Publications by authors named "Dawn L DeMeo"

169 Publications

Significant spirometric transitions and Preserved Ratio Impaired Spirometry (PRISm) among ever-smokers.

Chest 2021 Sep 27. Epub 2021 Sep 27.

Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, MA, USA.

Background: Emerging data from longitudinal studies suggest that PRISm, defined by proportionate reductions in FEV and FVC, is a heterogeneous population with frequent transitions to other lung function categories relative to individuals with normal and obstructive spirometry. Controversy regarding the clinical significance of these transitions exists (e.g., whether transitions merely reflect measurement variability or "noise").

Research Question: Are individuals with PRISm enriched for transitions associated with substantial changes in lung function?

Study Design And Methods: Current and former smokers enrolled in COPDGene with spirometry available at Phases 1-3 (enrollment, 5-year, and 10-year follow-up) were analyzed. Post-bronchodilator lung function categories were: PRISm=FEV<80% predicted with FEV/FVC ratio≥0.7, GOLD0=FEV≥80% predicted and FEV/FVC ≥0.7, and obstruction=FEV/FVC<0.7. "Significant-transition" status was affirmative if a subject belonged to ≥2 spirometric categories and had >10% change in FEV% and/or FVC% predicted between consecutive visits. "Ever-PRISm" was present if a subject had PRISm at any visit. Logistic regression examined the association between "significant-transitions" and "ever-PRISm" status, adjusted for age, sex, race, FEV% predicted, current smoking, pack-years, BMI, and ever-positive bronchodilator response.

Results: Among subjects with complete data (n=1,775) over 10.1±0.4 years of follow-up, the prevalence of PRISm remained consistent (10.4%-11.3%) between P1-P3, but nearly half of subjects with PRISm transitioned into or out of PRISm at each visit. 19.7% of subjects had a "significant transition"; "ever-PRISm" was a significant predictor of "significant transitions" (OR=10.3, 95%CI=7.9-13.5, OR=14.9, 95%CI=10.9-20.7). Results were similar with additional adjustment for radiographic emphysema and gas trapping, when lower limit of normal criteria were used to define lung function categories, and when FEV alone (regardless of change in FVC%) was used to define "significant transitions" .

Interpretation: PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time.
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http://dx.doi.org/10.1016/j.chest.2021.09.021DOI Listing
September 2021

Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.

Am J Hum Genet 2021 Oct 27;108(10):1836-1851. Epub 2021 Sep 27.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.007DOI Listing
October 2021

Longitudinal change in blood DNA epigenetic signature after smoking cessation.

Epigenetics 2021 Oct 6:1-12. Epub 2021 Oct 6.

Pulmonary Center, Boston University School of Medicine, Boston, MA, USA.

Cigarette smoking is associated with epigenetic changes that may be reversible following smoking cessation. Whole blood DNA methylation was evaluated in Framingham Heart Study Offspring (n = 169) and Third Generation (n = 30) cohort participants at two study visits 6 years apart and in Atherosclerosis Risk in Communities (ARIC) study (n = 222) participants at two study visits 20 years apart. Changes in DNA methylation (delta β values) at 483,565 cytosine-phosphate-guanine (CpG) sites and differentially methylated regions (DMRs) were compared between participants who were current, former, or never smokers at both visits (current-current, former-former, never-never, respectively), versus those who quit in the interim (current-former). Interim quitters had more hypermethylation at four CpGs annotated to , one CpG annotated to , and one intergenic CpG (cg21566642) compared with current-current smokers (FDR < 0.02 for all), and two significant DMRs were identified. While there were no significant differentially methylated CpGs in the comparison of interim quitters and former-former smokers, 106 DMRs overlapping with small nucleolar RNA were identified. As compared with all non-smokers, current-current smokers additionally had more hypermethylation at two CpG sites annotated to and , respectively, and another intergenic CpG (cg14339116). Gene transcripts associated with smoking cessation were implicated in immune responses, cell homoeostasis, and apoptosis. Smoking cessation is associated with early reversion of blood DNA methylation changes at CpG sites annotated to and towards those of never smokers. Associated gene expression suggests a role of longitudinal smoking-related DNA methylation changes in immune response processes.
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http://dx.doi.org/10.1080/15592294.2021.1985301DOI Listing
October 2021

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease.

