higher activation and exhaustion of CD4+ T-cells were associated with risk of natural-cause and non-HIV-related mortality, adjusting for age, demographic, behavioral, HIV-related, and cardiometabolic factors at baseline. Additional adjustment for time-varying viral load and CD4+ T-cell count did not attenuate these associations. CD8+ T-cell markers were not associated with any outcomes adjusting for baseline factors.

Conclusions: Persistent CD4+ T-cell activation and exhaustion may contribute to excess long-term mortality risk in women with HIV, independent of HIV disease progression.
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http://dx.doi.org/10.1093/infdis/jiab433DOI Listing
August 2021

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.

Genome Med 2021 Aug 26;13(1):136. Epub 2021 Aug 26.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.

Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
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http://dx.doi.org/10.1186/s13073-021-00917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394596PMC
August 2021

Associations between dietary fatty acid patterns and cognitive function in the Hispanic Community Health Study/Study of Latinos.

Br J Nutr 2021 Aug 26:1-35. Epub 2021 Aug 26.

Department of Agriculture Nutrition and Food Systems, University of New Hampshire.

Our objective was to quantify the cross-sectional associations between dietary fatty acid (DFA) patterns and cognitive function among Hispanic/Latino adults. This study included data from 8,942 participants of the Hispanic Community Health Study/Study of Latinos, a population-based cohort study (weighted age 56.2 y and proportion female 55.2%). The NCI (National Cancer Institute) method was used to estimate dietary intake from two 24-hr recalls. We derived DFA patterns using principal components analysis with 26 fatty acid and total plant and animal monounsaturated fatty acid (MUFA) input variables. Global cognitive function was calculated as the average z-score of 4 neurocognitive tests. Survey linear regression models included multiple potential confounders such as age, sex, education, depressive symptoms, physical activity, energy intake, and cardiovascular disease. DFA patterns were characterized by consumption of long-chain saturated fatty acids (SFA), animal-based MUFA, and trans fatty acids (Factor 1); short to medium-chain SFA (Factor 2); very-long-chain omega-3 polyunsaturated fatty acids (PUFA) (Factor 3); very-long-chain SFA and plant-based MUFA and PUFA (Factor 4). Factor 2 was associated with greater scores for global cognitive function (β=0.037 ± 0.012) and the Digit Symbol Substitution (DSS) (β=0.56±0.17), Brief Spanish English Verbal Learning-Sum (B-SEVLT) (β=0.23 ± 0.11), and B-SEVLT-Recall (β=0.11 ± 0.05) tests (P<0.05 for all). Factors 1 (β=0.04 ± 0.01) and 4 (β=0.70 ± 0.18) were associated with the DSS test (P<0.05 for all). Consumption of short to medium-chain SFA may be associated with higher cognitive function among U.S.-residing Hispanic/Latino adults. Prospective studies are necessary to confirm these findings.
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http://dx.doi.org/10.1017/S0007114521003275DOI Listing
August 2021

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

Commun Biol 2021 07 28;4(1):918. Epub 2021 Jul 28.

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.
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http://dx.doi.org/10.1038/s42003-021-02431-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319323PMC
July 2021

Menopause is associated with immune activation in women with HIV.

J Infect Dis 2021 Jun 26. Epub 2021 Jun 26.

Division of HIV, Infectious Diseases, and Global Medicine, University of California San Francisco, San Francisco, CA, USA.

Background: Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown.

Methods: In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1), were measured at 674 person-visits spanning ≤2 years.

Results: Menopause (post- vs. pre-menopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (B [95% CI]=161.89ng/mL [18.37, 305.41] and 65.48 ng/mL [6.64, 124.33], respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI: 16.63, 484.79; p=0.04), but not in the pre-menopausal or post-menopausal periods.

Conclusions: In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during the menopausal transition warrants further investigation.
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http://dx.doi.org/10.1093/infdis/jiab341DOI Listing
June 2021

Brief Report: Subclinical Carotid Artery Atherosclerosis Is Associated With Increased Expression of Peripheral Blood IL-32 Isoforms Among Women Living With HIV.

J Acquir Immune Defic Syndr 2021 10;88(2):186-191

CHUM-Research Centre, Montréal, Quebec, Canada.

