ABCMdb

PMID: 22427236

Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bodeker H, Keim V, Ruffert C, Mossner J, Kage A, Stumvoll M, Groneberg D, Kruger R, Luck W, Treiber M, Becker M, Witt H
CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?
Gut. 2012 Mar 17., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln Results Frequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. Login to comment 69 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Tyr1092* ABCC7 p.Ile1005Arg ABCC7 p.Asp1152His ABCC7 p.Leu997Phe ABCC7 p.Glu60* The following CFTR variants were analysed with specific FRET probes: p.E60X, p.R75Q, p.G85E, p.R117H, p.I148T, c.621 +1G>T (IVS4+1G>T), c.711+1G>T (IVS5+1G>T), c.1078delT, p.R334W, p.R347P, 9-13TG, 5-9T, p.A455E, p.M470V, p.F508del, c.1716G>A (p.E528E), c.1717-1G>A (IVS10-1G>A), p.G542X, p.S549N, p.R553X, p.R560T, c.1898+1G>A (IVS12 +1G>A), c.2143delT, c.2183AA>G, c.2562T>G, c.2657+5G>A (IVS14B+5G>A), p.L997F, p.I1005R, p.Y1092X, p.D1152H, p.R1162X, c.3659delC, p.S1235R, p.S1251N, p.W1282X, p.N1303K, and c.4389G>A. Login to comment 72 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Tyr1092* ABCC7 p.Ile1005Arg ABCC7 p.Asp1152His ABCC7 p.Leu997Phe ABCC7 p.Glu60* The following CFTR variants were analysed with specific FRET probes: p.E60X, p.R75Q, p.G85E, p.R117H, p.I148T, c.621 +1G>T (IVS4+1G>T), c.711+1G>T (IVS5+1G>T), c.1078delT, p.R334W, p.R347P, 9-13TG, 5-9T, p.A455E, p.M470V, p.F508del, c.1716G>A (p.E528E), c.1717-1G>A (IVS10-1G>A), p.G542X, p.S549N, p.R553X, p.R560T, c.1898+1G>A (IVS12 +1G>A), c.2143delT, c.2183AA>G, c.2562T>G, c.2657+5G>A (IVS14B+5G>A), p.L997F, p.I1005R, p.Y1092X, p.D1152H, p.R1162X, c.3659delC, p.S1235R, p.S1251N, p.W1282X, p.N1303K, and c.4389G>A. Login to comment 77 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln We excluded CFTR variants p.R75Q, p.I148T, the poly-T tract and p.E528E, PRSS1 variant p.S124F, SPINK1 variants c.1-52G>T and p.P55S, and CTRC variants p.R37Q, p.K151N and p.K172E from all calculations, because of missing functional data or a missing genetic association. Login to comment 80 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln We excluded CFTR variants p.R75Q, p.I148T, the poly-T tract and p.E528E, PRSS1 variant p.S124F, SPINK1 variants c.1-52G>T and p.P55S, and CTRC variants p.R37Q, p.K151N and p.K172E from all calculations, because of missing functional data or a missing genetic association. Login to comment 91 ABCC7 p.Ile148Thr ABCC7 p.Ser1235Arg Notably, p.I148T was never found in cis with c.3199del6, and p.S1235R was always associated with p.G628 (wild-type). Login to comment 94 ABCC7 p.Ile148Thr ABCC7 p.Ser1235Arg Notably, p.I148T was never found in cis with c.3199del6, and p.S1235R was always associated with p.G628 (wild-type). Login to comment 107 ABCC7 p.Arg117His ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln Except one (p.R117H (7T/7T)/p. S1235), these compound heterozygotes were excluded in the overall computations, because CFTR variant p.R75Q, p.I148T, 5T or p.E528E was present in at least one allele. Login to comment 111 ABCC7 p.Arg117His ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln Except one (p.R117H (7T/7T)/p. S1235), these compound heterozygotes were