J Cachexia Sarcopenia Muscle 2021 Sep 15. Epub 2021 Sep 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.

Methods: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data.

Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.

Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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http://dx.doi.org/10.1002/jcsm.12782DOI Listing
September 2021

An effective processing pipeline for harmonizing DNA methylation data from Illumina's 450K and EPIC platforms for epidemiological studies.

BMC Res Notes 2021 Sep 8;14(1):352. Epub 2021 Sep 8.

Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Objective: Illumina BeadChip arrays are commonly used to generate DNA methylation data for large epidemiological studies. Updates in technology over time create challenges for data harmonization within and between studies, many of which obtained data from the older 450K and newer EPIC platforms. The pre-processing pipeline for DNA methylation is not trivial, and influences the downstream analyses. Incorporating different platforms adds a new level of technical variability that has not yet been taken into account by recommended pipelines. Our study evaluated the performance of various tools on different versions of platform data harmonization at each step of pre-processing pipeline, including quality control (QC), normalization, batch effect adjustment, and genomic inflation. We illustrate our novel approach using 450K and EPIC data from the Diabetes Autoimmunity Study in the Young (DAISY) prospective cohort.

Results: We found normalization and probe filtering had the biggest effect on data harmonization. Employing a meta-analysis was an effective and easily executable method for accounting for platform variability. Correcting for genomic inflation also helped with harmonization. We present guidelines for studies seeking to harmonize data from the 450K and EPIC platforms, which includes the use of technical replicates for evaluating numerous pre-processing steps, and employing a meta-analysis.
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http://dx.doi.org/10.1186/s13104-021-05741-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424820PMC
September 2021

Molecular markers of aging, exercise capacity, & physical activity in COPD.

Respir Med 2021 Aug 14;187:106576. Epub 2021 Aug 14.

Pulmonary, Allergy, And Critical Care Medicine Section, VA Boston Healthcare System, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Background: Exercise capacity (EC) and physical activity (PA) are independent, potentially modifiable predictors of clinical outcomes in COPD. Molecular measures of biological age may help characterize variability in EC and PA observed among COPD patients.

Methods: Veterans with COPD (FEV/FVC<0.7 or emphysema on chest computed tomography) enrolled in 2 cohorts at VA Boston completed questionnaires, a 6-min walk distance (6MWD) for EC, and blood collection at enrollment. PA data (average daily step count) was collected using an HJ-720 ITC pedometer over ≥5 days. A subset of subjects returned for repeat assessment after 12 weeks. DNA methylation data was generated using the HumanMethylationEPIC platform; epigenetic estimates of biological age and age acceleration were generated using established algorithms. Multivariable models examined the associations between biological age, 6MWD, PA and future acute exacerbations (AEs), adjusting for chronological age, sex, race, smoking status, pack-years, body mass index, cohort, and estimated cell counts.

Results: Subjects (n = 269) were predominantly male (98.5%), white (92.9%), and elderly (70.6 ± 8.5 years) with average FEV% of 57.7 ± 21.1, 6MWD of 374.3 ± 93.5 m, and daily steps of 3043.4 ± 2374 at baseline. In adjusted models, multiple measures of baseline epigenetic age and age acceleration were inversely associated with 6MWD; only GrimAge was inversely associated with PA. Longitudinal change in Hannum-Age was inversely associated with change in EC at 12 weeks (n = 94). No measures of biological age were significantly associated with prospective AEs over 1.3 ± 0.3 years.

Conclusions: Epigenetic measures of biological age are independent predictors of EC and PA, but not AEs, among individuals with COPD.
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http://dx.doi.org/10.1016/j.rmed.2021.106576DOI Listing
August 2021

Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors.

