A novel application of data-consistent inversion to overcome spurious inference in genome-wide association studies.

The genome-wide association studies (GWAS) typically use linear or logistic regression models to identify associations between phenotypes (traits) and genotypes (genetic variants) of interest. However, the use of regression with the additive assumption has potential limitations. First, the normality assumption of residuals is the one that is rarely seen in practice, and deviation from normality increases the Type-I error rate. Second, building a model based on such an assumption ignores genetic structures, like, dominant, recessive, and protective-risk cases. Ignoring genetic variants may result in spurious conclusions about the associations between a variant and a trait. We propose an assumption-free model built upon data-consistent inversion (DCI), which is a recently developed measure-theoretic framework utilized for uncertainty quantification. This proposed DCI-derived model builds a nonparametric distribution on model inputs that propagates to the distribution of observed data without the required normality assumption of residuals in the regression model. This characteristic enables the proposed DCI-derived model to cover all genetic variants without emphasizing on additivity of the classic-GWAS model. Simulations and a replication GWAS with data from the COPDGene demonstrate the ability of this model to control the Type-I error rate at least as well as the classic-GWAS (additive linear model) approach while having similar or greater power to discover variants in different genetic modes of transmission.

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of P<1.6×10-4, we identified 3 genes (ATP1B1, ARVCF, and LIPG) associated with CAC and 2 genes (ABCG8 and EIF2B2) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis. CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

Suspected Bronchiectasis and Mortality in Adults With a History of Smoking Who Have Normal and Impaired Lung Function : A Cohort Study.

BACKGROUND: Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis-defined as incidental bronchiectasis on computed tomography (CT) images plus clinical manifestation-is associated with increased mortality in adults with a history of smoking with normal spirometry and preserved ratio impaired spirometry (PRISm) is unknown. OBJECTIVE: To determine the association between suspected bronchiectasis and mortality in adults with normal spirometry, PRISm, and obstructive spirometry. DESIGN: Prospective, observational cohort. SETTING: The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. PARTICIPANTS: 7662 non-Hispanic Black or White adults, aged 45 to 80 years, with 10 or more pack-years of smoking history. Participants who were former and current smokers were stratified into normal spirometry (n = 3277), PRISm (n = 986), and obstructive spirometry (n = 3399). MEASUREMENTS: Bronchiectasis identified by CT was ascertained using artificial intelligence-based measurements of an airway-to-artery ratio (AAR) greater than 1 (AAR >1), a measure of bronchial dilatation. The primary outcome of "suspected bronchiectasis" was defined as an AAR >1 of greater than 1% plus 2 of the following: cough, phlegm, dyspnea, and history of 2 or more exacerbations. RESULTS: Among the 7662 participants (mean age, 60 years; 52% women), 1352 (17.6%) had suspected bronchiectasis. During a median follow-up of 11 years, 2095 (27.3%) died. Ten-year mortality risk was higher in participants with suspected bronchiectasis, compared with those without suspected bronchiectasis (normal spirometry: difference in mortality probability [Pr], 0.15 [95% CI, 0.09 to 0.21]; PRISm: Pr, 0.07 [CI, -0.003 to 0.15]; obstructive spirometry: Pr, 0.06 [CI, 0.03 to 0.09]). When only CT was used to identify bronchiectasis, the differences were attenuated in the normal spirometry (Pr, 0.04 [CI, -0.001 to 0.08]). LIMITATIONS: Only 2 racial groups were studied. Only 1 measurement was used to define bronchiectasis on CT. Symptoms of suspected bronchiectasis were nonspecific. CONCLUSION: Suspected bronchiectasis was associated with a heightened risk for mortality in adults with normal and obstructive spirometry. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Carriers of rare damaging CCR2 genetic variants are at lower risk of atherosclerotic disease.

Background: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease. Methods: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the CCR2 gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated. Results: A total of 45 predicted LoF or damaging missense variants were identified in the CCR2 gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent CCR2 damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (ORUKB: 0.62 95%CI: 0.39-0.96; ORexternal: 0.64 95%CI: 0.34-1.19; ORpooled: 0.64 95%CI: 0.450.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging CCR2 variants. Conclusions: Heterozygous carriers of damaging CCR2 variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

Race-Specific Spirometry Equations Do Not Improve Models of Dyspnea and Quantitative Chest CT Phenotypes.

