TRPV6, a new entrant as a susceptibility gene in chronic pancreatitis: evidence from a systematic review and meta-analysis

BACKGROUND: Pancreatitis, a debilitating disease, is orchestrated by many etiological factors. Besides the known causal genes, including PRSS1, SPINK1, CPA1, CFTR, etc., of late, TRPV6 has emerged as a new candidate in the list. We aimed to investigate the role of TRPV6 and its genetic variations in the etiopathology of pancreatitis. METHODS: We conducted a systematic review and meta-analysis of published articles on TRPV6 and pancreatitis in the databases including PubMed, Google Scholar, Medline, and Web of Science. Pooled odds ratios (pORs) and 95% confidence intervals (CIs) were determined to evaluate the associations of common TRPV6 variants with the risk of pancreatitis. Bioinformatic analysis was also performed to evaluate the pathogenicity of reported variants. RESULTS: Unlike controls, the pathogenic TRPV6 variations were overrepresented in pancreatitis cases from diverse ethnicities. We observed a cumulative inverse association of p.Ala18Ser (pooled OR = 0.51; 95%CI:0.4–0.61; p < 0.001) with the pancreatitis risk. A high risk of developing pancreatitis was found in subjects harbouring the variant genotype of p.Ile223Thr (pOR = 1.75; 95%CI:1.03–2.47;p < 0.001). A dysregulated Ca2+ ion homeostasis is central in modulating the pancreatitis risk among subjects harbouring TRPV6 variants. CONCLUSION: Evidence suggests that TRPV6 is a novel gene to modulate the pancreatitis risk, and the defective variants can be inherited in families. This discovery offers a novel target for therapeutic intervention as well. The findings of the study support the inclusion of TRPV6 in genetic testing panels for pancreatitis, while recognizing that further large-scale studies will help refine its clinical utility.