Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis

Abstract

A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.

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“…In particular, N34S SPINK1 mutation is seen in about 40% of patients with idiopathic CP compared with 15–20% in western patients with idiopathic CP . Recently, we have shown that polymorphisms in CLDN2 and MORC4 genes are also associated with CP in India as has been reported in Caucasian patients with CP . In view of the differences in the etiology of CP between our patient population and western patients with predominantly alcohol‐related CP, the results of our study should be validated in other patient populations before their generalizability is accepted.…”

Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

“…Linking CP and PDAC from a genetic standpoint would be an extremely useful tool for identifying CP patients at risk of developing PDAC. We have selected five SNPs that have been studied and validated in CP and tested these in a large case‐control study, comprising almost 3,000 PDAC cases and 5,000 controls in the context of the international PANDoRA consortium. Our results do not suggest a strong effect of these five selected SNPs in PDAC susceptibility, although one of the variants, PRSS1‐PRSS2‐ rs10273639, showed a tendency of increasing the disease risk in the carriers of the minor allele ( p = 0.023).…”

The Emerging Role of MORC Family Proteins in Cancer Development and Bone Homeostasis

“…In addition to the common domains, MORC4 consists of four potential SUMOylation sites and is able to recruit Targeting of C‐terminal binding protein (CtBP) corepressors (Liggins et al, ). Further, MORC4 has been implicated in the occurrence of several kinds of inflammatory diseases, like Crohn's disease, ulcerative colitis (Soderman et al, ), tropical calcific pancreatitis (Paliwal et al, ), and alcohol or non‐alcohol chronic pancreatitis (Aghdassi et al, ; Derikx et al, ; Giri et al, ). Differential expression of MORC4 was found in diffuse large B‐cell lymphoma.…”