excluded in the overall computations, because CFTR variant p.R75Q, p.I148T, 5T or p.E528E was present in at least one allele. Login to comment 112 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln In addition, 24/660 (3.6%) patients and 2/1700 (0.1%) controls were trans-heterozygotes in that CFTR variants p.R75Q, p.I148T, 5T and p.E528E were essential for trans-heterozygous status (p<0.0001, OR 30.8, 95% CI 7.3 to 131). Login to comment 116 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln In addition, 24/660 (3.6%) patients and 2/1700 (0.1%) controls were trans-heterozygotes in that CFTR variants p.R75Q, p.I148T, 5T and p.E528E were essential for trans-heterozygous status (p<0.0001, OR 30.8, 95% CI 7.3 to 131). Login to comment 118 ABCC7 p.Arg75Gln In these cases, the over-representation is also most probably due to the strengthening of p.R122H (PRSS1) and p.N34S (SPINK1) as shown for CFTR p.R75Q (see below). Login to comment 120 ABCC7 p.Arg75Gln SPINK1 variant p.N34S (heterozygous and homozygous) was found in combination with CFTR variants p.R75Q (heterozygous and homozygous) in 6/660 patients (0.9%), with 5T in Table 1 Distribution of SPINK1, CTRC and PRSS1 variants in patients and controls Gene Variant Patients Controls p Value OR (95% CI) PRSS1 p.A16V 14/660 (2.1%) 0/1758 <0.0001 78.9 (4.7 to 1325) p.N29I 8/660 (1.2%) 0/1758 <0.0001 45.8 (2.6 to 795.4) p.N29T 1/660 (0.2%) 0/1758 NS e p.R116C 2/660 (0.3%) 0/1758 NS e p.R122C 5/660 (0.8%) 0/1758 0.002 29.5 (1.6 to 534.8) p.R122H 25/660 (3.8%) 0/1758 <0.0001 141.1 (8.6 to 2323) p.S124F* 1/660 (0.2%) 0/1758 NS e Total 55/660 (8.3%) 0/1758 <0.0001 322.4 (19.8 to 5230) SPINK1 c. Login to comment 122 ABCC7 p.Arg75Gln In these cases, the over-representation is also most probably due to the strengthening of p.R122H (PRSS1) and p.N34S (SPINK1) as shown for CFTR p.R75Q (see below). Login to comment 124 ABCC7 p.Arg75Gln SPINK1 variant p.N34S (heterozygous and homozygous) was found in combination with CFTR variants p.R75Q (heterozygous and homozygous) in 6/660 patients (0.9%), with 5T in Table 1 Distribution of SPINK1, CTRC and PRSS1 variants in patients and controls Gene Variant Patients Controls p Value OR (95% CI) PRSS1 p.A16V 14/660 (2.1%) 0/1758 <0.0001 78.9 (4.7 to 1325) p.N29I 8/660 (1.2%) 0/1758 <0.0001 45.8 (2.6 to 795.4) p.N29T 1/660 (0.2%) 0/1758 NS e p.R116C 2/660 (0.3%) 0/1758 NS e p.R122C 5/660 (0.8%) 0/1758 0.002 29.5 (1.6 to 534.8) p.R122H 25/660 (3.8%) 0/1758 <0.0001 141.1 (8.6 to 2323) p.S124F* 1/660 (0.2%) 0/1758 NS e Total 55/660 (8.3%) 0/1758 <0.0001 322.4 (19.8 to 5230) SPINK1 c. Login to comment 125 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln Pancreas Gut 2013;62:582-592. doi:10.1136/gutjnl-2011-300645 8/660 patients (1.2%), and with p.E528E (heterozygous and homozygous) in 6/660 patients (0.9%) compared with 1/1758 (0.06%) controls for combination with p.R75Q and 5T, and 2/ 1758 controls (0.1%) for combination with p.E528E (p.R75Q: p&#bc;0.002, OR 16.1, 95% CI 1.92 to 134; 5T: p&#bc;0.0002, OR 21.6, 95% CI 2.7 to 172.8; p.E528E: p&#bc;0.008, OR 8, 95% CI 1.6 to 40). Login to comment 127 ABCC7 p.Arg75Gln Thereafter, no significant association was obtained (p.R75Q: 6/109 patients, 5.5%, 1/26 controls, 