Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis

The CEL-HYB1 hybrid allele of the carboxyl ester lipase ( CEL ) gene and its pseudogene ( CELP ) has been associated with chronic pancreatitis (CP). Recent work indicated that amino acid positions 488 and 548 in CEL-HYB1 determined pathogenicity. Haplotype Thr488-Ile548 was associated with CP while haplotypes Thr488-Thr548 and Ile488-Thr548 were benign. However, functional analysis revealed that Thr488 is the primary determinant of CEL-HYB1 misfolding and associated endoplasmic reticulum (ER) stress. To address this contradiction, we analyzed a cohort from Hungary and found significantly increased CEL-HYB1 carrier frequency in CP cases (9/319, 2.8%) versus controls (5/618, 0.8%), yielding an odds ratio of 3.6 (95% confidence interval 1.2–10.7, P = 0.024). All CEL-HYB1 positive carriers from Hungary had the Thr488-Thr548 haplotype. We analyzed the haplotype distribution of reported CEL-HYB1 carriers from three European cohorts and found that 14/29 CP cases from Germany and 2/6 CP cases from Poland carried the Thr488-Ile548 haplotype, which was absent in CEL-HYB1 positive controls from Germany (n = 13) and Poland (n = 8). All patients (n = 17) and controls (n = 9) from France carrying CEL-HYB1 contained the Thr488-Thr548 haplotype. Functional studies using transfected cells indicated that both CEL-HYB1 haplotypes induced significant ER stress and the Thr488-Ile548 haplotype had a stronger effect. We conclude that the Thr488-Thr548 haplotype of CEL-HYB1 is widespread in Europe and increases CP risk by almost fourfold. In contrast, the Thr488-Ile548 haplotype is regionally restricted, but confers markedly stronger CP risk.