Background: Persistent inflammation in HIV infection is associated with elevated cardiovascular disease (CVD) risk, even with viral suppression. Identification of novel surrogate biomarkers can enhance CVD risk stratification and suggest novel therapies. We investigated the potential of interleukin 32 (IL-32), a proinflammatory multi-isoform cytokine, as a biomarker for subclinical carotid artery atherosclerosis in virologically suppressed women living with HIV (WLWH).

Methods And Results: Nested within the Women's Interagency HIV Study, we conducted a cross-sectional comparison of IL-32 between 399 WLWH and 100 women without HIV, followed by a case-control study of 72 WLWH (36 carotid artery plaque cases vs. 36 age-matched controls without plaque). Plasma IL-32 protein was measured by ELISA, and mRNA of IL-32 isoforms (IL-32α, β, γ, D, ε, and θ) was quantified by reverse transcription polymerase chain reaction from peripheral blood mononuclear cells. Plasma IL-32 protein levels were higher in WLWH compared with women without HIV (P = 0.02). Among WLWH, although plasma IL-32 levels did not differ significantly between plaque cases and controls, expression of IL-32 isoforms α, β, and ε mRNA was significantly higher in peripheral blood mononuclear cells from cases (P = 0.01, P = 0.005, and P = 0.018, respectively). Upregulation of IL-32β and IL-32ε among WLWH with carotid artery plaque persisted after adjustment for age, race/ethnicity, smoking, systolic blood pressure, body mass index, and history of hepatitis C virus (P = 0.04 and P = 0.045); the adjusted association for IL-32α was marginally significant (P = 0.07).

Conclusions: IL-32 isoforms should be studied further as potential CVD biomarkers. This is of particular interest in WLWH by virtue of altered IL-32 levels in this population.
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http://dx.doi.org/10.1097/QAI.0000000000002746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434945PMC
October 2021

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

Gut 2021 Jun 14. Epub 2021 Jun 14.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objective: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.

Method: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.

Results: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using . We identified a novel association between a host functional variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut , a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut and serum indolepropionate only among genetically lactase non-persistent individuals.

Conclusion: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.
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http://dx.doi.org/10.1136/gutjnl-2021-324053DOI Listing
June 2021

Sleep apnea, coronary artery calcium density and cardiovascular events: results from the Multi-Ethnic Study of Atherosclerosis (MESA).

J Clin Sleep Med 2021 May 14. Epub 2021 May 14.

Icahn School of Medicine at Mount Sinai, New York, NY.

Study Objectives: Evaluate the association between obstructive sleep apnea (OSA), coronary artery calcium (CAC) density, and cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods: We analyzed 1041 participants with non-zero CAC scores who had polysomnography and CAC density data from the fifth examination of MESA. OSA was defined as apnea-hypopnea index [AHI] ≥ 15 events/hour. Multivariable linear regression models were used to evaluate the independent association between OSA and CAC density. Additionally, we evaluated the impact of OSA on associations of CAC measures with incident CVD events by testing for interaction in Cox proportional hazard regression models.

Results: Our analytical sample was 45% female with a mean age of 70.6 +/- 9 years. Of this sample, 36.7% (n=383/1041) had OSA (AHI≥15). OSA was inversely and weakly associated with CAC density (β= -0.09, 95% CI -0.17 to -0.02, p=0.014) and remained significantly associated after controlling for traditional cardiovascular risk factors (β= -0.08, 95% CI -0.16 to 0, p=0.043). However, this inverse association was attenuated after controlling for BMI (β=-0.05, 95% CI -0.13 to 0.02, p=0.174). The mean follow-up period for CVD events was 13.3 +/- 2.8 years. Additionally, exploratory analysis demonstrated that CAC density was independently and inversely associated with CVD events only in the non-OSA subgroup (AHI≤15) (HR 0.509 [CI 0.323 - 0.801], p=0.0035).

Conclusions: OSA was associated with lower CAC density, but this association was attenuated by BMI. Further, increased CAC density was associated with a reduced risk of CVD events only in individuals within the non-OSA group in exploratory analysis.
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http://dx.doi.org/10.5664/jcsm.9356DOI Listing
May 2021

Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis.

