Impact of Amerindian ancestry on clinical outcomes in Crohn's disease and ulcerative colitis in a Latino population

Abstract

Research in Inflammatory Bowel Disease (IBD) assessing the genetic structure and its association with IBD phenotypes is needed, especially in IBD-underrepresented populations such as the South American IBD population. Aim. We examine the correlation between Amerindian ancestry and IBD phenotypes within a South American cohort and investigate the association between previously identified IBD risk variants and phenotypes. We assessed the ancestral structure (IBD = 291, Controls = 51) to examine the association between Amerindian ancestry (AMR) and IBD variables. Additionally, we analyzed the influence of known IBD genetic risk factors on disease outcomes. We used Chi-square and Fisher's tests to analyze the relationship between phenotypes and ancestry proportions, calculating odds ratios (OR) and confidence intervals (CI). Logistic regression examined genetic variants associations with IBD outcomes, and classification models for predicting prolonged remission were developed using decision tree and random forest techniques. The median distribution of global ancestry was 58% European, 39% Amerindian, and 3% African. There were no significant differences in IBD risk based on ancestry proportion between cases and controls. In Ulcerative colitis (UC), patients with a high Amerindian Ancestry Proportion (HAAP) were significantly linked to increased chances of resective surgery (OR = 4.27, CI = 1.41-12.94, p = 0.01), pouch formation (OR = 7.47, CI = 1.86-30.1, p = 0.003), and IBD reactivation during COVID-19 infection (OR = 5.16, CI = 1.61-6.53, p = 0.005). Whereas, in the Crohn's Disease (CD) group, the median Amerindian ancestry proportion was lower in the group with perianal disease (33.5% versus 39.5%, P value = 0.03). CD patients with High Amerindian Ancestry proportion had lower risk for surgery (OR = 0.17, CI = 0.03-0.83, P value = 0.02). Our study highlights the impact of Amerindian ancestry on IBD phenotypes, suggesting a role for genetic and ancestral factors in disease phenotype. Further investigation is needed to unravel the underlying mechanisms driving these associations.

Keywords: Ancestry; Inflammatory bowel disease; South America.

Fig. 1

Population Structure and Genetic Ancestry Composition of Chilean Individuals. (A) Principal Component Analysis (PCA): PCA plot of SNP data showing clustering by superpopulation (AFR: African populations, AMR: American populations, EAS: East Asian populations, EUR: European populations, SAS: South Asian populations). PC1 (47%) and PC2 (26%) capture most of the genetic variation, with Chilean individuals clustering with the Admixed American populations, reflecting their admixed ancestry. (B) Global ancestry proportions of Chilean individuals inferred using ADMIXTURE (K = 3). Three primary ancestry components are identified: European (EUR, green), Amerindian (AMR, orange), and African (AFR, red). Reference populations from 1000 Genomes Project (ASW, TSI, IBS, MXL, PUR, CLM, PEL) were included for comparison. (C) Ancestry Proportions: Boxplots displaying the proportion of European, Amerindian, and African ancestry in the Chilean cohort. The results highlight the predominance of European (x = 58%) and Amerindian(x = 39%) ancestry, with a smaller African (x = 3%) component.

Fig. 2

Impact of Amerindian Ancestry on Clinical Variables in IBD Subgroups. (A) Median Amerindian ancestry proportion across various clinical features in IBD (Median group yes versus Median group no). A higher median Amerindian ancestry proportion was associated with early-onset IBD/UC, a severe disease course (IBD), and UC flare during COVID-19 infection. Conversely, a lower median Amerindian ancestry proportion is linked to prolonged clinical and endoscopic remission in UC and IBD, current use of biological therapy in IBD, and perianal disease in CD (B) High Amerindian Ancestry Proportion Impact on Clinical Outcomes. We defined HAAP as an Amerindian ancestry proportion equal to or greater than 43%. In the UC group, a high proportion of patients with HAAP had a history of pouch formation, surgical resection, and IBD flare during a COVID-19 infection. Conversely, most patients who achieved clinical and endoscopic remission over a year (UC), underwent resective surgery (CD), had a previous history of gastrointestinal infection (IBD), experienced past infection by Clostridioides (IBD), or had prolonged clinical and endoscopic remission (IBD) did not have HAAP. IBD: Inflammatory Bowel Disease, UC: Ulcerative Colitis, CD: Crohn’s Disease, HAAP: High Amerindian Ancestry Proportion, COVID-19=Coronavirus 19 infection.

Fig. 3

Top ten features identified in the Decision Tree model for predicting Prolonged Clinical and Endoscopic Remission. In this classifier model for predicting prolonged clinical and endoscopic remission, the most important features were associated with a severe phenotype, including a history of surgical failure, use of anti-TNFa medication, and relapse within the past years. Other significant predictors included sex, creatinine levels, and the genetic variant rs921720.

Fig. 4

Top ten features identified in the Random Forest model for predicting Prolonged Clinical and Endoscopy Remission. The Random Forest classifier for Prolonged Clinical and Endoscopic Remission identified several key clinical features. These included characteristics associated with a severe phenotype, such as a history of surgical failure, use of anti-TNF medication, and relapse within the past years. Additionally, features such as clinical and endoscopic remission over a year, creatinine levels, hemoglobin levels, age at diagnosis, loss of response to anti-TNF medication, Glutamato Piruvate Transaminase (GPT) levels, white cell count, the genetic variant rs7236492, and clinical remission were also found to be significant predictors.