BMC Pulm Med 2021 Jul 14;21(1):235. Epub 2021 Jul 14.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied.

Methods: We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy.

Results: In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41-8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09-1.49), male sex (OR 3.60, CI 2.20-5.90), non-Hispanic white race (OR 3.33, CI 1.71-6.50), current smoking (OR 2.55, CI 1.49-4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38-8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05-0.35) and nocturnal (OR 0.46, CI 0.21-0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center.

Conclusions: In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.
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http://dx.doi.org/10.1186/s12890-021-01585-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278596PMC
July 2021

Genome-wide association analysis of COVID-19 mortality risk in SARS-CoV-2 genomes identifies mutation in the SARS-CoV-2 spike protein that colocalizes with P.1 of the Brazilian strain.

Genet Epidemiol 2021 10 22;45(7):685-693. Epub 2021 Jun 22.

Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome-wide association studies (GWAS), we looked at the association between whole-genome sequencing (WGS) data of the virus and COVID-19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single-stranded SARS-CoV-2 genomes of COVID-19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome-wide significance (p values of 4.09e-09 and 4.41e-23, respectively), though only 25,088 bp remained significant in follow-up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e-13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow-up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real-time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.
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http://dx.doi.org/10.1002/gepi.22421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426743PMC
October 2021

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD.

Respir Res 2021 Apr 27;22(1):127. Epub 2021 Apr 27.

Research and Development, GlaxoSmithKline, Collegeville, PA, USA.

Background: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.

Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).

Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log-transformed sRAGE was associated with 105 ± 22 mL lower FEV and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.

Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
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http://dx.doi.org/10.1186/s12931-021-01686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076883PMC
April 2021

Residential PM exposure and the nasal methylome in children.

Environ Int 2021 08 16;153:106505. Epub 2021 Apr 16.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Rationale: PMinduced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known.

Objectives: We aimed to study associations of fine particulate matter PM exposure with DNA methylation in nasal cells.

Methods: We conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina MethylationEPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA).

Results: In adjusted analyses, we found 362 CpGs associated with 1-year PM (FDR < 0.05), 20 CpGs passing Bonferroni correction (P < 7.0x10) and 10 Differentially Methylated Regions (DMRs). In 445 PIAMA participants (mean age 16.3 years) 11 of 203 available CpGs replicated at P < 0.05. We observed differential DNAm at/near genes implicated in cell cycle, immune and inflammatory responses. There were no CpGs or regions associated with PM levels at 1-day, 1-week, or 1-month prior to sample collection, although 2 CpGs were associated with past 3-month PM.

Conclusion: We observed wide-spread DNAm variability associated with average past year PM exposure but we did not detect associations with shorter-term exposure. Our results suggest that nasal DNAm marks reflect chronic air pollution exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106505DOI Listing
August 2021

Metabolomic Profiling Reveals Sex Specific Associations with Chronic Obstructive Pulmonary Disease and Emphysema.

Metabolites 2021 Mar 11;11(3). Epub 2021 Mar 11.

Division of Medicine, National Jewish Health, Denver, CO 80206, USA.

Susceptibility and progression of lung disease, as well as response to treatment, often differ by sex, yet the metabolic mechanisms driving these sex-specific differences are still poorly understood. Women with chronic obstructive pulmonary disease (COPD) have less emphysema and more small airway disease on average than men, though these differences become less pronounced with more severe airflow limitation. While small studies of targeted metabolites have identified compounds differing by sex and COPD status, the sex-specific effect of COPD on systemic metabolism has yet to be interrogated. Significant sex differences were observed in 9 of the 11 modules identified in COPDGene. Sex-specific associations by COPD status and emphysema were observed in 3 modules for each phenotype. Sex stratified individual metabolite associations with COPD demonstrated male-specific associations in sphingomyelins and female-specific associations in acyl carnitines and phosphatidylethanolamines. There was high preservation of module assignments in SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) and similar female-specific shift in acyl carnitines. Several COPD associated metabolites differed by sex. Acyl carnitines and sphingomyelins demonstrate sex-specific abundances and may represent important metabolic signatures of sex differences in COPD. Accurately characterizing the sex-specific molecular differences in COPD is vital for personalized diagnostics and therapeutics.
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http://dx.doi.org/10.3390/metabo11030161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999201PMC
March 2021

DNA methylation architecture of the ACE2 gene in nasal cells of children.

