Background: Telomere length (TL) is a predictor of lung cancer risk, but the direction of this association differs between and prospective and case-control studies. This discrepancy may be attributed to reverse causation in the latter, due to disease-related changes in TL that is measured after diagnosis or treatment. To overcome these limitations and characterize the relationship between TL and lung cancer risk we carried out observational and mediation analyses, and a 2-stage Mendelian Randomization (MR) analysis, where we developed novel genetic instruments for TL and tested the association with lung cancer using 20 OncoArray studies in the Transdisciplinary Research in Cancer of the Lung group of the International Lung Cancer Consortium.
Methods: The observational analysis examined TL measured using qPCR in 1128 cases and 928 controls. Odds ratios (OR) for TL were adjusted for age, sex and cigarette pack-years. Mediation analysis was used to estimate the% of the lung cancer association in 5p15 that operates through TL. To develop novel TL instruments, variants identified through deep sequencing of the 5p15 locus were genotyped in 900 controls. Variants that met MR criteria were combined into a single instrumental variable (IV), and its association with TL was estimated. We also used 6 previously identified TL predictors (p<5×10-8) as genetic instruments: rs10165485 (ACYP2), rs10936599 (TERC), rs11100479 (NAF1), rs9420907 (OBFC1), rs6028466 (DHX35), rs755017 (RTEL1). For these SNPs association estimates for TL were obtained from the literature. To estimate the association with lung cancer risk, we tested all 7 IVs using data from 14324 lung cases and 10783 controls in OncoArray. Lastly, to obtain a summary estimate for the causal effect of TL on lung cancer risk, ORs from OncoArray were combined with â-TL estimates using a likelihood-based MR model.
Results: The observational analysis suggested that longer TL is associated with decreased lung cancer risk (OR = 0.94, p = 0.04). This was more pronounced for squamous carcinoma (OR = 0.77, p = 1.1×10-4). We also showed that TL mediates up to 8% (p<0.05) of the lung cancer signal in 5p15. In the first stage of the MR analysis, we identified 8 5p15 SNPs that were associated with TL (p<5×10-3), including 6 novel rare variants, not previously associated with TL. Together these variants were reliably associated with TL (â = 0.15, p = 1.8×10-7) and explained 2.3% of variance in TL. Using this new instrument and 6 other SNPs as IVs, our MR analysis showed that longer TL is a risk factor for lung cancer (OR = 1.77, 95% CI: 1.32-1.54), especially adenocarcinoma (OR = 2.02, 95% CI: 1.29-3.71).
Conclusions: We developed novel genetic instruments for TL, and confirmed that genetically predicted longer TL is associated with increased lung cancer risk. These findings suggest that previously reported associations of long TL with decreased risk were likely due to residual confounding by smoking, age and/or reverse causation.