3.9%, p&#bc;1.0; 5T: 8/109 patients, 7.3%, 1/26 controls, 3.9%, p&#bc;1.0; p.E528E: 6/109 patients, 5.5%, 2/26 controls, 7.7%, p&#bc;0.7). Login to comment 128 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln In contrast, 6/31 (19.4%) patients with p.R75Q also carried p.N34S, whereas only 1/60 (1.7%) of controls with p.R75Q showed the p.N34S variant, representing the data expected in patients and controls. Login to comment 129 ABCC7 p.Arg75Gln On analysis of about 200 parents for CFTR, p.R75Q was found to pass from one parent to the child in 6/13 cases (46%) only, which further underlines that this variant most likely does not contribute to disease pathogenesis. Login to comment 130 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln doi:10.1136/gutjnl-2011-300645 Pancreas 8/660 patients (1.2%), and with p.E528E (heterozygous and homozygous) in 6/660 patients (0.9%) compared with 1/1758 (0.06%) controls for combination with p.R75Q and 5T, and 2/ 1758 controls (0.1%) for combination with p.E528E (p.R75Q: p¼0.002, OR 16.1, 95% CI 1.92 to 134; 5T: p¼0.0002, OR 21.6, 95% CI 2.7 to 172.8; p.E528E: p¼0.008, OR 8, 95% CI 1.6 to 40). Login to comment 132 ABCC7 p.Arg75Gln Thereafter, no significant association was obtained (p.R75Q: 6/109 patients, 5.5%, 1/26 controls, 3.9%, p¼1.0; 5T: 8/109 patients, 7.3%, 1/26 controls, 3.9%, p¼1.0; p.E528E: 6/109 patients, 5.5%, 2/26 controls, 7.7%, p¼0.7). Login to comment 133 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln In contrast, 6/31 (19.4%) patients with p.R75Q also carried p.N34S, whereas only 1/60 (1.7%) of controls with p.R75Q showed the p.N34S variant, representing the data expected in patients and controls. Login to comment 134 ABCC7 p.Arg75Gln On analysis of about 200 parents for CFTR, p.R75Q was found to pass from one parent to the child in 6/13 cases (46%) only, which further underlines that this variant most likely does not contribute to disease pathogenesis. Login to comment 135 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Glu585* ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg1158* ABCC7 p.Ser1235Arg ABCC7 p.Ala120Thr ABCC7 p.Asp1152His ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Leu997Phe ABCC7 p.Ile507Val ABCC7 p.Arg74Gln ABCC7 p.Tyr84His ABCC7 p.His667Tyr ABCC7 p.Gly691Arg Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p&#bc;0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment 137 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln *Variants p.R75Q, p.I148T and p.E528E were excluded from calculations because of their similar frequencies in patients and controls. Login to comment 140 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Glu585* ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg1158* ABCC7 p.Ser1235Arg ABCC7 p.Ala120Thr ABCC7 p.Asp1152His ABCC7 p.Phe508Cys ABCC7 p.Arg668Cys ABCC7 p.Leu997Phe ABCC7 p.Ile507Val ABCC7 p.Arg74Gln ABCC7 p.Tyr84His ABCC7 p.His667Tyr ABCC7 p.Gly691Arg Variant distribution in patients aged >20 and <20 years In younger patients, overall PRSS1 variants were 2.9-fold more common (>20 years: 9/239, 3.8%; <20 years: 46/421, 10.9%; p¼0.001, OR 3.1, 95% CI 1.5 to 6.5), whereas overall SPINK1 variants were similarly distributed (56/239, 23.4%; 