Sci Rep 2021 03 29;11(1):7107. Epub 2021 Mar 29.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity. The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean = 12.71%) and 3 sites greater DNAm (mean = 1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference = 3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference = 1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference = 7.86%) and females (mean absolute difference = 8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences. Findings need to be confirmed among adults and patients with risk factors for COVID-19 severity.
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http://dx.doi.org/10.1038/s41598-021-86494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007733PMC
March 2021

Sex and Gender Omic Biomarkers in Men and Women With COPD: Considerations for Precision Medicine.

Authors:
Dawn L DeMeo

Chest 2021 Jul 18;160(1):104-113. Epub 2021 Mar 18.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Sex and gender differences in lung health and disease are imperative to consider and study if precision pulmonary medicine is to be achieved. The development of reliable COPD biomarkers has been elusive, and the translation of biomarkers to clinical care has been limited. Useful and effective biomarkers must be developed with attention to clinical heterogeneity of COPD; inherent heterogeneity exists related to grouping women and men together in the studies of COPD. Considering sex and gender differences and influences related to -omics may represent progress in susceptibility, diagnostic, prognostic, and therapeutic biomarker development and clinical innovation to improve the lung health of men and women.
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http://dx.doi.org/10.1016/j.chest.2021.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295903PMC
July 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

DNA methylation perturbations may link altered development and aging in the lung.

Aging (Albany NY) 2021 01 19;13(2):1742-1764. Epub 2021 Jan 19.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Fetal perturbations in DNA methylation during lung development may reveal insights into the enduring impacts on adult lung health and disease during aging that have not been explored altogether before. We studied the association between genome-wide DNA-methylation and post-conception age in fetal-lung (n=78, 42 exposed to in-utero-smoke (IUS)) tissue and chronological age in adult-lung tissue (n=160, 114 with Chronic Obstructive Pulmonary Disease) using multi-variate linear regression models with covariate adjustment and tested for effect modification by phenotypes. Overlapping age-associations were evaluated for functional and tissue-specific enrichment using the Genotype-Tissue-Expression (GTEx) project. We identified 244 age-associated differentially methylated positions and 878 regions overlapping between fetal and adult-lung tissues. Hyper-methylated CpGs (96%) were enriched in transcription factor activity (FDR adjusted P=2x10) and implicated in developmental processes including embryonic organ morphogenesis, neurogenesis and growth delay. Hypo-methylated CpGs (2%) were enriched in oxido-reductase activity and VEGFA-VEGFR2 Signaling. Twenty-one age-by-sex and eleven age-by-pack-years interactions were statistically significant (FDR<0.05) in adult-lung tissue. DNA methylation in transcription factors during development in fetal lung recapitulates in adult-lung tissue with aging. These findings reveal molecular mechanisms and pathways that may link disrupted development in early-life and age-associated lung diseases.
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http://dx.doi.org/10.18632/aging.202544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880367PMC
January 2021

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Mol Psychiatry 2021 06 7;26(6):1832-1845. Epub 2021 Jan 7.

Erasmus MC, University Medical Center Rotterdam, Generation R Study Group, Rotterdam, The Netherlands.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.
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http://dx.doi.org/10.1038/s41380-020-00976-0DOI Listing
June 2021

Genome-Wide Sex and Gender Differences in Cancer.

Front Oncol 2020 23;10:597788. Epub 2020 Nov 23.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.