Front Immunol 2021 15;12:664371. Epub 2021 Apr 15.

University of Montreal Hospital Centre (CRCHUM)-Research Centre, Montréal, QC, Canada.

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; and species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH.
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http://dx.doi.org/10.3389/fimmu.2021.664371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083984PMC
April 2021

HIV, hepatitis C virus and risk of new-onset left ventricular dysfunction in women.

AIDS 2021 08;35(10):1647-1655

Cardiology Section, San Francisco VA Healthcare System and Department of Medicine, University of California San Francisco, San Francisco, CA.

Background: HIV and HCV have each been linked with cardiac dysfunction. Studies of HIV have often lacked appropriate controls and primarily involved men, whereas data for HCV are sparse.

Methods: We performed repeat echocardiography over a median interval of 12 years in participants from the Women's Interagency HIV Study in order to evaluate the relationships of HIV and HCV with incident left ventricular (LV) dysfunction (systolic or diastolic).

Results: Of the 311 women included (age 39 ± 9), 70% were HIV-positive and 20% HCV-positive. Forty three participants (13.8%) developed LV dysfunction, of which 79.1% was diastolic. Compared with participants with neither infection, the group with HIV--HCV coinfection showed a significantly increased risk of incident LV dysfunction after adjustment for risk factors [RR = 2.96 (95% CI = 1.05-8.31)], but associations for the HCV monoinfected and HIV monoinfected groups were not statistically significant [RR = 2.54 (0.83-7.73) and RR = 1.66 (0.65-4.25), respectively]. Comparison of HCV-positive and HCV-negative women showed a significantly increased risk independent of covariates [RR = 1.96 (1.02-3.77)] but this was not the case for HIV-positive vs. HIV-negative women [RR = 1.43 (0.76-2.69)]. There was no evidence of HCV-by-HIV interaction. A more restrictive definition of LV diastolic dysfunction led to fewer incident cases, but a similar, though nonsignificant, risk estimate for HCV.

Conclusion: Among mostly middle-aged women, HCV but not HIV infection was associated with a pronounced risk of incident LV dysfunction. Although the influence of residual confounding cannot be excluded, these findings bolster the potential benefits that could be realized by adopting recent recommendations for expanding HCV screening and treatment.
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http://dx.doi.org/10.1097/QAD.0000000000002920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286303PMC
August 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Dietary factors, gut microbiota, and serum trimethylamine-N-oxide associated with cardiovascular disease in the Hispanic Community Health Study/Study of Latinos.

Am J Clin Nutr 2021 06;113(6):1503-1514

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Trimethylamine-N-oxide (TMAO), a diet-derived and gut microbiota-related metabolite, is associated with cardiovascular disease (CVD). However, major dietary determinants and specific gut bacterial taxa related to TMAO remain to be identified in humans.

Objectives: We aimed to identify dietary and gut microbial factors associated with circulating TMAO.

Methods: This cross-sectional study included 3972 participants (57.3% women) aged 18-74 y from the Hispanic Community Health Study/Study of Latinos in the United States. Dietary information was collected by 24-h dietary recalls at baseline interview (2008-2011), and baseline serum TMAO and its precursors were measured by an untargeted approach. Gut microbiome was profiled by shotgun metagenomic sequencing in a subset of participants (n = 626) during a follow-up visit (2016-2018). Logistic and linear regression were used to examine associations of inverse-normalized metabolites with prevalent CVD, dietary intake, and bacterial species, respectively, after adjustment for sociodemographic, behavioral, and clinical factors.

Results: TMAO was positively associated with prevalent CVD (case number = 279; OR = 1.34; 95% CI: 1.17, 1.54, per 1-SD). Fish (P = 1.26 × 10-17), red meat (P = 3.33 × 10-16), and egg (P = 3.89 × 10-5) intakes were top dietary factors positively associated with TMAO. We identified 9 gut bacterial species significantly associated with TMAO (false discovery rate <0.05). All 4 species positively associated with TMAO belong to the order Clostridiales, of which 3 might have homologous genes encoding carnitine monooxygenase, an enzyme converting carnitine to trimethylamine (TMA). The red meat-TMAO association was more pronounced in participants with higher abundances of these 4 species compared with those with lower abundance (Pinteraction = 0.013), but such microbial modification was not observed for fish-TMAO or egg-TMAO associations.

