MHC-Related Shared Genetic Susceptibility Between Ulcerative Colitis and Gastric Cancer in East Asians

Observational studies in East Asia have not shown increased gastric cancer risk in ulcerative colitis, whereas a previous genetic analysis reported a positive association. Because both diseases have major histocompatibility complex (MHC) signals, we assessed whether the association was most apparent in MHC variants under ancestry-matched instrument selection.

We performed a two-stage, two-sample Mendelian randomization study of 12 East Asian datasets (11 immune-related phenotypes) and a gastric cancer genome-wide association study (7921 cases; 159,201 controls), with instruments selected against the 1000 Genomes East Asian panel. For ulcerative colitis, we compared all, MHC, and non-MHC variants, evaluated signal overlap at HLA-DQA1/DQB1, and assessed cross-disease specificity.

Ulcerative colitis was the only phenotype associated with gastric cancer after false-discovery-rate correction (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.09-1.24; q = 1.37 × 10^-4). The MHC estimate was similar (OR 1.18, 95% CI 1.11-1.26), whereas the non-MHC estimate was close to 1 but rested on only two variants and remained imprecise (OR 1.00, 95% CI 0.86-1.17). The traits showed overlapping signals at HLA-DQA1/DQB1, and the MHC variants were associated with several other immune diseases.

The positive association was most apparent in MHC variants that were not specific to ulcerative colitis. The association therefore appears to be largely carried by pleiotropic MHC variants, although these data cannot establish the pathway that explains it.