Dataset Information

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

ABSTRACT:

Background

Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV₁) <80% predicted and FEV₁/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.

Methods

We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.

Results

22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (r_g) between PRISm and spirometric COPD (r_g=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (r_g=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits.

Conclusion

This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

SUBMITTER: Higbee DH

PROVIDER: S-EPMC10765494 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

Higbee Daniel H DH Lirio Alvin A Hamilton Fergus F Granell Raquel R Wyss Annah B AB London Stephanie J SJ Bartz Traci M TM Gharib Sina A SA Cho Michael H MH Wan Emily E Silverman Edwin E Crapo James D JD Lominchar Jesus V T JVT Hansen Torben T Grarup Niels N Dantoft Thomas T Kårhus Line L Linneberg Allan A O'Connor George T GT Dupuis Josée J Xu Hanfie H De Vries Maaike M MM Hu Xiaowei X Rich Stephen S SS Barr R Graham RG Manichaikul Ani A Wijnant Sara R A SRA Brusselle Guy G GG Lahousse Lies L Li Xuan X Hernández Cordero Ana I AI Obeidat Ma'en M Sin Don D DD Harris Sarah E SE Redmond Paul P Taylor Adele M AM Cox Simon R SR Williams Alexander T AT Shrine Nick N John Catherine C Guyatt Anna L AL Hall Ian P IP Davey Smith George G Tobin Martin D MD Dodd James W JW

The European respiratory journal 20240104 1

<h4>Background</h4>Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV<sub>1</sub>) <80% predicted and FEV<sub>1</sub>/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.<h4>Methods</h4>We undertook a genome-wide association study (GWAS) of PRISm in UK Bioba ...[more]

PMID: 38097206

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Project description:IntroductionTo analyse the relationship between diabetes, its severity (including blood glucose levels, disease duration, antidiabetic drug use and number of comorbidities) and preserved ratio impaired spirometry (PRISm) using data from the National Health and Nutrition Examination Survey (NHANES).MethodsThis cross-sectional study collected data from the NHANES database from 2007 to 2012. PRISm was defined as having a forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio ≥0.7 and an FEV1 predicted value <80%. We examined the relationship between diabetes duration, fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), log-transformed homeostasis model assessment for insulin resistance, C reactive protein and the number of comorbidities with PRISm in the entire population. We analysed the relationship between antidiabetic drug use and PRISm, specifically in the diabetes population. Logistic regression models were used, and results were reported as OR.ResultsA total of 5783 participants with normal spirometry or PRISm were included in the analysis. Diabetes was associated with 2.19 times higher odds of PRISm compared with non-diabetic participants. Longer disease duration increased PRISm odds by 2% per year. Each 1-unit increase in HbA1c and each 10 mg/dL increase in FPG were associated with 24% and 6% higher odds of PRISm, respectively. No relationship was found between insulin resistance and PRISm after adjusting for covariates. An increase of 1 mg/dL in CRP was associated with 18% higher odds of PRISm. A higher number of diabetes-related comorbidities was strongly associated with PRISm. No significant relationship was found between antidiabetic drug use and PRISm.ConclusionsSevere diabetes status, such as higher blood glucose levels, longer disease duration and a greater number of comorbidities, is associated with an increased risk of PRISm. Effective blood glucose control, self-management and regular monitoring of lung function are crucial for diabetes management.

Project description:ImportanceChronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood.ObjectiveTo examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults.Design, setting, and participantsThe National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018).ExposuresParticipants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted.Main outcomes and measuresMain outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities.ResultsAmong all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]).Conclusions and relevanceIn a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

Dataset Information

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

Background

Methods

Results

Conclusion

Publications

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

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