• PANCREATITIS
• ALCOHOL
• GENE MUTATION
• TRYPSIN
• TRYPSINOGEN

To the Editor,

We read with great interest the article by Derikx et al 1 reporting a replication study of the association between common variants at the PRSS1–PRSS2 and CLDN2–MORC4 loci and chronic pancreatitis (CP). In agreement with the results originally reported by Whitcomb et al,2 they showed that the rs10273639 T allele at the PRSS1–PRSS2 locus protected against CP, whereas the rs7057398 C allele in RIPPLY1 and rs12688220 T allele in MORC4 at the CLDN2–MORC4 locus increased disease susceptibility.1 It has been recognised that geographical differences exist in the genetics of pancreatitis.3 Because the previous studies1 ,2 employed subjects of European ancestry only, we aimed to refine the association in Japanese patients with CP.

The three variants were genotyped by direct sequencing in 272 patients (men, n=245) with alcoholic CP (ACP), 197 patients (men, n=97) with idiopathic sporadic CP (ICP) and 480 controls (men, n=246). ACP was diagnosed in patients with CP who had consumed at least 80 g ethanol/day for at least 2 years in men or 60 g/day in women.1 All subjects were Japanese.

The allele and genotype frequencies of the variants are summarised in tables 1 and 2, respectively. The frequency of the PRSS1–PRSS2 rs10273639 T allele in the Japanese controls (77.8%) was higher than that in the previously studied European populations (42.4%; p<0.0001).1 The rs10273639 T allele showed the strongest association with male patients with ACP (p=0.0001, OR 0.57, 95% CI 0.43 to 0.76; table 1). An association was also observed for the comparison between male patients with ICP (p=0.0059, OR 0.59, 95% CI 0.40 to 0.86). We could not find a significant association between the rs10273639 and ACP in women, but this might have resulted from the small sample size (n=27). The TT genotype was under-represented in male patients with ACP (p=0.0001, OR 0.50, 95% CI 0.35 to 0.72) as well as in those with ICP (p=0.011, OR 0.53, 95% CI 0.33 to 0.86). The frequency of the RIPPLY1 rs7057398 C allele was higher in male patients with ACP (p=4.2×10⁻⁸, OR 2.78, 95% CI 1.90 to 4.08) and in patients with ICP (p=0.004 in men and p=0.0005 in women) than that in controls (table 1). Similarly, the MORC4 rs12688220 T allele was associated with ACP (p=3.7×10⁻⁷ in men and p=0.031 in women) and ICP (p=0.007 in men and p=0.001 in women).

We here showed that the three variants, originally identified by the results of a genome-wide association study,2 were associated with CP in Japan, suggesting that the association exists worldwide. Of note, the association of these variants with CP was found in patients with ACP and also in patients with ICP. Although the meta-analysis reported by Derikx et al 1 did not show an association, the association was significant in German patients with non-ACP, which accounted for more than half of the subjects included in the meta-analysis. The environmental factors that interact with these common variants and increase the risk of pancreatitis in patients with ICP are unknown. Possible candidate factors might include smaller amounts of alcohol and smoking.4 We have previously reported a nationwide case–control study in Japan showing that alcohol consumption of <80 g/day is associated with a risk of CP.4 In cases with CP, ORs (95% CI) for alcohol consumption of ≥20 to <40, ≥40 to <60 and ≥60 to <80 g/day were 2.6 (1.2 to 5.5), 3.2 (1.5 to 7.1) and 9.2 (4.1 to 20.3), respectively.4 Identification of such factors would contribute to further understanding of the pathobiology of CP and novel therapeutic approaches against this intractable disease.