BACKGROUND: Race-specific spirometry reference equations are used globally to interpret lung function for clinical, research, and occupational purposes, but inclusion of race is under scrutiny. RESEARCH QUESTION: Does including self-identified race in spirometry reference equation formation improve the ability of predicted FEV1 values to explain quantitative chest CT abnormalities, dyspnea, or Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification? STUDY DESIGN AND METHODS: Using data from healthy adults who have never smoked in both the National Health and Nutrition Survey (2007-2012) and COPDGene study cohorts, race-neutral, race-free, and race-specific prediction equations were generated for FEV1. Using sensitivity/specificity, multivariable logistic regression, and random forest models, these equations were applied in a cross-sectional analysis to populations of individuals who currently smoke and individuals who formerly smoked to determine how they affected GOLD classification and the fit of models predicting quantitative chest CT phenotypes or dyspnea. RESULTS: Race-specific equations showed no advantage relative to race-neutral or race-free equations in models of quantitative chest CT phenotypes or dyspnea. Race-neutral reference equations reclassified up to 19% of Black participants into more severe GOLD classes, while race-neutral/race-free equations may improve model fit for dyspnea symptoms relative to race-specific equations. INTERPRETATION: Race-specific equations offered no advantage over race-neutral/race-free equations in three distinct explanatory models of dyspnea and chest CT scan abnormalities. Race-neutral/race-free reference equations may improve pulmonary disease diagnoses and treatment in populations highly vulnerable to lung disease.

Longitudinal Assessment of Multimorbidity Medication Patterns among Smokers in the COPDGene Cohort.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers.

Heterogeneity and Progression of Chronic Obstructive Pulmonary Disease: Emphysema-Predominant and Non-Emphysema-Predominant Disease.

While variation in emphysema severity between patients with chronic obstructive pulmonary disease (COPD) is well-recognized, clinically applicable definitions of the emphysema-predominant disease (EPD) and non-emphysema-predominant disease (NEPD) subtypes have not been established. To study the clinical relevance of the EPD and NEPD subtypes, we tested the association of these subtypes with prospective decline in forced expiratory volume in 1 second (FEV1) and mortality among 3,427 subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grade 2-4 COPD at baseline in the Genetic Epidemiology of COPD (COPDGene) Study, an ongoing national multicenter study that started in 2007. NEPD was defined as airflow obstruction with less than 5% computed tomography (CT) quantitative densitometric emphysema at -950 Hounsfield units, and EPD was defined as airflow obstruction with 10% or greater CT emphysema. Mixed-effects models for FEV1 demonstrated larger average annual FEV1 loss in EPD subjects than in NEPD subjects (-10.2 mL/year; P < 0.001), and subtype-specific associations with FEV1 decline were identified. Cox proportional hazards models showed higher risk of mortality among EPD patients versus NEPD patients (hazard ratio = 1.46, 95% confidence interval: 1.34, 1.60; P < 0.001). To determine whether the NEPD/EPD dichotomy is captured by previously described COPDGene subtypes, we used logistic regression and receiver operating characteristic (ROC) curve analysis to predict NEPD/EPD membership using these previous subtype definitions. The analysis generally showed excellent discrimination, with areas under the ROC curve greater than 0.9. The NEPD and EPD COPD subtypes capture important aspects of COPD heterogeneity and are associated with different rates of disease progression and mortality.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease.

INTRODUCTION: Recent evidence suggests a high prevalence of undiagnosed chronic obstructive pulmonary disease (COPD). These individuals are at risk of exacerbations and delayed treatment. We analyzed an at-risk population for the prevalence of abnormal spirometry to provide clarity into who should undergo early spirometry. METHODS: We analyzed data from the COPDGene study. Participants with ≥10 pack-years of smoking were included. Individuals with self-reported or physician-diagnosed COPD, asthma, chronic bronchitis, emphysema and/or were on inhalers were excluded. Parsimonious multivariable logistic regression models identified factors associated with abnormal spirometry, defined as either airflow obstruction (AFO) or preserved ratio impaired spirometry. Variables were selected for the final model using a stepwise backward variable elimination process which minimized Akaike information criterion (AIC). Similarly, during the 5-year follow-up period, we assessed factors associated with incident diagnosis of COPD. RESULTS: Of 5055 individuals, 1064 (21%) had undiagnosed AFO. Age, pack-years, current smoking and a history of acute bronchitis were associated with AFO while body mass index, female sex, and Black race were inversely associated. Among 2800 participants with 5-year follow-up, 532 (19%) had an incident diagnosis of COPD. Associated risk factors included mMRC ≥2, chronic productive cough, respiratory exacerbations during the follow-up period, and abnormal spirometry. Age was inversely associated. CONCLUSIONS: The prevalence of undiagnosed COPD is high in at-risk populations. We found multiple factors associated with undiagnosed COPD and incident diagnosis of COPD at follow up. These results can be used to identify those at risk for undiagnosed COPD to facilitate earlier diagnosis and treatment.