Despite their known importance in clinical medicine, differences based on sex and gender are among the least studied factors affecting cancer susceptibility, progression, survival, and therapeutic response. In particular, the molecular mechanisms driving sex differences are poorly understood and so most approaches to precision medicine use mutational or other genomic data to assign therapy without considering how the sex of the individual might influence therapeutic efficacy. The mandate by the National Institutes of Health that research studies include sex as a biological variable has begun to expand our understanding on its importance. Sex differences in cancer may arise due to a combination of environmental, genetic, and epigenetic factors, as well as differences in gene regulation, and expression. Extensive sex differences occur genome-wide, and ultimately influence cancer biology and outcomes. In this review, we summarize the current state of knowledge about sex-specific genetic and genome-wide influences in cancer, describe how differences in response to environmental exposures and genetic and epigenetic alterations alter the trajectory of the disease, and provide insights into the importance of integrative analyses in understanding the interplay of sex and genomics in cancer. In particular, we will explore some of the emerging analytical approaches, such as the use of network methods, that are providing a deeper understanding of the drivers of differences based on sex and gender. Better understanding these complex factors and their interactions will improve cancer prevention, treatment, and outcomes for all individuals.
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http://dx.doi.org/10.3389/fonc.2020.597788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719817PMC
November 2020

Epigenetics and pulmonary diseases in the horizon of precision medicine: a review.

Eur Respir J 2021 06 10;57(6). Epub 2021 Jun 10.

Dept of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Naples, Italy

Epigenetic mechanisms represent potential molecular routes which could bridge the gap between genetic background and environmental risk factors contributing to the pathogenesis of pulmonary diseases. In patients with COPD, asthma and pulmonary arterial hypertension (PAH), there is emerging evidence of aberrant epigenetic marks, mainly including DNA methylation and histone modifications which directly mediate reversible modifications to the DNA without affecting the genomic sequence. Post-translational events and microRNAs can be also regulated epigenetically and potentially participate in disease pathogenesis. Thus, novel pathogenic mechanisms and putative biomarkers may be detectable in peripheral blood, sputum, nasal and buccal swabs or lung tissue. Besides, DNA methylation plays an important role during the early phases of fetal development and may be impacted by environmental exposures, ultimately influencing an individual's susceptibility to COPD, asthma and PAH later in life. With the advances in omics platforms and the application of computational biology tools, modelling the epigenetic variability in a network framework, rather than as single molecular defects, provides insights into the possible molecular pathways underlying the pathogenesis of COPD, asthma and PAH. Epigenetic modifications may have clinical applications as noninvasive biomarkers of pulmonary diseases. Moreover, combining molecular assays with network analysis of epigenomic data may aid in clarifying the multistage transition from a "pre-disease" to "disease" state, with the goal of improving primary prevention of lung diseases and its subsequent clinical management.We describe epigenetic mechanisms known to be associated with pulmonary diseases and discuss how network analysis could improve our understanding of lung diseases.
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http://dx.doi.org/10.1183/13993003.03406-2020DOI Listing
June 2021

DNA Methylation Architecture of the ACE2 gene in Nasal Cells.

medRxiv 2020 Sep 16. Epub 2020 Sep 16.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity.1,2 The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean=12.71%) and 3 sites greater DNAm (mean=1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference=3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference=1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference=7.86%) and females (mean absolute difference=8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences.
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http://dx.doi.org/10.1101/2020.08.25.20182105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523147PMC
September 2020

Sex-specific associations with DNA methylation in lung tissue demonstrate smoking interactions.

