Rationale: Interstitial lung abnormalities (ILA) are radiologic abnormalities on chest computed tomography scans that have been associated with an early or mild form of pulmonary fibrosis. Although ILA have been associated with radiologic progression, it is not known if specific imaging patterns are associated with progression or risk of mortality.Objectives: To determine the role of imaging patterns on the risk of death and ILA progression.Methods: ILA (and imaging pattern) were assessed in 5,320 participants from the AGES-Reykjavik Study, and ILA progression was assessed in 3,167 participants. Multivariable logistic regression was used to assess factors associated with ILA progression, and Cox proportional hazards models were used to assess time to mortality.Measurements and Main Results: Over 5 years, 327 (10%) had ILA on at least one computed tomography, and 1,435 (45%) did not have ILA on either computed tomography. Of those with ILA, 238 (73%) had imaging progression, whereas 89 (27%) had stable to improved imaging; increasing age and copies of MUC5B genotype were associated with imaging progression. The definite fibrosis pattern was associated with the highest risk of progression (odds ratio, 8.4; 95% confidence interval, 2.7-25; P = 0.0003). Specific imaging patterns were also associated with an increased risk of death. After adjustment, both a probable usual interstitial pneumonia and usual interstitial pneumonia pattern were associated with an increased risk of death when compared with those indeterminate for usual interstitial pneumonia (hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P = 0.001; hazard ratio, 3.9; 95% confidence interval, 2.3-6.8; P , 0.0001), respectively.Conclusions: In those with ILA, imaging patterns can be used to help predict who is at the greatest risk of progression and early death.
With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein’s genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.
We investigated the association between interstitial lung abnormalities (ILA) and self-reported measures of health and functional status in 5764 participants from the Age, Gene/Environment Susceptibility-Reykjavik study. The associations of ILA to activities of daily living (ADLs), general health status and physical activity were explored using logistic regression models. Participants with ILA were less likely to be independent in ADLs (OR 0.70; 95% CI 0.55 to 0.90) to have good or better self-reported health (OR 0.66; 95% CI 0.52 to 0.82) and to participate in physical activity (OR 0.72; CI 0.56 to 0.91). The results demonstrate ILA’s association with worsening self-reported health and functional status.
The term interstitial lung abnormalities (ILA) was coined to define a precursory stage of idiopathic pulmonary fibrosis and encompasses a set of radiological changes seen in interstitial lung diseases (ILD) but are often of lesser magnitude [1]. ILA have been associated with age, many environmental and genetic risk factors and pulmonary symptoms of idiopathic pulmonary fibrosis [1, 2]. ILA have also been associated with reduced exercise capacity and self-reported health and function [3–5].
Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models but human studies are lacking. We examined associations of circulating levels of DHA, and other polyunsaturated fatty acids, with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA, n=6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000-2012), Framingham Heart Study (2005-2011), and Age Gene/Environment Susceptibility (2002-2006) Study (total n=10,193). Polyunsaturated fatty acid levels were from fasting blood samples and extracted from plasma phospholipids (MESA and Age Gene/Environment Susceptibility) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalizations due to ILD (adjusted rate ratio 0.69 per standard deviation increment (95% CI 0.48, 0.99) and a lower rate of death due to ILD (adjusted hazard ratio 0.68 per standard deviation increment, 95% CI 0.47, 0.98). Higher DHA was associated with less interstitial lung abnormalities on CT (pooled adjusted odds ratio 0.65 per natural log increment; 95% CI 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and less lung abnormalities on CT in a meta-analysis of population-based cohorts.
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