NKX2–3 RS10883365 is associated with disease susceptibility to both Crohn's disease and ulcerative colitis while IRGM RS13361189 variant allele increased the risk for Crohn's disease in Eastern European patients
Background: Sequence variants in the autophagy gene IRGM and NKX2–3 has been reported to contribute to Crohn's disease (CD) Susceptibility while ECM1 to ulcerative colitis (UC) in genome-wide association scans in North America and Western Europe. The aim of this study was to investigate variants of the above genes and examine genotype-phenotype relationships in a independent Eastern European IBD cohorts.
Methods: 1707 Hungarian and Czech subjects were analysed (CD: 810, age: 37.1±12.6 years, duration: 10.7±8.4 years and UC: 428, age: 43.7±15.0 years, duration: 12.6±9.9 years, and 469 healthy controls). IRGM rs13361189, NKX2–3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCycler allele discrimination method. Detailed clinical phenotypes were determined by reviewing the medical charts.
Results: NKX2–3 rs10883365 variant allele was associated with increased risk for both CD (p=0.009, OR: 1.24, 95%CI: 1.06–1.48) and UC (p=0.001, OR: 1.36, 95%CI: 1.13–1.63), while variant IRGM allele inceased the risk for CD (p=0.029, OR: 1.36, 95%CI: 1.03–1.79). In contrast, ECM1 rs13294 was not associated with either CD or UC. In CD, presence of the variant IRGM allele was associated with colon only location (in carriers: 25% vs. wild-type: 17.1%, p=0.02, OR: 1.62, 95%CI: 1.07–2.44). In UC, homozygous carriage of the ECM1 variant allele was associated to cutaneous manifestations (11.5% in carriers vs. 3.7% in patients with wild-type, p=0.02, OR: 3.36, 95%CI: 1.48–7.63). In addition, carriage of the variant alleles did not predict use of or resistance to steroids, azathioiprine or need for or medium term efficacy of infliximab, need for surgery or smoking habits.
Conclusions: We confirmed that NKX2–3 and IRGM are susceptibility loci for IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations found in this study.