Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn’s disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; Pcombined = 4.88 × 10−94). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10−4). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.
Objective
Genome wide association studies (GWAS) of gastric cancer have reported differences in SNP associations for tumor subtypes, particularly when divided by location into the gastric cardia versus the noncardia.
Design
Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric noncardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 noncardia cases, and 7548 controls for replication from two Chinese studies and one from Korean. From the GWAS we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer, and 1 SNP in MUC1 for replication testing.
Results
We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p = 2.77×10−12) and noncardia cancers (p = 3.95×10−21) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77–0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric noncardia cancer risk (p = 2.50 ×10−8), with OR (95% CI) of 1.18 (1.12–1.26), but there was only a nominal association for cardia cancer (p = 1.47×10−2). We also confirmed a previously reported association for rs4072037 in MUC1 with p = 6.59×10−8 for total GC and similar estimates for cardia and noncardia cancers. Three SNPs in PSCA previously reported to be associated with gastric noncardia cancer showed no apparent association for cardia cancer.
Conclusion
Our results suggest that associations for SNPs with gastric cancer show some different results by tumor location in the stomach.
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