DOP20 Genetic of vitamin D as predictor of response to adalimumab in Crohn’s Disease
Cusato, J.(1);Ribaldone, D.G.(1);Bertani, L.(2);Antonucci, M.(1);Tomasello, C.(3);Caviglia, G.P.(1);Dibetto, S.(1);Mangia, M.(1);Astegiano, M.(4);D'Avolio, A.(1)
(1)University of Turin, Department of Medical Sciences, Turin, Italy;(2)University of Pisa, Department of Translational Research and New Technologies in Medicine and Surgery, Pisa, Italy;(3)Ospedale Maria Vittoria, S.C. Farmacie Ospedaliere, Turin, Italy;(4)Molinette hospital, Unit of Gastroenterology, Turin, Italy
Background
Personalised medicine is the direction towards are converging many efforts of experts in inflammatory bowel diseases (IBDs). The advent of biological drugs, with anti-TNF as first category, have revolutionized the managements of these patients. Unfortunately, several unmet needs are present, like an efficacy in about two third of the patients, onset of side effects like infections, paradoxical IMIDs. Being able to treat with these drugs only patients who will respond would avoid losing time without disease improvement and possible side effects.
Vitamin D is important for several biological functions, such as regulation of the immune response and modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. Vitamin D is activated by cytochrome (CYP) 27B1, inactivated by CYP24A1, transported in kidney by Vitamin D binding protein (VDBP, encoded by GC gene) and carries out its activities through its receptor (VDR).
No data are available concerning vitamin D genetics and response to anti-TNF drug adalimumab.
The aim of this study was to describe the relationship between vitamin D pathway-related gene single nucleotide polymorphisms (SNPs) and adalimumab clinical outcome in a cohort of patients affected by Crohn’s disease.
Methods
We performed a multi-centre prospective study including patients affected by Crohn’s disease who started adalimumab therapy. SNPs in CYP27B1, CYP24A1, GC and VDR genes were analysed. Clinical outcome was considered as clinical response and remission at 3 months of therapy.
Results
We enrolled 69 patients. Median age was 40 (IQR 31-56) years, males were 40 (58%). Median basal calprotectin was 396 (IQR 188-851) mg/Kg, and 36 (53.7%) had a positive PCR value.
We documented the following associations: CYP27B1+2838 CT/TT with perianal disease (p= 0.002), basal calprotectin (p= 0.018) and T3 calprotectin (p= 0.035), figure 1; CYP27B1-1260 GT/TT with perianal disease (p= 0.006), basal calprotectin (p= 0.036) and T3 calprotectin (p= 0.024); VDR ApaI CA/AA with basal calprotectin (p= 0.014) and T3 calprotectin (p= 0.036); VDR BsmI GA/AA with perianal disease (p= 0.036), and GC 1296 TG/GG with basal calprotectin (p= 0.014), figure 2.
GC 1296 TG/GG genotype polymorphism (p= 0.044, figure 3) predicted clinical remission at multivariate analysis.
Finally, median concentrations adalimumab trough levels at 3 months were 7.4 (IQR 5.5; 11.7) ug/mL. CYP24A1 3999 (p=0.025) and VDR TaqI (p=0.016) SNPs affected these levels.Conclusion
This is the first study reporting the association between vitamin D pathway-related genetics and adalimumab treatment in a cohort of patients affected by IBD. Further studies in different and larger cohorts are needed to clarify these aspects.