Crohn's Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes.

Marta Kaczmarek-Ryś,Ryszard Słomski,Tomasz Banasiewicz,Wojciech Cichy,Andrzej Hnatyszyn,Emilia Lis,Piotr Krokowicz,Maciej Borejsza-Wysocki,Jarosław Walkowiak,Jacek Paszkowski,Andrzej Pławski,Agnieszka Dobrowolska,Elżbieta Czkwianianc,Iwona Krela-Kaźmierczak,Szymon Tytus Hryhorowicz

doi:10.3390/jcm10173777

Abstract

The genetic background and the determinants influencing the disease form, course, and onset of inflammatory bowel disease (IBD) remain unresolved. We aimed to determine the NOD2 gene haplotypes and their relationship with IBD occurrence, clinical presentation, and onset, analyzing a cohort of 578 patients with IBD, including children, and 888 controls. Imaging or endoscopy with a histopathological confirmation was used to diagnose IBD. Genotyping was performed to assess the differences in genotypic and allelic frequencies. Linkage disequilibrium was analyzed, and associations between haplotypes and clinical data were evaluated. We emphasized the prevalence of risk alleles in all analyzed loci in patients with Crohn disease (CD). Interestingly, c.2722G>C and c.3019_3020insC alleles were also overrepresented in ulcerative colitis (UC). T-C-G-C-insC, T-C-G-T-insC, and T-T-G-T-wt haplotypes were correlated with the late-onset form of CD (OR = 23.01, 5.09, and 17.71, respectively), while T-T-G-T-wt and C-C-G-T-wt were prevalent only in CD children (OR = 29.36, and 12.93, respectively; p-value = 0.001). In conclusion, the presence of c.3019_3020insC along with c.802C>T occurred as the most fundamental contributing diplotype in late-onset CD form, while in CD children, the mutual allele in all predisposing haplotypes was the c.2798 + 158T. Identifying the unique, high-impact haplotypes supports further studies of the NOD2 gene, including haplotypic backgrounds.

Highlights

The incidence of inflammatory bowel disease (IBD) in Western European populations has been estimated at 100–300 per 100,000 and. most alarmingly, it is still increasing [1].Despite extensive studies over the past decade [2,3,4,5,6,7], the etiology and pathogenesis of IBD are still not fully understood
In CD patients, the risk alleles are prevalent. Their frequencies are different comparing patients with CD and ulcerative colitis (UC). This observation led us to conclude that the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene and its sequence variations remain among the most critical genetic backgrounds of IBD, contributing to susceptibility to Crohn’s disease
Two decades of research and numerous scientific reports have not yet unraveled the molecular basis of IBD. They have shown that CD and UC are distinct diseases conditioned by multiple genetic factors [21,22,23,24]; the NOD2 gene and its sequence variations remain the most influential genetic disease-triggering factors

Summary

Introduction

The incidence of inflammatory bowel disease (IBD) in Western European populations has been estimated at 100–300 per 100,000 and. most alarmingly, it is still increasing [1].Despite extensive studies over the past decade [2,3,4,5,6,7], the etiology and pathogenesis of IBD are still not fully understood. In 1996 [8], identified the 16q12 region of the human genome as the first disease-associated locus (IBD1). The discovery of the NOD2 gene in this locus led to the subsequent research and identification of IBD-related vulnerability loci. Genomewide association studies (GWASs) and subsequent replication studies have provided further insights on IBD’s pathogenesis by determining over 200 genetic risk loci and over 30 non-conservative mutations in the NOD2 gene [6,9,10,11,12,13,14]. The role of novel IBD-associated loci, of which around 30 are shared between Crohn’s disease (CD) and ulcerative colitis (UC), is still less known than IBD1, within which DNA sequence variations remain the most influential genetic disease-triggering factors

Objectives

Methods

Results

Conclusion