P1298 The Paradoxical Impact of Amerindian Ancestry on Clinical Phenotypes in Crohn’s Disease and Ulcerative Colitis: A Study in a South American Population
Authors: Pérez T , Bustamante M L , Alvares D , Alvarez-Lobos M , Azocar L , Segovia Melero R , Ascui G , Aguilar N , Estela R , Hernández-Rocha C , Silva V , Kalmer L , De La Vega A , Arriagada E , Pavez-Ovalle C , Moraga Quinteros C , Miquel J F , Di Genova A 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD) is on the rise in South America, but this population remains underrepresented in IBD genetic studies. Moreover, the genetic structure varies across South American countries, highlighting the need for studies that assess genetic structure and its association with IBD phenotypes. We conducted a study to examine the correlation between Amerindian ancestry and IBD phenotypes within a South American cohort. Additionally, we investigated the association between previously identified IBD risk variants and IBD phenotypes.

Methods
We performed a global ancestry analysis using ADMIXTURE. For our analyses, we employed a reference panel of populations obtained from the 1000 Genomes Project and HapMap. We assessed ancestral structure in 291 IBD patients and 51 controls, aiming to examine the association between Amerindian (AMR) ancestry and IBD variables. Additionally, we evaluated the impact of previously identified IBD risk variants on IBD clinical outcomes. To compare the different groups, we used statistical tests (Chi-square for frequency and Mann-Whitney U test for median comparisons). Predictive models were developed to analyse the data in greater detail.

Results
The median ancestry distribution was 58% European, 39% Amerindian, and 2% African. There were no significant differences in IBD risk based on ancestry proportions between cases and controls. Ulcerative colitis (UC) patients diagnosed before the age of 40 had a higher median proportion of Amerindian ancestry compared to those diagnosed later (39.9% versus 37.4%, P-value = 0.01). In contrast, UC patients with prolonged clinical and endoscopic remission had a lower median proportion of Amerindian ancestry (35% versus 39%, P-value = 0.02). In the Crohn’s disease (CD) group, the median proportion of Amerindian ancestry was lower in those with perianal disease compared to those without this condition (33.5% versus 39.5%, P-value = 0.03). Additionally, only 6% of patients who underwent resection surgery had a higher proportion of Amerindian ancestry. The presence of at least one outcome associated with a severe disease course was the most important predictor for prolonged remission, with an importance of 85% in the decision tree and 75% in the Random Forest model. Among the SNPs associated with prolonged clinical and endoscopic remission, the reference genotype was found to be the most prevalent for the following SNPs: rs6568421, rs11150589, rs6837335, and rs4656958.

Conclusion
Our study suggests an impact of Amerindian ancestry on IBD phenotypes. Additionally, variations in the influence of Amerindian ancestry were observed between UC and CD patients. Further research is needed to unravel the underlying mechanisms driving these associations.

References
Ye BD, McGovern DPB. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Exp Rev Clin Immunol 2016;12:1091–1107. doi: 10.1080/1744666X.2016.1184972
Jostins L, Ripke S, Weersma RK, et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012;491:119–124.4
Liu JZ, Van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015;47:979–986.
Walker DG, Williams HR, Bancil AS, et al. Ethnicity differences in genetic susceptibility to ulcerative colitis: A comparison of Indian Asians and white Northern Europeans. Inflamm Bowel Dis 2013;19:2888–2894.
Pérez-Jeldres T, Pizarro B, Ascui G, et al. Ethnicity influences phenotype and clinical outcomes: comparing a South American with a North American inflammatory bowel disease cohort. Medicine 2022;101:e30216.
Pérez-Jeldres T, Magne F, Ascui G, et al. Amerindian ancestry proportion as a risk factor for inflammatory bowel diseases: results from a Latin American Andean cohort. Front Med (Lausanne). 2023;10:1258395. Published 2023 Oct 27. doi:10.3389/fmed.2023.1258395