Epigenetics 2021 Jun 22;16(6):692-703. Epub 2020 Sep 22.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Cigarette smoking impacts DNA methylation, but the investigation of sex-specific features of lung tissue DNA methylation in smokers has been limited. Women appear more susceptible to cigarette smoke, and often develop more severe lung disease at an earlier age with less smoke exposure. We aimed to analyse whether there are sex differences in DNA methylation in lung tissue and whether these DNA methylation marks interact with smoking. We collected lung tissue samples from former smokers who underwent lung tissue resection. One hundred thirty samples from white subjects were included for this analysis. Regression models for sex as a predictor of methylation were adjusted for age, presence of COPD, smoking variables and technical batch variables revealed 710 associated sites. 294 sites demonstrated robust sex-specific methylation associations in foetal lung tissue. Pathway analysis identified 6 nominally significant pathways including the mitophagy pathway. Three CpG sites demonstrated a suggested interaction between sex and pack-years of smoking: GPR132, ANKRD44 and C19orf60. All of them were nominally significant in both male- and female-specific models, and the effect estimates were in opposite directions for male and female; GPR132 demonstrated significant association between DNA methylation and gene expression in lung tissue ( < 0.05). Sex-specific associations with DNA methylation in lung tissue are wide-spread and may reveal genes and pathways relevant to sex differences for lung damaging effects of cigarette smoking.
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http://dx.doi.org/10.1080/15592294.2020.1819662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143227PMC
June 2021

A Risk Prediction Model for Mortality Among Smokers in the COPDGene® Study.

Chronic Obstr Pulm Dis 2020 Oct;7(4):346-361

University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.

Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.

Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.

Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883903PMC
October 2020

Sex and gender: modifiers of health, disease, and medicine.

Lancet 2020 08;396(10250):565-582

Division of Gastroenterology, Duke University Medical Center Durham, NC, USA; Durham VA Medical Center, Durham, NC, USA.

Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.
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http://dx.doi.org/10.1016/S0140-6736(20)31561-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440877PMC
August 2020

Association of Neutrophil to Lymphocyte Ratio With Pulmonary Function in a 30-Year Longitudinal Study of US Veterans.

JAMA Netw Open 2020 07 1;3(7):e2010350. Epub 2020 Jul 1.

Laboratory of Environmental Precision Biosciences, Mailman School of Public Health, Columbia University, New York, New York.

Importance: Chronic obstructive pulmonary disease (COPD) is a critical public health burden. The neutrophil to lymphocyte ratio (NLR), an inflammation biomarker, has been associated with COPD morbidity and mortality; however, its associations with lung function decline and COPD development are poorly understood.

Objective: To explore the associations of NLR with lung function decline and COPD risks.

Design, Setting, And Participants: This longitudinal cohort study included white male veterans in the US with more than 30 years of follow-up to investigate the associations of NLR with lung function, COPD, and hypomethylation of cg05575921, the top DNA methylation marker of lung function changes in response to tobacco smoking. This study included 7466 visits from 1549 participants, each examined up to 13 times between 1982 and 2018. A subgroup of 1411 participants without COPD at baseline were selected to analyze the association of NLR with incident COPD. Data were analyzed from September 2019 to January 2020.

Exposures: The primary exposure was NLR, which was estimated using automated whole blood cell counts based on a blood sample collected at each visit. The methylation level of cg05575921 was measured in blood DNA from a subgroup of 1228 visits.

Main Outcomes And Measures: The outcomes of interest were lung function, measured as forced respiratory volume in the first second (FEV1) in liters, forced vital capacity (FVC) in liters, percentage of FVC exhaled in the first second (FEV1/FVC), and maximal midexpiratory flow rate (MMEF) in liters per minute and COPD status, defined as meeting the Global Initiative for Chronic Obstructive Lung Diseases stage II (or higher) criteria. Both outcomes were measured as each visit.

Results: Among 1549 included men (mean [SD] age, 68.3 [9.3] years) with 7466 visits from 1982 to 2018, a 1-unit increase in NLR was associated with statistically significant mean (SE) decreases of 0.021 (0.004) L in FEV1, 0.016 (0.005) L in FVC, 0.290% (0.005) L in FVC, 0.290% (0.065%) in FEV1/FVC, and 3.65 (0.916) L/min MMEF. Changes in NLR up to approximately 10 years were associated with corresponding longitudinal changes in lung function. Furthermore, this increase in NLR was associated with 9% higher odds of COPD (odds ratio, 1.09 [95% CI, 1.03-1.15]) for all visits and 27% higher risk of incident COPD (odds ratio, 1.07 [95% CI, 1.07-1.51]) for participants without COPD at baseline. Additionally, a 1-unit increase in NLR was associated with a mean (SE) decrease of 0.0048 (0.0021 in cg05575921 hypomethylation, which may mediate the adverse association of NLR-related inflammation on lung function.