Artificial Intelligence-based CT Assessment of Bronchiectasis: The COPDGene Study.

Background CT is the standard method used to assess bronchiectasis. A higher airway-to-artery diameter ratio (AAR) is typically used to identify enlarged bronchi and bronchiectasis; however, current imaging methods are limited in assessing the extent of this metric in CT scans. Purpose To determine the extent of AARs using an artificial intelligence-based chest CT and assess the association of AARs with exacerbations over time. Materials and Methods In a secondary analysis of ever-smokers from the prospective, observational, multicenter COPDGene study, AARs were quantified using an artificial intelligence tool. The percentage of airways with AAR greater than 1 (a measure of airway dilatation) in each participant on chest CT scans was determined. Pulmonary exacerbations were prospectively determined through biannual follow-up (from July 2009 to September 2021). Multivariable zero-inflated regression models were used to assess the association between the percentage of airways with AAR greater than 1 and the total number of pulmonary exacerbations over follow-up. Covariates included demographics, lung function, and conventional CT parameters. Results Among 4192 participants (median age, 59 years; IQR, 52-67 years; 1878 men [45%]), 1834 had chronic obstructive pulmonary disease (COPD). During a 10-year follow-up and in adjusted models, the percentage of airways with AARs greater than 1 (quartile 4 vs 1) was associated with a higher total number of exacerbations (risk ratio [RR], 1.08; 95% CI: 1.02, 1.15; P = .01). In participants meeting clinical and imaging criteria of bronchiectasis (ie, clinical manifestations with ≥3% of AARs >1) versus those who did not, the RR was 1.37 (95% CI: 1.31, 1.43; P < .001). Among participants with COPD, the corresponding RRs were 1.10 (95% CI: 1.02, 1.18; P = .02) and 1.32 (95% CI: 1.26, 1.39; P < .001), respectively. Conclusion In ever-smokers with chronic obstructive pulmonary disease, artificial intelligence-based CT measures of bronchiectasis were associated with more exacerbations over time. Clinical trial registration no. NCT00608764 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Schiebler and Seo in this issue.

Pre-Clinical Autoimmunity in Lupus Relatives: Self-Reported Questionnaires and Immune Dysregulation Distinguish Relatives Who Develop Incomplete or Classified Lupus From Clinically Unaffected Relatives and Unaffected, Unrelated Individuals.

Systemic lupus erythematosus (SLE) is propelled by pathogenic autoantibody (AutoAb) and immune pathway dysregulation. Identifying populations at risk of reaching classified SLE is essential to curtail inflammatory damage. Lupus blood relatives (Rel) have an increased risk of developing SLE. We tested factors to identify Rel at risk of developing incomplete lupus (ILE) or classified SLE vs. clinically unaffected Rel and healthy controls (HC), drawing from two unique, well characterized lupus cohorts, the lupus autoimmunity in relatives (LAUREL) follow-up cohort, consisting of Rel meeting <4 ACR criteria at baseline, and the Lupus Family Registry and Repository (LFRR), made up of SLE patients, lupus Rel, and HC. Medical record review determined ACR SLE classification criteria; study participants completed the SLE portion of the connective tissue disease questionnaire (SLE-CSQ), type 2 symptom questions, and provided samples for assessment of serum SLE-associated AutoAb specificities and 52 plasma immune mediators. Elevated SLE-CSQ scores were associated with type 2 symptoms, ACR scores, and serology in both cohorts. Fatigue at BL was associated with transition to classified SLE in the LAUREL cohort (p≤0.01). Increased levels of BLyS and decreased levels of IL-10 were associated with type 2 symptoms (p<0.05). SLE-CSQ scores, ACR scores, and accumulated AutoAb specificities correlated with levels of multiple inflammatory immune mediators (p<0.05), including BLyS, IL-2Rα, stem cell factor (SCF), soluble TNF receptors, and Th-1 type mediators and chemokines. Transition to SLE was associated with increased levels of SCF (p<0.05). ILE Rel also had increased levels of TNF-α and IFN-γ, offset by increased levels of regulatory IL-10 and TGF-ß (p<0.05). Clinically unaffected Rel (vs. HC) had higher SLE-CSQ scores (p<0.001), increased serology (p<0.05), and increased inflammatory mediator levels, offset by increased IL-10 and TGF-ß (p<0.01). These findings suggest that Rel at highest risk of transitioning to classified SLE have increased inflammation coupled with decreased regulatory mediators. In contrast, clinically unaffected Rel and Rel with ILE demonstrate increased inflammation offset with increased immune regulation, intimating a window of opportunity for early intervention and enrollment in prevention trials.