Conclusion: In US Hispanics/Latinos, fish, red meat, and egg intakes are major dietary factors associated with serum TMAO. The identified potential TMA-producing gut microbiota and microbial modification on the red meat-TMAO association support microbial TMA production from dietary carnitine, whereas the fish-TMAO association is independent of gut microbiota.
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http://dx.doi.org/10.1093/ajcn/nqab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168354PMC
June 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Menopausal status and observed differences in the gut microbiome in women with and without HIV infection.

Menopause 2021 01 11;28(5):491-501. Epub 2021 Jan 11.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.

Objective: Gut microbiota respond to host physiological phenomena, yet little is known regarding shifts in the gut microbiome due to menopausal hormonal and metabolic changes in women. HIV infection impacts menopause and may also cause gut dysbiosis. We therefore sought to determine the association between menopausal status and gut microbiome composition in women with and without HIV.

Methods: Gut microbiome composition was assessed in stool from 432 women (99 premenopausal HIV+, 71 premenopausal HIV-, 182 postmenopausal HIV+, 80 postmenopausal HIV-) via 16S rRNA gene sequencing. We examined cross-sectional associations of menopause with gut microbiota overall diversity and composition, and taxon and inferred metagenomic pathway abundance. Models were stratified by HIV serostatus and adjusted for age, HIV-related variables, and other potential confounders.

Results: Menopause, ie post- versus premenopausal status, was associated with overall microbial composition only in women with HIV (permutational MANOVA of Jensen Shannon Divergence: P = 0.01). In women with HIV, menopause was associated with enrichment of gram-negative order Enterobacteriales, depletion of highly abundant taxa within Prevotella copri, and alterations in other low-abundance taxa. Additionally, menopause in women with HIV was associated with enrichment of metagenomic pathways related to Enterobacteriales, including degradation of amino acids and phenolic compounds, biosynthesis of enterobactin, and energy metabolism pathways. Menopause-related differences in some low-abundance taxa were also observed in women without HIV.

Conclusions: A changing gut microbiome may be an overlooked phenomenon of reproductive aging in women with HIV. Longitudinal assessments across all reproductive stages are necessary to confirm these findings and identify health implications.
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http://dx.doi.org/10.1097/GME.0000000000001730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068580PMC
January 2021

Plasma Lipidomic Profiles and Risk of Diabetes: 2 Prospective Cohorts of HIV-Infected and HIV-Uninfected Individuals.

J Clin Endocrinol Metab 2021 03;106(4):999-1010

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Objectives: Antiretroviral therapy (ART) use is associated with disrupted lipid and glucose metabolism in people with HIV infection. We aimed to identify plasma lipid species associated with risk of diabetes in the context of HIV infection.

Research Design And Methods: We profiled 211 plasma lipid species in 491 HIV-infected and 203 HIV-uninfected participants aged 35 to 55 years from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Cox proportional hazards model was used to examine associations between baseline lipid species and incident diabetes (166 diabetes cases were identified during a median follow-up of 12.6 years).

Results: We identified 11 lipid species, representing independent signals for 8 lipid classes/subclasses, associated with risk of diabetes (P < 0.05 after FDR correction). After adjustment for multiple covariates, cholesteryl ester (CE) (22:4), lysophosphatidylcholine (LPC) (18:2), phosphatidylcholine (PC) (36:4), phosphatidylcholine plasmalogen (34:3), and phosphatidylethanolamine (PE) (38:2) were associated with decreased risk of diabetes (HRs = 0.70 to 0.82 per SD increment), while diacylglycerol (32:0), LPC (14:0), PC (38:3), PE (36:1), and triacylglycerol (50:1) were associated with increased risk of diabetes (HRs = 1.26 to 1.56 per SD increment). HIV serostatus did not modify any lipid-diabetes associations; however, most of these lipid species were positively associated with HIV and/or ART use, including 3 diabetes-decreased ( CE [22:4], LPC [18:2], PE [38:2]) and all 5 diabetes-increased lipid species.