Conclusions And Relevance: These findings suggest that NLR may be a clinically relevant biomarker associated with high risk of lung function impairment and COPD alone or in combination with DNA methylation profiles.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.10350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358911PMC
July 2020

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

Lancet Respir Med 2020 07;8(7):696-708

Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

Funding: US National Institutes of Health, Wellcome Trust.
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http://dx.doi.org/10.1016/S2213-2600(20)30101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429152PMC
July 2020

Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues.

Cell Rep 2020 06;31(12):107795

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Sex differences manifest in many diseases and may drive sex-specific therapeutic responses. To understand the molecular basis of sex differences, we evaluated sex-biased gene regulation by constructing sample-specific gene regulatory networks in 29 human healthy tissues using 8,279 whole-genome expression profiles from the Genotype-Tissue Expression (GTEx) project. We find sex-biased regulatory network structures in each tissue. Even though most transcription factors (TFs) are not differentially expressed between males and females, many have sex-biased regulatory targeting patterns. In each tissue, genes that are differentially targeted by TFs between the sexes are enriched for tissue-related functions and diseases. In brain tissue, for example, genes associated with Parkinson's disease and Alzheimer's disease are targeted by different sets of TFs in each sex. Our systems-based analysis identifies a repertoire of TFs that play important roles in sex-specific architecture of gene regulatory networks, and it underlines sex-specific regulatory processes in both health and disease.
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http://dx.doi.org/10.1016/j.celrep.2020.107795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898458PMC
June 2020

Co-methylation analysis in lung tissue identifies pathways for fetal origins of COPD.

Eur Respir J 2020 10 29;56(4). Epub 2020 Oct 29.

Channing Division of Network Medicine, Dept of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA

COPD likely has developmental origins; however, the underlying molecular mechanisms are not fully identified. Investigation of lung tissue-specific epigenetic modifications such as DNA methylation using network approaches might facilitate insights linking smoke (IUS) exposure and risk for COPD in adulthood.We performed genome-wide methylation profiling for adult lung DNA from 160 surgical samples and 78 fetal lung DNA samples isolated from discarded tissue at 8-18 weeks of gestation. Co-methylation networks were constructed to identify preserved modules that shared methylation patterns in fetal and adult lung tissues and associations with fetal IUS exposure, gestational age and COPD.Weighted correlation networks highlighted preserved and co-methylated modules for both fetal and adult lung data associated with fetal IUS exposure, COPD and lower adult lung function. These modules were significantly enriched for genes involved in embryonic organ development and specific inflammation-related pathways, including Hippo, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Wnt, mitogen-activated protein kinase and transforming growth factor-β signalling. Gestational age-associated modules were remarkably preserved for COPD and lung function, and were also annotated to genes enriched for the Wnt and PI3K/AKT pathways.Epigenetic network perturbations in fetal lung tissue exposed to IUS and of early lung development recapitulated in adult lung tissue from ex-smokers with COPD. Overlapping fetal and adult lung tissue network modules highlighted putative disease pathways supportive of exposure-related and age-associated developmental origins of COPD.
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http://dx.doi.org/10.1183/13993003.02347-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087182PMC
October 2020

The Association of Multiparity with Lung Function and Chronic Obstructive Pulmonary Disease-Related Phenotypes.

Chronic Obstr Pulm Dis 2020 Apr;7(2):86-98

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Background: Apparent increased female susceptibility to chronic obstructive pulmonary disease (COPD) suggests sex hormones modulate disease pathogenesis. Little is known about associations between multiparity and lung function in smokers.