Relationship Between a Vitamin D Genetic Risk Score and Autoantibodies Among First-Degree Relatives of Probands With Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Objective: Higher 25-hydroxyvitamin D (25(OH)D) levels have been associated with reduced risk for autoimmune diseases and are influenced by vitamin D metabolism genes. We estimated genetically-determined vitamin D levels by calculating a genetic risk score (GRS) and investigated whether the vitamin D GRS was associated with the presence of autoantibodies related to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in those at increased risk for developing RA and SLE, respectively. Methods: In this cross-sectional study, we selected autoantibody positive (aAb+) and autoantibody negative (aAb-) individuals from the Studies of the Etiologies of Rheumatoid Arthritis (SERA), a cohort study of first-degree relatives (FDRs) of individuals with RA (189 RA aAb+, 181 RA aAb-), and the Lupus Family Registry and Repository (LFRR), a cohort study of FDRs of individuals with SLE (157 SLE aAb+, 185 SLE aAb-). Five SNPs known to be associated with serum 25(OH)D levels were analyzed individually as well as in a GRS: rs4588 (GC), rs12785878 (NADSYN1), rs10741657 (CYP2R1), rs6538691 (AMDHD1), and rs8018720 (SEC23A). Results: Both cohorts had similar demographic characteristics, with significantly older and a higher proportion of males in the aAb+ FDRs. The vitamin D GRS was inversely associated with RA aAb+ (OR = 0.85, 95% CI = 0.74-0.99), suggesting a possible protective factor for RA aAb positivity in FDRs of RA probands. The vitamin D GRS was not associated with SLE aAb+ in the LFRR (OR = 1.09, 95% CI = 0.94-1.27). The SEC23A SNP was associated with RA aAb+ in SERA (OR = 0.65, 95% CI = 0.43-0.99); this SNP was not associated with SLE aAb+ in LFRR (OR = 1.41, 95% CI = 0.90 - 2.19). Conclusion: Genes associated with vitamin D levels may play a protective role in the development of RA aAbs in FDRs of RA probands, perhaps through affecting lifelong vitamin D status. The GRS and the SEC23A SNP may be of interest for future investigation in pre-clinical RA. In contrast, these results do not support a similar association in SLE FDRs, suggesting other mechanisms involved in the relationship between vitamin D and SLE aAbs not assessed in this study.

10-Year Follow-Up of Lung Function, Respiratory Symptoms, and Functional Capacity in the COPDGene Study.

Rationale: The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]) study provides a unique cohort to examine these trajectories, and now 10-year follow-up data are available. Objectives: This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers. Methods: We analyzed available longitudinal data for COPDGene participants who did not change smoking status over three visits spanning approximately 10 years of follow-up. Change in postbronchodilator forced expiratory volume in 1 second (FEV1), St. George's Respiratory Questionnaire (SGRQ), and 6-minute walk distance (6MWD) from Phase 1 to Phase 3 were examined using linear mixed models. Terms were included in the models to estimate mean progression separately for current and former cigarette smokers. Models were stratified by baseline Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry stages as well as by new 2019 COPDGene classification. Results: The mean age at enrollment of the 9,103 participants in this analysis was 59.8 years (SD = 9.2 yr); 46.4% were women, and 32.6% were African American. In all GOLD COPD groups, including participants with normal spirometry, and all groups categorized by 2019 COPDGene classification, FEV1 decreased, SGRQ increased (indicating higher symptom burden), and 6MWD decreased over the 10-year follow-up period. Current smokers exhibited a greater mean loss of FEV1 over the study period than former smokers for all groups except those with preserved ratio impaired spirometry. For both SGRQ and 6MWD, rates of progression tended to be similar for former and current smokers except for 6MWD in the highest severity groups, in which former smokers had greater progression. However, this could be impacted by some current smokers with faster progression who had quit smoking and were dropped from analyses. Conclusions: Progression in FEV1, SGRQ, and 6MWD overall appears to be slow, and the change over time in groups traditionally characterized as not having disease closely mirrors that of the groups with COPD at all GOLD stages. Current cigarette smokers had greater loss of FEV1 than former smokers, whereas SGRQ and 6MWD changes were more similar between current and former cigarette smokers.