Conclusions: This study identified multiple plasma lipid species associated with incident diabetes. Regardless of the directions of their associations with diabetes, most diabetes-associated lipid species were elevated in ART-treated people with HIV infection. This suggests a complex role of lipids in the link between ART and diabetes in HIV infection.
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http://dx.doi.org/10.1210/clinem/dgab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993589PMC
March 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nat Commun 2020 10 14;11(1):5182. Epub 2020 Oct 14.

The Institute for Translational Genomics and Population Sciences, The Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.
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http://dx.doi.org/10.1038/s41467-020-18334-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598941PMC
October 2020

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.

Am J Hum Genet 2020 11 7;107(5):849-863. Epub 2020 Oct 7.

Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA. Electronic address:

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEV = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675000PMC
November 2020

Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis.

Rheumatology (Oxford) 2021 04;60(4):1676-1686

Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Objectives: How insulin-like growth factor-1 (IGF-1) is related to OA is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian randomization (MR) to determine causality.

Methods: Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using Hospital Episode Statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score as an instrument. Multivariable MR included BMI as an additional exposure (instrumented by BMI genetic risk score). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample MR (2SMR) using summary statistics from Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) (IGF-1, N = 30 884) and the recent genome-wide association study meta-analysis (N = 455 221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN).

Results: A total of 332 092 adults in UK Biobank had complete data. Their mean (s.d.) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand OA [odds ratio per doubling = 0.87 (95% CI 0.82, 0.93)], and an increased odds of hip OA [1.04 (1.01, 1.07)], but was unrelated to knee OA [0.99 (0.96, 1.01)]. Using 1SMR, we found strong evidence for an increased risk of hip [odds ratio per s.d. increase = 1.57 (1.21, 2.01)] and knee [1.30 (1.07, 1.58)] OA with increasing IGF-1 concentration. By contrast, we found no evidence for a causal effect of IGF-1 concentration on hand OA [0.98 (0.57, 1.70)]. Results were consistent when estimated using 2SMR and in multivariable MR analyses accounting for BMI.

Conclusion: We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.
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http://dx.doi.org/10.1093/rheumatology/keaa597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023994PMC
April 2021

Current Smoking Raises Risk of Incident Hypertension: Hispanic Community Health Study-Study of Latinos.

Am J Hypertens 2021 03;34(2):190-197

Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Hypertension has been implicated as a smoking-related risk factor for cardiovascular disease but the dose-response relationship is incompletely described. Hispanics, who often have relatively light smoking exposures, have been understudied in this regard.

Methods: We used data from a 6-year follow-up study of US Hispanic adults aged 18-76 to address the dose-response linking cigarette use with incident hypertension, which was defined by measured blood pressure above 140/90 mm Hg or initiation of antihypertensive medications. Adjustment was performed for potential confounders and mediators, including urinary albumin-to-creatinine ratio which worsened over time among smokers.

Results: Current smoking was associated with incident hypertension, with a threshold effect above 5 cumulative pack-years of smoking (vs. never smokers, hazard ratio for hypertension [95% confidence interval] of 0.95 [0.67, 1.35] for 0-5 pack-years, 1.47 [1.05, 2.06] for 5-10 pack-years, 1.40 [1.00, 1.96] for 10-20 pack-years, and 1.34 [1.09, 1.66] for ≥20 pack-years, P = 0.037). In contrast to current smokers, former smokers did not appear to have increased risk of hypertension, even at the highest cumulative pack-years of past exposure.

Conclusions: The results confirm that smoking constitutes a hypertension risk factor in Hispanic adults. A relatively modest cumulative dose of smoking, above 5 pack-years of exposure, raises risk of hypertension by over 30%. The increased hypertension risk was confined to current smokers, and did not increase further with higher pack-year levels. The lack of a smoking-hypertension association in former smokers underscores the value of smoking cessation.
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http://dx.doi.org/10.1093/ajh/hpaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951044PMC
March 2021

A longitudinal analysis of nondaily smokers: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Ann Epidemiol 2020 09 23;49:61-67. Epub 2020 Jun 23.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY. Electronic address:

Purpose: Nondaily smoking is increasing in the United States and common among Hispanic/Latino smokers. We characterized factors related to longitudinal smoking transitions in Hispanic/Latino nondaily smokers.

