p.Arg75Gln, a CFTR variant involved in the risk of CFTR-related disorders?

c.224G>A, p.Arg75Gln (R75Q) presumably leads to an amino-acid change from arginine to glutamine in the membrane-spanning domain of the CFTR protein. Initially reported as a benign sequence variation, p.Arg75Gln was shown to be associated with a high risk of pancreatitis, a risk that was strikingly higher when p.Arg75Gln was combined with a SPINK1 variant. In addition, it was shown that p.Arg75Gln alters bicarbonate but not chloride conductance and that the mutation also induces exon 3 skipping. To investigate the role of p.Arg75Gln in idiopathic chronic pancreatitis (ICP), we performed genotyping of the CFTR gene in 880 patients with ICP, 198 patients with idiopathic bronchiectasis (IB), 74 patients with classical cystic fibrosis (CF), 48 patients with congenital bilateral absence of the vas deferens (CBAVD) and 148 healthy controls. p.Arg75Gln variant was identified in 3.3% (29/880) of patients with ICP, 3.3% (9/272) patients with a pulmonary disease, 2.1% (1/48) of patients with CBAVD and 4.7% (7/148) of healthy controls. It was frequently associated with the c.[1210-12T[7];1408A>G] (T7-p.Val470) allele and this CFTR genetic background could not explain the putative pathogenicity of this variant. To assess whether CFTR and SPINK1 mutations are co-inherited in pancreatitis, we sequenced SPINK1 gene exon 3 in the 46 patients who were previously identified to be heterozygous for p.Arg75Gln. Two SPINK1 pancreatitis-associated variants, p.Asn34Ser and p.Pro55Ser, were found in 6 patients: 4 of 29 (13.8%) patients with ICP (3 p.Asn34Ser and 1 p.Pro55Ser), 1 of 7 (14.3%) healthy controls (p.Asn34Ser) and 1 of 9 (11.1%) patients with IB (p.Pro55Ser). Our study does not confirm that the CFTR p.Arg75Gln mutation confers a significant risk of pancreatitis both when considered individually and with a concurrent SPINK1 mutation, suggesting the role of other genetic and environmental factors.