Significant Spirometric Transitions and Preserved Ratio Impaired Spirometry Among Ever Smokers.

BACKGROUND: Emerging data from longitudinal studies suggest that preserved ratio impaired spirometry (PRISm), defined by proportionate reductions in FEV1 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 (eg, 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 the Genetic Epidemiology of COPD (COPDGene) study with spirometry available in phases 1 through 3 (enrollment, 5-year follow-up, and 10-year follow-up) were analyzed. Postbronchodilator lung function categories were as follows: PRISm (FEV1 < 80% predicted with FEV1/FVC ratio ≥ 0.7), Global Initiative for Chronic Obstructive Lung Disease grade 0 (FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7), and obstruction (FEV1/FVC < 0.7). Significant transition status was affirmative if a subject belonged to two or more spirometric categories and had > 10% change in FEV1 % predicted 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, FEV1 % 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 phases 1 through 3, but nearly one-half of subjects with PRISm transitioned into or out of PRISm at each visit. Among all subjects, 19.7% had a significant transition; ever-PRISm was a significant predictor of significant transitions (unadjusted OR, 10.3; 95% CI, 7.9-13.5; adjusted 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 FEV1 alone (regardless of change in FVC % predicted) was used to define significant transitions. INTERPRETATION: PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT000608764; URL: www. CLINICALTRIALS: gov.

Small Airway Disease and Emphysema Are Associated with Future Exacerbations in Smokers with CT-derived Bronchiectasis and COPD: Results from the COPDGene Cohort.

Background Chronic obstructive pulmonary disease (COPD) and bronchiectasis can overlap and share pathologic features, such as small airway disease (SAD). Whether the presence of SAD and emphysema in smokers with CT-derived bronchiectasis is associated with exacerbations is unknown. Purpose To assess whether SAD and emphysema in smokers with CT-derived bronchiectasis are associated with future exacerbations. Materials and Methods SAD and emphysema were quantified using the parametric response map method in former and current heavy smokers with and without bronchiectasis at CT from the COPDGene Study (from July 2009 to July 2018). Exacerbations were prospectively assessed through biannual follow-up. An exacerbation was defined as an increase in or new onset of respiratory symptoms treated with antibiotics and/or corticosteroids. Severe exacerbations were defined as those that required hospitalization. The association of a high burden of SAD (≥15.6%) and high burden of emphysema (≥5%) at CT with exacerbations was assessed with generalized linear mixed models. Results Of 737 participants, 387 (median age, 64 years [interquartile range, 58-71 years]; 223 women) had CT-derived bronchiectasis. During a 9-year follow-up, after adjustment for age, sex, race, body mass index, current smoking status, pack-years, exacerbations before study entry, forced expiratory volume in 1 second, or FEV1, and bronchiectasis severity CT score, high burden of SAD and high burden of emphysema were associated with a higher number of exacerbations per year (relative risk [RR], 1.89 [95% CI: 1.54, 2.33] and 1.37 [95% CI: 1.13, 1.66], respectively; P ≤ .001 for both). Results were comparable among participants with bronchiectasis meeting criteria for COPD (n = 197) (RR, 1.67 [95% CI: 1.23, 2.27] for high burden of SAD and 1.51 [95% CI: 1.20, 1.91] for high burden of emphysema; P ≤ .001 for both). Conclusion In smokers with CT-derived bronchiectasis and chronic obstructive pulmonary disease, structural damage to lung parenchyma and small airways was associated with a higher number of exacerbations per year. Clinical trial registration no. NCT00608764 © RSNA, 2021.