Methods: The Hispanic Community Health Study/Study of Latinos is a population-based cohort study of Hispanics/Latinos aged 18-74 years. Multinomial logistic regression assessed the baseline factors (2008-2011) associated with follow-up smoking status (2014-2017) in nondaily smokers (n = 573), accounting for complex survey design.

Results: After ∼6 years, 41% of nondaily smokers became former smokers, 22% became daily smokers, and 37% remained nondaily smokers. Factors related to follow-up smoking status were number of days smoked in the previous month, household smokers, education, income, and insurance. Those smoking 16 or more of the last 30 days had increased risk of becoming a daily smoker [vs. < 4 days; relative risk ratio (RRR) = 5.65, 95% confidence interval (95% CI) = 1.96-16.33]. Greater education was inversely associated with transitioning to daily smoking [>high school vs.
Conclusions: Many Hispanic/Latino nondaily smokers became daily smokers, which may increase their risk of adverse health outcomes. Addressing different smoking patterns in primary care may be useful to prevent smoking-related diseases.
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http://dx.doi.org/10.1016/j.annepidem.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506143PMC
September 2020

Are sedentary behavior and physical activity independently associated with cardiometabolic benefits? The Hispanic Community Health Study/Study of Latinos.

BMC Public Health 2020 Sep 14;20(1):1400. Epub 2020 Sep 14.

Department of Epidemiology & Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer Bldg, 1312C, Bronx, New York, 10461, USA.

Background: Whether physical activity can reduce cardiometabolic risk particularly in understudied populations such as US Hispanics/Latinos is of public health interest. We prospectively examined the association of physical activity and cardiometabolic biomarkers in n = 8049 participants of the Hispanic Community Health Study/Study of Latinos, a community-based cohort study of 16,415 adults aged 18-74 yr who self-identified as Hispanic/Latino from four US urban centers.

Methods: We assessed physical activity using accelerometry in 2008-2011 at visit 1. We assessed cardiometabolic biomarkers twice: once at visit 1 and collected a second measure in 2014-2017 at visit 2. We used survey linear regression models with changes in cardiometabolic markers as the dependent variables and quartiles of sedentary behavior or whether adults met guidelines for moderate-to-vigorous physical activity as the independent variables.

Results: In normoglycemic adults without cardiovascular disease, but not in adults with evidence of cardiometabolic disease, those who were in the lowest quartile for sedentary behavior (< 10.08 h/day) had a significant decline in mean LDL-cholesterol of - 3.94 mg/dL (95% CI: - 6.37, - 1.52) compared to adults in the highest quartile (≥13.0 h/day) who exhibited a significant increase in LDL-cholesterol of 0.14 mg/dL (95% CI, - 2.15,2.42) over the six year period (P < 0.02 in fully adjusted models.) There was also a trend toward lower mean increase in HbA1c comparing the lowest with the highest quartile of sedentary behavior. Overall regardless of glycemic level or evidence of cardiometabolic disease, adults who met guidelines for moderate-to-vigorous physical activity at visit 1, had significantly lower mean increases in level of fasting glucose compared to adults not meeting guidelines in fully adjusted models.

Conclusions: In this cohort of Hispanics/Latinos, being free of cardiometabolic disease and having low levels of sedentary behavior were associated with health benefits. Among all adults regardless of cardiometabolic disease, meeting guidelines for moderate-to-vigorous physical activity was associated with health benefits. Overall these data suggest that an active lifestyle may blunt the association of advancing age with worsening cardiometabolic risk factors.
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http://dx.doi.org/10.1186/s12889-020-09497-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490882PMC
September 2020

Accelerometer-assessed physical activity and incident diabetes in a population covering the adult life span: the Hispanic Community Health Study/Study of Latinos.

Am J Clin Nutr 2020 11;112(5):1318-1327

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: The association between accelerometer-assessed physical activity and risk of diabetes remains unclear, especially among US Hispanic/Latino adults who have lower levels of physical activity and a higher diabetes burden compared with other racial/ethnical populations in the country.