73/421, Table 2 CFTR variants detected by melting curve analysis Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing, severe) p.F508del 44/660 (6.7%) 48/1758 (2.7%) <0.0001 2.5 (1.7 to 3.9) p.R117H (5T/7T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.G542X 1/660 (0.2%) 1/1758 (0.06%) NS e c.1717-1G>A 3/660 (0.5%) 1/1758 (0.06%) NS e p.E585X 0/660 1/1758 (0.06%) NS e c.2183AA>G 0/660 1/1758 (0.06%) NS e p.R1158X 1/660 (0.2%) 0/1758 NS e p.R1162X 1/660 (0.3%) 0/1758 NS e p.N1303K 3/660 (0.5%) 0/1758 NS e Total 55/660 (8.3%) 53/1758 (3%) <0.0001 2.9 (2 to 4.3) CFTR (CF-causing mild) p.R117H (7T/7T) 13/660 (2%) 8/1758 (0.5%) 0.0009 4.4 (1.8 to 10.7) p.R117H (7T/9T) 3/660 (0.5%) 1/1758 (0.06%) NS e p.R347H 1/660 (0.2%) 0/1758 NS e p.R347P 1/660 (0.2%) 0/1758 NS e p.A455E 1/660 (0.2%) 0/1758 NS e c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.D1152H 3/660 (0.5%) 5/1758 (0.3%) NS e Total 23/660 (3.5%) 14/1758 (0.8%) <0.0001 4.5 (2.3 to 8.8) CFTR (non CF-causing) p.R74Q 2/660 (0.3%) 0/1758 NS e p.R75Q (het)* 29/660 (4.4%) 59/1758 (3.4%) NS e p.R75Q (hom)* 2/660 (0.3%) 1/1758 (0.06%) NS e p.Y84H 0/660 1/1758 (0.06%) NS e p.A120T 0/660 1/1758 (0.06%) NS e p.I148T* 4/660 (0.6%) 11/1758 (0.6%) NS e p.I507V 1/660 (0.2%) 2/1758 (0.1%) NS e p.F508C 1/660 (0.2%) 0/1758 NS e c.1716+12T>C 0/660 1/1758 (0.06%) NS e p.E528E (het)* 36/660 (5.5%) 82/1758 (4.7%) NS e p.E528E (hom)* 0/660 2/1758 (0.1%) NS e c.1898+8C>G 0/660 1/1758 (0.06%) NS e p.H667Y 1/660 (0.2%) 0/1758 NS e p.R668C 5/660 (0.8%) 3/1758 (0.2%) NS e p.G691R 0/660 1/1758 (0.06%) NS e p.L997F 5/660 (0.8%) 6/1758 (0.3%) NS e p.S1235R 10/660 (1.5%) 18/1758 (1.0%) NS e Total (excluded)* 25/660 (3.8%) 45/1758 (2.6%) NS e CFTR (CF-causing) Total (all) 78/660 (11.8%) 67/1758 (3.8%) <0.0001 3.4 (2.4 to 4.8) CFTR (all) Total (excluded)* 103/660 (15.6%) 112/1758 (6.4%) <0.0001 2.7 (2 to 3.6) The table is divided into three parts. Login to comment 142 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln *Variants p.R75Q, p.I148T and p.E528E were excluded from calculations because of their similar frequencies in patients and controls. Login to comment 144 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Arg1158* ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.His667Tyr Table 4 Homozygous and compound heterozygous patients and controls with at least two CFTR, SPINK1 or CTRC variants Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing severe or CF-causing mild/CF-causing mild) p.F508del/p.R117H (7T/9T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.R347H 1/660 (0.2%) 0/1758 NS e p.F508del/p.D1152Hy 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.R1158X 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.1717-1G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/9T)/p.N1303K 1/660 (0.2%) 0/1758 NS e p.D1152Hy/p.N1303K 1/660 (0.2%) 0/1758 NS e Total 9/660 (1.4%) 1/1758 (0.06%) 0.002 16.1 (1.9 to 134.2) CFTR (CF-causing severe or CF-causing mild or non-CF-causing/Non-CF-causing) p.F508del/p.R75Q* 0/660 1/1758 (0.06%) NS e p.F508del/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R75Q*/5T* 1/660 (0.2%) 1/1758 (0.06%) NS e p.R75Q*/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R117H (7T/7T)/p.R75Q* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.E528E* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.S1235R 1/660 (0.2%) 0/1758 NS e p.I148T*/5T* 0/660 1/1758 (0.06%) NS e p.R347P/p.E528E* 1/660 (0.2%) 0/1758 NS e p.E528E*/5T* 1/660 (0.2%) 4/1758 (0.23%) NS e p.H667Y/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/p.E528E* 0/660 1/1758 (0.06%) NS e p.D1152Hy/5T* 1/660 (0.2%) 0/1758 NS e p.S1235R/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e Total 17/660 (2.6%) 14/1758 (0.8%) 0.001 3.3 (1.6 to 6.7) CFTR Total (all, excluded)* 10/660 (1.5%) 1/1758 (0.06%) <0.0001 27 (3.5 to 211.7) SPINK1 p.N34S (hom) 17/660 (2.6%) 0/1758 <0.0001 95.6 (5.7 to 1594) p.N34S (het)/c.(1-215G>A;194+2T>C) 7/660 (1.1%) 0/1758 <0.0001 40.4 (2.3 to 708.2) Total 24/660 (3.6%) 0/1758 <0.0001 135.4 (8.2 to 2231) CTRC p.R254W (hom) 1/546 (0.2%) 0/1700 NS e p.R254W/p.V235I 1/546 (0.2%) 0/1700 NS e Total 2/546 (0.4%) 0/1700 NS e For CFTR compound heterozygous carriers, calculations were performed for patients and controls carrying a combination of one CF-causing severe or a CF-causing mild in addition with one CF-causing mild variant (upper section). Login to comment 146 ABCC7 p.Arg117His ABCC7 p.Ser1235Arg All compound heterozygotes in this section except one (p.R117H (7T/7T)/p.S1235R) carry CFTR variants that were not over-represented in patients on at least one allele. Login to comment 147 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln *Compound heterozygotes in that variants p.R75Q, p.I148T, 5T-allele, and p.E528E were essential for compound heterozygous status were excluded from calculations. Login to comment 148 ABCC7 p.Asp1152His yVariant p.D1152H can have a broad phenotype and might be classified as a CF-causing severe variant. Login to comment 150 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Arg1158* ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.His667Tyr Table 4 Homozygous and compound heterozygous patients and controls with at least two CFTR, SPINK1 or CTRC variants Gene Variant Patients Controls p Value OR (95% CI) CFTR (CF-causing severe or CF-causing mild/CF-causing mild) p.F508del/p.R117H (7T/9T) 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.R347H 1/660 (0.2%) 0/1758 NS e p.F508del/p.D1152Hy 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.2657+5G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.R1158X 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/c.1717-1G>A 1/660 (0.2%) 0/1758 NS e p.R117H (7T/9T)/p.N1303K 1/660 (0.2%) 0/1758 NS e p.D1152Hy/p.N1303K 1/660 (0.2%) 0/1758 NS e Total 9/660 (1.4%) 1/1758 (0.06%) 0.002 16.1 (1.9 to 134.2) CFTR (CF-causing severe or CF-causing mild or non-CF-causing/Non-CF-causing) p.F508del/p.R75Q* 0/660 1/1758 (0.06%) NS e p.F508del/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e p.F508del/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R75Q*/5T* 1/660 (0.2%) 1/1758 (0.06%) NS e p.R75Q*/p.E528E* 2/660 (0.3%) 2/1758 (0.1%) NS e p.R117H (7T/7T)/p.R75Q* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.E528E* 1/660 (0.2%) 0/1758 NS e p.R117H (7T/7T)/p.S1235R 1/660 (0.2%) 0/1758 NS e p.I148T*/5T* 0/660 1/1758 (0.06%) NS e p.R347P/p.E528E* 1/660 (0.2%) 0/1758 NS e p.E528E*/5T* 1/660 (0.2%) 4/1758 (0.23%) NS e p.H667Y/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/5T* 1/660 (0.2%) 0/1758 NS e p.L997F/p.E528E* 0/660 1/1758 (0.06%) NS e p.D1152Hy/5T* 1/660 (0.2%) 0/1758 NS e p.S1235R/5T* 2/660 (0.3%) 1/1758 (0.06%) NS e Total 17/660 (2.6%) 14/1758 (0.8%) 0.001 3.3 (1.6 to 6.7) CFTR Total (all, excluded)* 10/660 (1.5%) 1/1758 (0.06%) <0.0001 27 (3.5 to 211.7) SPINK1 p.N34S (hom) 17/660 (2.6%) 0/1758 <0.0001 95.6 (5.7 to 1594) p.N34S (het)/c.