P1191 Genetic determinants for smoking behaviour improve our understanding of sporadic versus familial Inflammatory Bowel Disease

Abstract

Abstract Background Inflammatory bowel disease (IBD) is influenced by genetic and environmental factors. The latter are often difficult to quantify and may vary over time, unlike genetics. Here, instead of looking at actual smoking behaviour, we explored the impact of genetic determinants of smoking behaviour on IBD risk in sporadic and familial IBD. Methods We calculated polygenic scores (PRS) for smoking initiation, smoking cessation, age of smoking initiation, and cigarettes per day in 2784 sporadic cases (1700 CD, 1084 UC), 682 non-IBD controls, and 60 multiplex IBD families with ≥3 affected first-degree relatives (FDR) (142 CD, 31 UC and 100 unaffected FDR). PRS were calculated for different p-value thresholds (5e-8, 1e-5, 0.01, 0.05, 0.1, 0.5 and 1), and based on effect estimates of Saunders et al (Nature 2022, table 1). Groups were compared using logistic regression. P<1.43e-3 was the significance threshold for Bonferroni correction. Results Sporadic IBD cases had a higher PRS for smoking initiation than controls (p=4.49e-3), which was driven by the CD cases (p=7.17e-4, fig 1A). CD cases also showed a trend for a higher PRS for cigarettes per day (p=0.026). In familial cases compared to unaffected FDR, we observed some differences in PRS for smoking, but none survived multiple testing (fig 1B). Comparing familial and sporadic cases, we found that the PRS for age at smoking initiation was higher in familial than in sporadic UC (p=9.09e-4, fig 1C). Familial CD showed a trend towards a lower PRS for age at smoking initiation (p=0.023) and smoking cessation (p=0.013) than sporadic CD. Familial CD cases are thus more at risk than sporadic CD cases as they genetically tend to start smoking younger, while the opposite is seen for UC. Also, unaffected FDR of UC families showed a lower PRS for age at smoking initiation (p=5.47e-5, fig 1D) than controls, giving them additional protection. The PRS for smoking cessation (p=3.88e-5) and cigarettes per day (p=4.47e-3) was greater in unaffected FDR of mixed families than in controls, while familial mixed cases had a lower cigarettes per day PRS than sporadic cases (p=1.59e-4). Conclusion We found that genetic determinants of smoking behaviour are associated with disease risk in familial and sporadic IBD. While CD risk overall is associated with a greater genetic propensity for smoking initiation, the higher risk in families is linked to genetic age at start of smoking. Meanwhile, unaffected FDR of these families are protected through a higher genetic propensity to stop smoking in mixed families, or to start smoking sooner in UC families, compared to population controls. This study improves our understanding of familial vs sporadic IBD, and could help stratify individuals at risk of IBD.