Research Question: We hypothesized that multiparity is associated with lung function and measures of emphysema and airway disease.

Study Design And Methods: Utilizing female participants from the 5-year follow up of the COPD Genetic Epidemiology (COPDGene) study we performed multivariable linear regressions to assess the effect of multiparity and number of pregnancies on forced expiratory volume in 1 second (FEV) percentage of predicted (% predicted), FEV/forced vital capacity (FVC), percent emphysema on computed tomography (CT) scans, and Pi10, a measure of airway thickening. We sampled never smokers and those with lower smoking exposure from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 dataset.

Results: We included 1820 participants from COPDGene and 418 participants from NHANES (321 never smokers, 97 ever smokers). In COPDGene, multiparity (beta coefficient [β] = -3.8, 95% confidence interval [CI]: [-6.5, -1.1], = 0.005) and higher number of pregnancies were associated with lower FEV % predicted. Multiparity was not associated with percent emphysema or Pi10. In individuals with no or mild obstruction, multiparity was associated with lower FEV % predicted. There was an interaction with multiparity and age on FEV % predicted ( = 0.025). In NHANES, there was no association between multiparity and FEV % predicted in never smokers or the lower smoking exposure group.

Interpretation: Multiparity was associated with lower FEV % predicted in current and former smokers in COPDGene study participants. These preliminary results emphasize the importance of smoking abstinence in women of child-bearing age.
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http://dx.doi.org/10.15326/jcopdf.7.2.2019.0166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454017PMC
April 2020

Epigenomic Assessment of Cardiovascular Disease Risk and Interactions With Traditional Risk Metrics.

J Am Heart Assoc 2020 04 20;9(8):e015299. Epub 2020 Apr 20.

JM-USDA Human Nutrition Research Center on Aging at Tufts University Boston MA.

Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics.
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http://dx.doi.org/10.1161/JAHA.119.015299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428544PMC
April 2020

Identification of Novel Alzheimer's Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data.

Sci Rep 2020 03 19;10(1):5029. Epub 2020 Mar 19.

Genetics and Aging Unit and McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer's Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (P = 1.83 × 10), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.
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http://dx.doi.org/10.1038/s41598-020-61883-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081222PMC
March 2020

A gene-diet interaction-based score predicts response to dietary fat in the Women's Health Initiative.

Am J Clin Nutr 2020 04;111(4):893-902

Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging, Boston, MA, USA.

Background: Although diet response prediction for cardiometabolic risk factors (CRFs) has been demonstrated using single genetic variants and main-effect genetic risk scores, little investigation has gone into the development of genome-wide diet response scores.

Objective: We sought to leverage the multistudy setup of the Women's Health Initiative cohort to generate and test genetic scores for the response of 6 CRFs (BMI, systolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, and fasting glucose) to dietary fat.

Methods: A genome-wide interaction study was undertaken for each CRF in women (n ∼ 9000) not participating in the dietary modification (DM) trial, which focused on the reduction of dietary fat. Genetic scores based on these analyses were developed using a pruning-and-thresholding approach and tested for the prediction of 1-y CRF changes as well as long-term chronic disease development in DM trial participants (n ∼ 5000).

Results: Only 1 of these genetic scores, for LDL cholesterol, predicted changes in the associated CRF. This 1760-variant score explained 3.7% (95% CI: 0.09, 11.9) of the variance in 1-y LDL cholesterol changes in the intervention arm but was unassociated with changes in the control arm. In contrast, a main-effect genetic risk score for LDL cholesterol was not useful for predicting dietary fat response. Further investigation of this score with respect to downstream disease outcomes revealed suggestive differential associations across DM trial arms, especially with respect to coronary heart disease and stroke subtypes.

Conclusions: These results lay the foundation for the combination of many genome-wide gene-diet interactions for diet response prediction while highlighting the need for further research and larger samples in order to achieve robust biomarkers for use in personalized nutrition.
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http://dx.doi.org/10.1093/ajcn/nqaa037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138684PMC
April 2020
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