2.4　Concluding Remarks

The phenotype of TCP has undergone a remarkable change over the last few decades.There is more heterogeneity in the clinical profile which has prompted the researchers to investigate newer aspects of the disease pathophysiology.In addition to the role of（micro）nutrient deficiencies and other environmental factors，involvement of genetics is being emphasized.Genetic studies have provided some insights about the mechanistic of the disease pathophysiology.Several studies including ours have indicated that akin to phenotypic heterogeneity，genetic heterogeneity also exists between TCP and CP in the West.Further，our recent report demonstrates that rs10273639/rs4726576 variants that regulate PRSS1 expression，and CLDN2-MORC4 loci variants（rs7057398 and rs12688220）predict risk for non-alcoholic chronic pancreatitis entities like TCP as well.These results bear significance on several aspects.Firstly，it is one of the first reports suggesting a direct role for PRSS1 in the pathogenesis of TCP.Secondly，co-inheritance of p.N34S SPINK1 with PRSS1 or CLDN2-MORC4 risk allele is predicted to have an influence on the age of onset/presentation.These observations suggest potential utility of risk screening for these variants.Thirdly，risk allele frequency at these two loci vary significantly between different ethnic groups:the significantly lower frequency of rs10273639 risk allele in Asian populations including Indians compared with Europeans undermine a central role for PRSS1 in CP in Asians；contrastingly，higher frequency of the inflammation related SNPs in CLDN2-MORC4 loci suggest a more prominent role for inflammatory pathway in TCP pathophysiology.Above observations clearly indicate that that genetic predisposition likely plays a significant role in pathogenesis of TCP.These risk factors work via both‘trypsin-central’and‘trypsinindependent’pathways（Fig.11.7）.These genetic differences along with the environmental factors（nutrition，alcohol abuse）might be responsible for the observed phenotypic differences.

Fig.11.7　Advanced model for chronic pancreatitis in Indians:The presence of PRSS1 rs4726576 risk allele results in increased expression of trypsinogen within the pancreatic acinar cells.Compounding presence of mutated CTSB，mutated SPINK1 and defective CTRC leads to increased and persistent intracellular trypsin activity.Functionally defective CPA1 along with the presence of CLDN2 variants work via an alternative‘trypsin-independent’pathway(https://www.daowen.com)