Inherited smoking behaviour and Human Epididymis Protein 4 predict smoking-related morbidity and mortality

Abstract: GENERAL AIM: To investigate prognostic markers identifying smokers with increased risk of smoking-related diseases in the population. BACKGROUND: Gene variance in the BDNF- respectively CHRNA-gene has been implicated in different smoking behaviours and the risk alleles have also demonstrated an additional risk increase of smoking-related diseases. The Human Epididymis Protein 4 (HE4) is a cancer biomarker that is also affected by active smoking. AIMS: To replicate the associations between the genotypes of BDNF and CHRNA with smoking phenotypes and to test if the genotypes predicted events from tobacco-related diseases. To investigate the association between smokers and HE4 and to test if altered HE4 could predict future events of smoking-related mortality and morbidity in the population (Study III) or 90-day mortality (Study IV) in an acute setting.SUBJECTS: Study I and II was based on the prospective, population-based cohort study of Malmö Diet and Cancer Study (MDCS)(n=30 447), and study III, on the sub-study MDC-Cardiovascular cohort (MDC-CC) (n=6102). In paper IV, a population presenting with acute dyspne at the emergency department of Malmö was investigated, ADYS (n= 963).METHODS: Genotyping of the two polymorphisms, rs4923461 (BDNF) and rs1051730 (CHRNA) was performed in MDCS and correlated to smoking behaviour. In all four studies, participants were stratified according to smoking status and Cox proportional hazard models were used to determine the correlations of the polymorphisms or the levels of HE4 to outcomes during follow-up. RESULTS: The associations with smoking behaviour were confirmed for both genotypes. In current smokers, the risk alleles of BDNF and CHRNA significantly predicted all-cause mortality. CHRNA also predicted a higher risk of incident smoking-related diseases. No associations were seen in never smokers. In MDC-CC, HE4-levels were distinctly elevated in current smokers but not in the ADYS-population. In MDC-CC, elevated HE4 predicted all-cause mortality irrespective of smoking status and in ADYS, HE4 strongly predicted 90-day mortality regardless of underlying disease or smoking status.CONCLUSION: Gene variance of BDNF and CHRNA have impact on smoking behaviour and predicts an increased risk of smoking-related complications in smokers. Plasma levels of HE4 predicts mortality in a long- and short-term perspective and may be used as a disease risk marker in smokers and possibly also in non-smokers. In the future, genotype of BDNF and CHRNA polymorphisms and HE4 levels may be helpful in identifying patients with a higher risk of complications.