Objectives: To examine the association between accelerometer-assessed physical activity and incident diabetes in a US Hispanic/Latino population.

Methods: We included 7280 participants of the Hispanic Community Health Study/Study of Latinos who aged 18-74 y and free of diabetes at baseline. Data on moderate-to-vigorous physical activity (MVPA) were collected using a 7-d accelerometer measurement. Incident diabetes was assessed after a mean ± SD of 6.0 ± 0.8 y using standard procedures including blood tests. RRs and 95% CIs of diabetes associated with MVPA were estimated using survey Poisson regressions. The associations of MVPA with 6-y changes in adiposity measures were also examined.

Results: A total of 871 incident cases of diabetes were identified. MVPA was inversely and nonlinearly associated with risk of diabetes (P-nonlinearity = 0.006), with benefits accruing rapidly at the lower end of MVPA range (<30 min/d) and leveling off thereafter. The association differed by population age (P-interaction = 0.006). Higher MVPA was associated with lower risk of diabetes among individuals older than 50 y (RRQ4 versus Q1 = 0.50; 95% CI: 0.35, 0.73; P-trend < 0.001) but not among younger individuals (RRQ4 versus Q1 = 0.98; 95% CI: 0.66, 1.47; P-trend = 0.92). An inverse association between MVPA and 6-y gain in waist circumference was also limited to the older group (P-interaction with age < 0.001).

Conclusions: Among US Hispanic/Latino adults, baseline accelerometer-derived MVPA was inversely associated with incident diabetes only among individuals aged 50 y and older. Further studies are needed to confirm our findings and to clarify potential mechanisms underlying the possible age differences in the MVPA-diabetes association. This study was registered at clinicaltrials.gov as NCT02060344.
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http://dx.doi.org/10.1093/ajcn/nqaa232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657343PMC
November 2020

Underuse of Cardiovascular Medications in Individuals With Known Lower Extremity Peripheral Artery Disease: HCHS/SOL.

J Am Heart Assoc 2020 08 5;9(16):e015451. Epub 2020 Aug 5.

Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx NY.

Background Underuse of cardiovascular medications for secondary prevention among individuals with peripheral artery disease (PAD) has been reported. Little is known about PAD treatment status in the Hispanic/Latino population in the United States, who may have limited access to health care and who have worse clinical outcomes than non-Hispanic individuals. Methods and Results We studied the use of cardiovascular therapies in 1244 Hispanic/Latino individuals recruited from 4 sites in the United States, including 826 individuals who reported diagnosis of PAD by physician and 418 individuals with coronary artery disease alone, in the Hispanic Community Health Study/Study of Latinos. We compared the prevalence of using antiplatelet therapy, lipid-lowering therapy and antihypertensive therapy by PAD and coronary artery disease status. Among those with PAD, we studied factors associated with taking cardiovascular medications, including demographic and socioeconomic factors, acculturation, access to health care and comorbidities, using multivariable regression models. The overall prevalence for individuals with PAD taking antiplatelet therapy, lipid-lowering therapy and, among hypertensive individuals, antihypertensive therapy was 31%, 26% and 57%, respectively. Individuals of Mexican background had the lowest use for all classes of cardiovascular medications. Older age, number of doctor visits and existing hypertension and diabetes mellitus were significantly associated with taking cardiovascular therapies in adjusted models. Compared with those with PAD alone, individuals with PAD and concurrent coronary artery disease were 1.52 (95% CI, 1.20-1.93) and 1.74 (1.30-2.32) times more likely to use antiplatelet agents and statins according to multivariable analysis. No significant difference of antihypertensive medication use was found among PAD patients with or without coronary artery disease. Conclusions Hispanic/Latino individuals with known PAD underuse cardiovascular medications recommended in clinical guidelines. More efforts should be directed to improve treatment in this important group.
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http://dx.doi.org/10.1161/JAHA.119.015451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660818PMC
August 2020

Classical monocyte transcriptomes reveal significant anti-inflammatory statin effect in women with chronic HIV.

Cardiovasc Res 2021 03;117(4):1166-1177

Laboratory of Inflammation Biology, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.

