Dataset Information

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

ABSTRACT:

Background

Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime pack-years smoked.

Methods

We analyzed data from participants of European ancestry in the Framingham Heart Study Original (n = 454) and Offspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data and genome-wide association study summary statistics from a recent study in the OncoArray Consortium. We used Cox proportional hazards regression models to assess risk and the interaction between pack-years smoked and genetic risk for lung cancer adjusting for European ancestry, age, sex, and education.

Results

We observed a significant submultiplicative interaction between pack-years and PRS on lung cancer risk (P = 0.09). Thus, the relative risk associated with each additional 10 pack-years smoked decreased with increasing genetic risk (HR = 1.56 at one SD below mean PRS, HR = 1.48 at mean PRS, and HR = 1.40 at one SD above mean PRS). Similarly, lung cancer risk per SD increase in the PRS was highest among those who had never smoked (HR = 1.55) and decreased with heavier smoking (HR = 1.32 at 30 pack-years).

Conclusions

These results suggest the presence of a submultiplicative interaction between pack-years and genetics on lung cancer risk, consistent with recent findings. Both smoking and genetics were significantly associated with lung cancer risk.

Impact

These results underscore the contributions of genetics and smoking on lung cancer risk and highlight the negative impact of continued smoking regardless of genetic risk.

SUBMITTER: Duncan MS

PROVIDER: S-EPMC10988206 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

Duncan Meredith S MS Diaz-Zabala Hector H Jaworski James J Tindle Hilary A HA Greevy Robert A RA Lipworth Loren L Hung Rayjean J RJ Freiberg Matthew S MS Aldrich Melinda C MC

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20240401 4

<h4>Background</h4>Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime pack-years smoked.<h4>Methods</h4>We analyzed data from participants of European ancestry in the Framingham Heart Study Original (n = 454) and Offspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data ...[more]

PMID: 38227004

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Project description:BackgroundThe use of a polygenic risk score (PRS) to improve risk prediction of coronary heart disease (CHD) events has been demonstrated to have clinical utility in the general adult population. However, the prognostic value of a PRS for CHD has not been examined specifically in older populations of individuals aged ≥70 years, who comprise a distinct high-risk subgroup. The objective of this study was to evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of older individuals without a history of cardiovascular events.MethodsWe used data from 12 792 genotyped, healthy older individuals enrolled into the ASPREE trial (Aspirin in Reducing Events in the Elderly), a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. Participants had no previous history of diagnosed atherothrombotic cardiovascular events, dementia, or persistent physical disability at enrollment. We calculated a PRS (meta-genomic risk score) consisting of 1.7 million genetic variants. The primary outcome was a composite of incident myocardial infarction or CHD death over 5 years.ResultsAt baseline, the median population age was 73.9 years, and 54.9% were female. In total, 254 incident CHD events occurred. When the PRS was added to conventional risk factors, it was independently associated with CHD (hazard ratio, 1.24 [95% CI, 1.08-1.42], P=0.002). The area under the curve of the conventional model was 70.53 (95% CI, 67.00-74.06), and after inclusion of the PRS increased to 71.78 (95% CI, 68.32-75.24, P=0.019), demonstrating improved prediction. Reclassification was also improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.15-0.28).ConclusionA PRS for CHD performs well in older people and improves prediction over conventional cardiovascular risk factors. Our study provides evidence that genomic risk prediction for CHD has clinical utility in individuals aged 70 years and older. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Project description:ImportanceGenetic and environmental factors are linked to Parkinson disease (PD), but the role of genetic susceptibility in the association between traffic-related air pollution (TRAP) and PD remains unclear.ObjectiveTo assess the gene-environment interaction between the polygenic risk score (PRS) for PD and long-term TRAP exposure and to estimate the joint effect with PD risk.Design, setting, and participantsThis population-based case-control study used a meta-analytical assessment of studies conducted in central California and Denmark. The Parkinson Environment and Genes (PEG) study in California (June 1, 2000, to July 31, 2017) included 634 patients with PD and 733 controls; the Parkinson Disease in Denmark (PASIDA) study (January 1, 2006, to December 31, 2017) included 966 patients with PD and 1045 controls. Data were analyzed from July 1 to October 31, 2024.ExposuresPRS was computed by summing the effect estimates of well-known risk alleles from an existing genome-wide association study's summary statistics using participants' genetic arrays. TRAP exposure was estimated using dispersion models to calculate long-term exposure (10- or 15-year means with a 5-year lag) to traffic-related pollutants (represented by carbon monoxide [CO] levels) at participants' residences.Main outcomes and measuresThe main outcome was diagnosis of PD. Using multivariable logistic regression, PD risk was estimated from interactions between PRS (per SD) and TRAP exposure (per IQR), with joint effects based on low (quartiles 1-3) and high (quartile 4) exposure levels.ResultsA total of 1600 patients with PD (mean [SD] age, 65.1 [9.9] years; 990 [61.9%] male) and 1778 controls (mean [SD] age, 64.5 [10.3] years; 992 [55.8%] male) were included. Meta-analytical estimates suggest that both higher PRS and increased TRAP exposure increased PD risk, with an interaction effect estimate of 1.06 (95% CI, 1.00-1.12). Joint effect analysis indicated that individuals with both high PRS and high TRAP exposure were at greatest risk of PD (odds ratio, 3.05; 95% CI, 2.23-4.19) compared with the reference group with a low PRS and low TRAP exposure, suggesting a synergistic effect.Conclusions and relevanceIn this gene-environment interaction study, a combination of long-term air pollution exposure and genetic susceptibility strongly contributed to the risk of developing PD. Widespread exposure to air pollution makes TRAP an important modifiable risk factor affecting large populations globally, particularly individuals with genetic vulnerability.