(1-215G>A;194+2T>C) 7/660 (1.1%) 0/1758 <0.0001 40.4 (2.3 to 708.2) Total 24/660 (3.6%) 0/1758 <0.0001 135.4 (8.2 to 2231) CTRC p.R254W (hom) 1/546 (0.2%) 0/1700 NS e p.R254W/p.V235I 1/546 (0.2%) 0/1700 NS e Total 2/546 (0.4%) 0/1700 NS e For CFTR compound heterozygous carriers, calculations were performed for patients and controls carrying a combination of one CF-causing severe or a CF-causing mild in addition with one CF-causing mild variant (upper section). Login to comment 152 ABCC7 p.Arg117His ABCC7 p.Ser1235Arg All compound heterozygotes in this section except one (p.R117H (7T/7T)/p.S1235R) carry CFTR variants that were not over-represented in patients on at least one allele. Login to comment 153 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln *Compound heterozygotes in that variants p.R75Q, p.I148T, 5T-allele, and p.E528E were essential for compound heterozygous status were excluded from calculations. Login to comment 154 ABCC7 p.Asp1152His yVariant p.D1152H can have a broad phenotype and might be classified as a CF-causing severe variant. Login to comment 155 ABCC7 p.Arg117His ABCC7 p.Arg75Gln p.R254W 1/546 (0.2%) 0/1700 NS e p.L14P p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.R117H (7T/7T)/ p.R75Q 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.K247_R254del p.E528E* 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.E528E* 1/546 (0.2%) 0/1700 NS e c. Login to comment 156 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Asn1303Lys ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln (1-215G>A; 194+2T>C) p.F508del 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.I507Vy 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.S1235Ry 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.R117H (5T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/ p.R117H (7T/9T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/p.E528E 1/660 (0.2%) 1/1758 (0.06%) NS e p.N34S (het) p.F508del/ p.E528E/5T/7T 0/660 1/1758 (0.06%) NS e p.N34S (het) p.R117H (7T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del 8/660 (1.2%) 0/1758 <0.0001 45.8 (2.6 to 795.4) p.N34S (het) p.R668Cy 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.S1235Ry 3/660 (0.5%) 0/1758 0.03 18.7 (1 to 363.2) p.N34S (het) p.N1303K 1/660 (0.2%) 0/1758 NS e p.R254W p.R117H (7T/7T)/ c.1717-1G>A 1/546 (0.2%) 0/1700 NS e p.R254W p.R668Cy 0/546 1/1700 (0.06%) NS e p.R254W p.L997Fy 1/546 (0.2%) 0/1700 NS e Total (all) 43/660 (6.5%) 3/1667 (0.2%) <0.0001 38.7 (12 to 125.1) Total (CF-causing) 33/660 (5%) 2/1667 (0.1%) <0.0001 43.8 (10.5 to 183.2) p.N29I p.R75Q 1/660 (0.2%) 0/1758 NS e p.R122C 5T/9T 1/660 (0.2%) 0/1758 NS e p.R122H p.R75Q 2/660 (0.3%) 0/1758 NS e p.R122H 5T/7T 2/660 (0.3%) 0/1758 NS e p.R122H p.E528E 3/660 (0.5%) 0/1758 0.03* 18.7 (1 to 363.2) p.N34S (het)/ c. Login to comment 159 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln (1-215G>A; 194+2T>C) p.E528E 1/660 (0.2%) 0/1758 NS e c.1-53C>T p.R75Q 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.R75Q (hom) 1/660 (0.2%) 0/1758 NS e p.N34S (hom) 5T/7T 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.E528E 2/660 (0.3%) 0/1758 NS e Continued Table 5 Continued PRSS1 SPINK1 CTRC CFTR Patients Controls p Value OR (95% CI) p.N34S (het) p.R75Q 4/660 (0.6%) 1/1758 (0.06%) 0.03* 10.7 (1.2 to 96.1) p.N34S (het) p.I148T 1/660 (0.2%) 0/1758 NS e p.N34S (het) 5T/7T 5/660 (0.8%) 0/1758 0.002 29.5 (1.6 to 534.8) p.R65Q p.R75Q 1/660 (0.2%) 0/1758 NS e p.R67C p.E528E 1/660 (0.2%) 0/1758 NS e p.G217S p.E528E 0/546 1/1700 (0.06%) NS e To obtain stringent results, the total number of patients (n&#bc;660) was used for calculations of p values, although some of the patients were not completely analysed. Login to comment 162 ABCC7 p.Arg117His ABCC7 p.Arg75Gln p.R254W 1/546 (0.2%) 0/1700 NS e p.L14P p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.R117H (7T/7T)/ p.R75Q 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.K247_R254del p.E528E* 1/546 (0.2%) 0/1700 NS e p.N34S (het) p.R254W p.E528E* 1/546 (0.2%) 0/1700 NS e c. Login to comment 163 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Asn1303Lys ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln (1-215G>A; 194+2T>C) p.F508del 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.I507Vy 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.S1235Ry 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.R117H (5T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/ p.R117H (7T/9T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del/p.E528E 1/660 (0.2%) 1/1758 (0.06%) NS e p.N34S (het) p.F508del/ p.E528E/5T/7T 0/660 1/1758 (0.06%) NS e p.N34S (het) p.R117H (7T/7T) 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.F508del 8/660 (1.2%) 0/1758 <0.0001 45.8 (2.6 to 795.4) p.N34S (het) p.R668Cy 1/660 (0.2%) 0/1758 NS e p.N34S (het) p.S1235Ry 3/660 (0.5%) 0/1758 0.03 18.7 (1 to 363.2) p.N34S (het) p.N1303K 1/660 (0.2%) 0/1758 NS e p.R254W p.R117H (7T/7T)/ c.1717-1G>A 1/546 (0.2%) 0/1700 NS e p.R254W p.R668Cy 0/546 1/1700 (0.06%) NS e p.R254W p.L997Fy 1/546 (0.2%) 0/1700 NS e Total (all) 43/660 (6.5%) 3/1667 (0.2%) <0.0001 38.7 (12 to 125.1) Total (CF-causing) 33/660 (5%) 2/1667 (0.1%) <0.0001 43.8 (10.5 to 183.2) p.N29I p.R75Q 1/660 (0.2%) 0/1758 NS e p.R122C 5T/9T 1/660 (0.2%) 0/1758 NS e p.R122H p.R75Q 2/660 (0.3%) 0/1758 NS e p.R122H 5T/7T 2/660 (0.3%) 0/1758 NS e p.R122H p.E528E 3/660 (0.5%) 0/1758 0.03* 18.7 (1 to 363.2) p.N34S (het)/ c. Login to comment 166 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln (1-215G>A; 194+2T>C) p.E528E 1/660 (0.2%) 0/1758 NS e c.1-53C>T p.R75Q 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.R75Q (hom) 1/660 (0.2%) 0/1758 NS e p.N34S (hom) 5T/7T 1/660 (0.2%) 0/1758 NS e p.N34S (hom) p.E528E 2/660 (0.3%) 0/1758 NS e Continued Rosendahl J, Landt O, Bernadova J, et al. Gut (2012). Login to comment 167 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln doi:10.1136/gutjnl-2011-300645 of 11 Pancreas Table 5 Continued PRSS1 SPINK1 CTRC CFTR Patients Controls p Value OR (95% CI) p.N34S (het) p.R75Q 4/660 (0.6%) 1/1758 (0.06%) 0.03* 10.7 (1.2 to 96.1) p.N34S (het) p.I148T 1/660 (0.2%) 0/1758 NS e p.N34S (het) 5T/7T 5/660 (0.8%) 0/1758 0.002 29.5 (1.6 to 534.8) p.R65Q p.R75Q 1/660 (0.2%) 0/1758 NS e p.R67C p.E528E 1/660 (0.2%) 0/1758 NS e p.G217S p.E528E 0/546 1/1700 (0.06%) NS e To obtain stringent results, the total number of patients (n¼660) was used for calculations of p values, although some of the patients were not completely analysed. Login to comment 171 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln CFTR variants, p.R75Q, p.I148T and p.E528E, were excluded from computations as explained before. Login to comment 174 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln In the lower section, trans-heterozygotes with non-CF-causing variants, p.R75Q, p.I148T, 5T-allele and p.E528E, are displayed, which were excluded from calculations because their over-representation is due to accumulation of the concomitant variant (eg, p.N34S) in patients (see Results section) or the CFTR variant displayed similar frequencies in patients and controls (p.R75Q, p.I148T, 5T-allel, and p.E528E). Login to comment 175 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln yCompound and trans-heterozygous carriers with p.R75Q, p.I148T, 5T-allele and p.E528E were excluded as explained before. Login to comment 179 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln CFTR variants, p.R75Q, p.I148T and p.E528E, were excluded from computations as explained before. Login to comment 183 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln yCompound and trans-heterozygous carriers with p.R75Q, p.I148T, 5T-allele and p.E528E were excluded as explained before. Login to comment 192 ABCC7 p.Ile148Thr ABCC7 p.Arg75Gln In contrast with other authors, we excluded CFTR variants p. R75Q, p.I148T, 5T and p.E528E from our calculations, because they were distributed similarly in patients and controls.30 31 Thereby, overall, CFTR variants displayed a 2.7-fold risk increase for CP development. Login to comment 206 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln In a recent study, trans-heterozygosity for SPINK1 p.N34S with CFTR p.R75Q was reported to increase CP risk.31 We also demonstrate a significant accumulation of p. N34S/p.R75Q trans-heterozygotes in patients (6/660, 0.9% vs controls 1/1758, 0.06%), and the data seem to portend an association for the combination of p.N34S with CFTR 5T-allele and p.E528E also. Login to comment 210 ABCC7 p.Arg75Gln Frequencies of p.R75Q in patients and controls carrying p.N34S were 6/109 (5.5%) and 1/26 (3.9%), respectively (p&#bc;1.0). Login to comment 216 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln In a recent study, trans-heterozygosity for SPINK1 p.N34S with CFTR p.R75Q was reported to increase CP risk.31 We also demonstrate a significant accumulation of p. N34S/p.R75Q trans-heterozygotes in patients (6/660, 0.9% vs controls 1/1758, 0.06%), and the data seem to portend an association for the combination of p.N34S with CFTR 5T-allele and p.E528E also. Login to comment 220 ABCC7 p.Arg75Gln Frequencies of p.R75Q in patients and controls carrying p.N34S were 6/109 (5.5%) and 1/26 (3.9%), respectively (p¼1.0). Login to comment