Aims: During virally suppressed chronic HIV infection, persistent inflammation contributes to the development of cardiovascular disease (CVD), a major comorbidity in people living with HIV (LWH). Classical blood monocytes (CMs) remain activated during antiretroviral therapy and are a major source of pro-inflammatory and pro-thrombotic factors that contribute to atherosclerotic plaque development and instability.

Methods And Results: Here, we identify transcriptomic changes in circulating CMs in peripheral blood mononuclear cell samples from participants of the Women's Interagency HIV Study, selected by HIV and subclinical CVD (sCVD) status. We flow-sorted CM from participants of the Women's Interagency HIV Study and deep-sequenced their mRNA (n = 92). CMs of HIV+ participants showed elevated interleukin (IL)-6, IL-1β, and IL-12β, overlapping with many transcripts identified in sCVD+ participants. In sCVD+ participants LWH, those reporting statin use showed reduced pro-inflammatory gene expression to a level comparable with healthy (HIV-sCVD-) participants. Statin non-users maintained an elevated inflammatory profile and increased cytokine production.

Conclusion: Statin therapy has been associated with a lower risk of cardiac events, such as myocardial infarction in the general population, but not in those LWH. Our data suggest that women LWH may benefit from statin therapy even in the absence of overt CVD.
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http://dx.doi.org/10.1093/cvr/cvaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983000PMC
March 2021

Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.

Circ Genom Precis Med 2020 08 30;13(4):e002680. Epub 2020 Jun 30.

Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill.

Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.

Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test.

Results: We identified 6 novels (, and ) and 87 known loci (adaptive sum of powered score test <5×10). Lead single-nucleotide polymorphism rs3211938 at was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci.

Conclusions: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
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http://dx.doi.org/10.1161/CIRCGEN.119.002680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520945PMC
August 2020

Depression and Psychosocial Stress Are Associated With Subclinical Carotid Atherosclerosis Among Women Living With HIV.

J Am Heart Assoc 2020 07 22;9(13):e016425. Epub 2020 Jun 22.

Department of Medicine Georgetown University Medical Center Washington DC.

Background To identify reasons for increased atherosclerotic risk among women living with HIV (WLWH), we evaluated the associations between psychosocial risk factors (depressive symptoms, perceived stress, and posttraumatic stress disorder symptoms) and subclinical atherosclerosis among WLWH and HIV-negative women. Methods and Results Carotid artery focal plaque (localized intima-media thickness >1.5 mm) was measured using B-mode ultrasound imaging in 2004-2005 and 2010-2012 in the Women's Interagency HIV Study. We created psychosocial risk groups using latent class analysis and defined prevalent plaque at the final measurement. We also examined repeated semiannual depression measures with respect to focal plaque formation throughout follow-up. The associations between latent class and prevalent plaque, and between depressive symptom persistence and plaque formation, were assessed separately by HIV status using multivariable logistic regression. Among 700 women (median age 47 years), 2 latent classes were identified: high (n=163) and low (n=537) psychosocial risk, with corresponding prevalence of depression (65%/13%), high stress (96%/12%), and probable posttraumatic stress disorder (46%/2%). Among WLWH, plaque prevalence was 23% and 11% in high versus low psychosocial risk classes (adjusted odds ratio [aOR], 2.12; 95% CI, 1.11-4.05) compared with 9% and 9% among HIV-negative women (aOR, 1.07; 95% CI, 0.24-4.84), respectively. New plaque formation occurred among 17% and 9% of WLWH who reported high depressive symptoms at ≥45% versus <45% of visits (aOR, 1.96; 95% CI, 1.06-3.64), compared with 9% and 7% among HIV-negative women (aOR, 0.82; 95% CI, 0.16-4.16), respectively. Conclusions Psychosocial factors were independent atherosclerotic risk factors among WLWH. Research is needed to determine whether interventions for depression and psychosocial stress can mitigate the increased risk of atherosclerosis for WLWH.
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http://dx.doi.org/10.1161/JAHA.120.016425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670495PMC
July 2020

Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Am J Clin Nutr 2020 07;112(1):57-65

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

Objectives: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

Methods: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

Results: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031).

Conclusions: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.
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http://dx.doi.org/10.1093/ajcn/nqaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326587PMC
July 2020
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