Project description:ImportanceThe risk of airflow limitation and chronic obstructive pulmonary disease (COPD) is influenced by combinations of cigarette smoking and genetic susceptibility, yet it remains unclear whether gene-by-smoking interactions are associated with quantitative measures of lung function.ObjectiveTo assess the interaction of cigarette smoking and polygenic risk score in association with reduced lung function.Design, setting, and participantsThis UK Biobank cohort study included UK citizens of European ancestry aged 40 to 69 years with genetic and spirometry data passing quality control metrics. Data was analyzed from July 2020 to March 2021.ExposuresPRS of combined forced expiratory volume in 1 second (FEV1) and percent of forced vital capacity exhaled in the first second (FEV1/FVC), self-reported pack-years of smoking, ever- vs never-smoking status, and current- vs former- or never-smoking status.Main outcomes and measuresFEV1/FVC was the primary outcome. Models were used to test for interactions with models, including the main effects of PRS, different smoking variables, and their cross-product terms. The association between pack-years of smoking and FEV1/FVC were compared for those in the highest vs lowest decile of estimated genetic risk for low lung function.ResultsWe included 319 730 individuals, of whom 24 915 (8%) had moderate-to-severe COPD cases, and 44.4% were men. Participants had a mean (SD) age 56.5 of (8.02) years. The PRS and pack-years were significantly associated with lower FEV1/FVC (PRS: β, -0.03; 95% CI, -0.031 to -0.03; pack-years: β, -0.0064; 95% CI, -0.0064 to -0.0063) and the interaction term (β, -0.0028; 95% CI, -0.0029 to -0.0026). A stepwise increment in estimated effect sizes for these interaction terms was observed per 10 pack-years of smoking exposure. The interaction of PRS with 11 to 20, 31 to 40, and more than 50 pack-years categories were β (interaction) -0.0038 (95% CI, -0.0046 to -0.0031); -0.013 (95% CI, -0.014 to -0.012); and -0.017 (95% CI, -0.019 to -0.016), respectively. There was evidence of significant interaction between PRS with ever- or never- smoking status (β, interaction; -0.0064; 95% CI, -0.0068 to -0.0060) and current or not-current smoking (β, interaction; -0.0091; 95% CI, -0.0097 to -0.0084). For any given level of pack-years of smoking exposure, FEV1/FVC was significantly lower for individuals in the tenth decile (ie, highest risk) than the first decile (ie, lowest risk) of genetic risk. For every 20 pack-years of smoking, those in the tenth decile compared with the first decile of genetic risk showed nearly a 2-fold reduction in FEV1/FVC.Conclusions and relevanceCOPD is characterized by diminished lung function, and our analyses suggest there is substantial interaction between genome-wide PRS and smoking exposures. While smoking was associated with decreased lung function across all genetic risk categories, the associations were strongest in individuals with higher estimated genetic risk.

Project description:ImportancePolygenic risk scores comprising millions of single-nucleotide polymorphisms (SNPs) could be useful for population-wide coronary heart disease (CHD) screening.ObjectiveTo determine whether a polygenic risk score improves prediction of CHD compared with a guideline-recommended clinical risk equation.Design, setting, and participantsA retrospective cohort study of the predictive accuracy of a previously validated polygenic risk score was assessed among 4847 adults of white European ancestry, aged 45 through 79 years, participating in the Atherosclerosis Risk in Communities (ARIC) study and 2390 participating in the Multi-Ethnic Study of Atherosclerosis (MESA) from 1996 through December 31, 2015, the final day of follow-up. The performance of the polygenic risk score was compared with that of the 2013 American College of Cardiology and American Heart Association pooled cohort equations.ExposuresGenetic risk was computed for each participant by summing the product of the weights and allele dosage across 6 630 149 SNPs. Weights were based on an international genome-wide association study.Main outcomes and measuresPrediction of 10-year first CHD events (including myocardial infarctions, fatal coronary events, silent infarctions, revascularization procedures, or resuscitated cardiac arrest) assessed using measures of model discrimination, calibration, and net reclassification improvement (NRI).ResultsThe study population included 4847 adults from the ARIC study (mean [SD] age, 62.9 [5.6] years; 56.4% women) and 2390 adults from the MESA cohort (mean [SD] age, 61.8 [9.6] years; 52.2% women). Incident CHD events occurred in 696 participants (14.4%) and 227 participants (9.5%), respectively, over median follow-up of 15.5 years (interquartile range [IQR], 6.3 years) and 14.2 (IQR, 2.5 years) years. The polygenic risk score was significantly associated with 10-year CHD incidence in ARIC with hazard ratios per SD increment of 1.24 (95% CI, 1.15 to 1.34) and in MESA, 1.38 (95% CI, 1.21 to 1.58). Addition of the polygenic risk score to the pooled cohort equations did not significantly increase the C statistic in either cohort (ARIC, change in C statistic, -0.001; 95% CI, -0.009 to 0.006; MESA, 0.021; 95% CI, -0.0004 to 0.043). At the 10-year risk threshold of 7.5%, the addition of the polygenic risk score to the pooled cohort equations did not provide significant improvement in reclassification in either ARIC (NRI, 0.018, 95% CI, -0.012 to 0.036) or MESA (NRI, 0.001, 95% CI, -0.038 to 0.076). The polygenic risk score did not significantly improve calibration in either cohort.Conclusions and relevanceIn this analysis of 2 cohorts of US adults, the polygenic risk score was associated with incident coronary heart disease events but did not significantly improve discrimination, calibration, or risk reclassification compared with conventional predictors. These findings suggest that a polygenic risk score may not enhance risk prediction in a general, white middle-aged population.

Dataset Information

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

Background

Methods

Results

Conclusions

Impact

Publications

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

Similar Datasets

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