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Chronic obstructive pulmonary disease (COPD) is a complex genetic disorder, strongly associated with smoking. However, 25-45% of the individuals who develop COPD have never been exposed to (environmental) smoking. We hypothesize that these individuals have a strong genetic susceptibility for COPD with rare, pathogenic genetic variants underlying its development. We studied 36 individuals from the prospective Dutch Lifelines cohort with COPD (LLN of FEV1/FVC In total, we found 7,638 unique predicted pathogenic genetic variants in the 36 selected individuals. All 36 individuals carry at least 1 variant (range 1-7) in the top-100 prioritized genes in the COPD network. GeneNetwork pathway analysis revealed that 56 of the prioritized genes were significantly enriched for biological processes involved in cilium functioning. Our results suggest that rare pathogenic variants in ciliary genes underlie non-smoking related COPD and their role in a mono- or oligogenic form of COPD should be further investigated.

There is ongoing debate on the association between eosinophil count and diseases, as previous studies were inconsistent. We studied the relationship of eosinophil count with 22 complex metabolic, cardiac, and pulmonary traits and diseases. From the population-based LifeLines Cohort Study (N = 167,729), 13,301 individuals were included. We focused on relationship of eosinophil count with three classes of metabolic (7 traits, 2 diseases), cardiac (6 traits, 2 diseases), and pulmonary (2 traits, 2 diseases) outcomes. Regression analyses were applied in overall, women and men, while adjusted for age, sex, BMI and smoking. A p-value of