P018 Host genetics of adaptive and innate immunity in inflammatory bowel disease

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Aim Our aim is to identify variants of adaptive and innate immunity genes associated with Ulcerative Colitis (UC) and Crohn’s disease (CD), the Inflammatory Bowel Diseases (IBD), to identify patients at risk of severe disease, inform treatment strategies, and highlight novel therapeutic opportunities. Specific alleles of the HLA class I and class II genes, involved in adaptive immunity, have been associated with disease as well as disease severity. Genes involved in innate immunity [e.g., the STimulator of INterferon Genes ( STING ) gene, and Killer Immunoglobulin-type Receptor ( KIR ) genes, which encode receptors on Natural Killer cells], and the Haptoglobin ( HP ) gene’s HP2 allele , which encodes Zonulin, a regulator of intestinal tight junctions (Zonulin is not encoded by the HP1 allele), may also play a role in IBD risk. Methods We have developed amplicon-based Fluidigm Access Array Illumina MiSeq next generation sequencing genotyping assays for the HLA, KIR, and STING genes, and a PCR-based assay for detecting the HP1 and HP2 HP alleles. We are genotyping 2141 subjects, including controls, CD and UC patients (including those with medically refractory disease) using these assays. We apply BIGDAWG software for case/control association analyses of genotyping data for HLA class I and class II alleles, KIR genes, STING variants and Zonulin. Results The rare (frequency = 0.006) DRB1 ∗ 01:03 allele confers the highest UC or CD risk (odds-ratio (OR) = 4.98 for UC, 6.25 for CD, and 12.59 for medically refractory UC). Kaplan–Meiers analysis of time from diagnosis to colectomy in MRUC showed a more rapid decline for DRB1 ∗ 01:03 positive UC patients vs. DRB1 ∗ 01:03 -negative patients (OR = 2.84, p = 1.79E−09). KIR2DL3 homozygotes are protective for UC in the presence of the HLA C1/C2 KIR ligand genotype (OR = 0.49, p = 6.03E−04). The HP2 allele was associated with UC (OR = 4.57, p = 1.1E-02), as was HP2 homozygosity (OR = 5.14, p = 2.4E-02). Conclusions Genotyping of innate and adaptive immune genes associated with UC and CD can have powerful predictive value. For example, the high risk conferred by DRB1 ∗ 01:03 for CD, UC and MRUC may warrant earlier intervention, closer monitoring, and counseling about the importance of compliance. Zonulin also appears to confer UC risk. Genotyping multiple loci may produce more accurate risk assessments.