Small Bowel Location, Stricturing Behavior, Vitamin D Receptor Polymorphism, and Metabolic Disease Susceptibility Genes Are Associated With NAFLD in Crohn’s Disease

Abstract

Introduction: The relationship between metabolic syndromes and IBD is complex; there are shared susceptibility genes; abnormal fat deposition in CD with pro-inflammatory effects; and a reported NAFLD prevalence of 8% in IBD compared to 30% of the ‘healthy’ U.S. population. Our aim was to investigate the prevalence of NAFLD in a tertiary referral center and investigate clinical, serologic, and genetic associations with NAFLD in IBD patients. Methods: Patients included in our IBD repository with abdominal imaging were eligible for inclusion. Charts, CT, and U.S. reports were reviewed to determine NAFLD status. Demographic, and clinical (Montreal classification, BMI), characteristics were obtained by chart review. Serology data (ASCA, OMPc, CBir1, anti-I2 & ANCA) were generated. Genotyping was performed by Illumina technology including genome-wide and immunochip platforms. Standard statistical tests were used to test for association with appropriate correction for population structure. Results: In 1,304 IBD cases (71% CD, 29% UC/IBDU) we observed an NAFLD prevalence of 9.7%. The Prevalence of NAFLD in CD and UC was similar. NAFLD IBD patients had increased BMI (p<2.2E-16). Table 1 shows CD phenotypic associations with NAFLD. NAFLD was not associated with disease extent in UC. There were no significant associations with NAFLD for age of IBD onset, gender, need for surgery, or smoking. In CD, we observed a strong correlation between anti-I2 level (p=0.005) and anti-I2 status (p=0.003) and NAFLD. In UC, ASCA IgG level was associated with NAFLD (p=0.001). CD serological quartile sum analyses revealed a trend towards association with NAFLD (p=0.06). Immunochip analyses revealed association with: metabolic disease genes (LECT2 (hepatokine linking obesity to insulin resistance), CCR5, CAMTA1, GRIP1) and other immune disease loci (TNFRSF1A, IRAK3) with p-values<10 (-5); as well as known IBD genes (CDKAL1, CALM3, vitamin D receptor (VDR), GPR183, IFNGR2/IL10RB (all p<0.05)). GWAS analyses revealed 4 loci p<10 (-5) including MYO5A (an insulin target in adipose tissue) and genes highly expressed in liver (SNTG2). These genes implicate insulin resistance and metabolic disease pathways in NAFLD development in IBD.Table 1: IBD Phenotypic Associations With NAFLDConclusion: NAFLD is associated with raised BMI and metabolic disease genes in IBD as well as stricturing small bowel disease and anti-I2 in CD. These findings may help identify IBD patients at risk of hepatotoxicity from medications such as methotrexate. Further work understanding this relationship is warranted.