Abstract C048: Multiethnic polygenic risk scores and smoking interactions for chronic obstructive lung disease
Authors: Polfus Linda M. , Lin Meng , Park S. Lani , Conti David , Porcel Jackie , Setiawan Veronica W. , Wilkens Lynne , Haiman Christopher A. , Le Marchand Loïc , Stram Daniel O. 
Published: September 2020

Abstract
Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US with differential risk across race/ethnicity groups and increases lung cancer risk. In the Multiethnic Cohort (MEC), an ethnically diverse prospective cohort (&gt;215,000) established in the early 1990’s in California and Hawaii, we found COPD prevalence was highest in African Americans, followed by European Americans, Native Hawaiians, Latinos and Japanese Americans. Family history and smoking are strong risk factors for COPD with heritability estimates ranging from 20-40%. However, large scale genomic studies (GWAS) have primarily focused on Europeans. Thus, ethnic-specific calibration of polygenic risk scores (PRS) for predicting COPD has the potential to identify those with greatest need for recommended screening and targeted prevention. Methods: Incident COPD case status was identified from linkage to Medicare claims files which followed a total of 17,291 for PRS analyses from 1998-2014. We performed Cox regression accounting for pack-years smoked and duration quit at two time points of 3,917 COPD cases with genetic data. Genotyped data from MEC individuals from multiple SNP arrays were imputed to the Haplotype Reference Consortium panel (~39 million SNPs). From this repository, we extracted 82 independent risk loci identified from the largest (250,000 European individuals) lung function/COPD GWAS to date from the UK Biobank. To calculate the COPD PRS, we matched imputed dosages to the 82 reported UK Biobank risk allele by locus and summed MEC genotypes under a standard additive general linear model. We compared two Cox regression models 1) not including PRS and 2) including PRS. Results: From epidemiologic analysis, we find that smoking is highly predictive of COPD risk (as expected) and that even after adjusting for pack-years of smoking and years quit racial disparities are evident, with African Americans (Hazard Ratio (HR): 1.25, p=3.7 × 10−6) and Japanese Americans (HR: 1.14, p=0.017) having slightly increased risk of disease compared to European Americans; whereas, Native Hawaiians have similar risk as European Americans (HR=0.95, p=0.48) and Latinos have decreased risk (HR: 0.75, p=2.43 × 10−8). Testing the PRS, we found an 8% increase risk per standard deviation (HR:1.08, p=5.41 × 10−6) while ethnic group differences in risk remained quite similar after adjustment for the PRS. Testing for interaction between pack-years and PRS, we found a suggestive increase of the smoking effect for those with the highest levels of PRS (p=0.09). Conclusion: Based on the racial disparities present from our COPD findings, particularly the increased risks among African Americans and Japanese Americans, we will examine the excess relative risk over a lifetime and within 5-year age intervals. We are currently expanding our MEC genotyped repository which should double our sample size, improve ability to detect PRS-smoking interactions, as well as test PRS for lung cancer.
Citation Format: Linda M. Polfus, Meng Lin, S. Lani Park, David Conti, Jackie Porcel, Veronica W. Setiawan, Lynne Wilkens, Christopher A. Haiman, Loïc Le Marchand, Daniel O. Stram. Multiethnic polygenic risk scores and smoking interactions for chronic obstructive lung disease [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C048.