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.
Highlights
Chronic pancreatitis (CP) is a progressive and irreversible inflammatory disorder of pancreas leading to abdominal pain, diabetes and exocrine insufficiency
Various risk factors for CP are known such as alcohol, smoking, hereditary, metabolic but etiology is not known in the majority of patients termed as having Idiopathic chronic pancreatitis (ICP) [2, 3]
Significance achieved at P = 0.05/9 (α = 0.0055) after Bonferroni correction
Summary
Chronic pancreatitis (CP) is a progressive and irreversible inflammatory disorder of pancreas leading to abdominal pain, diabetes and exocrine insufficiency. Various risk factors for CP are known such as alcohol, smoking, hereditary, metabolic but etiology is not known in the majority of patients termed as having Idiopathic chronic pancreatitis (ICP) [2, 3] Even in those with known risk factors, the role is not fully explained by the injurious agent such as alcohol, as most other individuals with same risk factor do not develop CP. The risk susceptibility for CP cannot be fully explained by known genetic mutations In this regard, a genome wide association study (GWAS) on pancreatitis identified polymorphisms at X-linked CLDN2 locus being robustly associated with recurrent acute pancreatitis and predominantly alcohol-related chronic pancreatitis in North American patients of European ancestry [10]
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