IMR Press / FBL / Volume 27 / Issue 6 / DOI: 10.31083/j.fbl2706168
Open Access Original Research
Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis
Show Less
1 University Children's Hospital Bonn, 53127 Bonn, Germany
2 Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany
3 Department for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, Germany
4 Christiane-Herzog CF-Ambulanz, Goethe-University, 60590 Frankfurt, Germany
5 Department of Respiratory Medicine, Amsterdam University Medical Centers (UMC), 1100 Amsterdam, The Netherlands
6 Laboratory of Experimental Pediatric Pneumology and Allergology, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58448 Witten, Germany
*Correspondence: (Sabina Schmitt-Grohé)
Academic Editors: Massimo Conese and Lorenzo Guerra
Front. Biosci. (Landmark Ed) 2022, 27(6), 168;
Submitted: 30 December 2021 | Revised: 15 February 2022 | Accepted: 17 February 2022 | Published: 30 May 2022
(This article belongs to the Special Issue Cystic fibrosis lung disease: from basic research to clinical issues)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Recently, we provided evidence that a single nucleotide polymorphism (SNP), rs41266431, on the gap junction protein alpha 4 (GJA4) gene, acts as a modifier for clinical disease severity in patients with cystic fibrosis (CF). These features are very similar to those of variants of the mannose-binding lectin (MBL). This study aimed to clarify whether the clinical disease phenotype associated with GJA4 variants is independent of MBL variants. Methods: One hundred and twelve patients with homozygous F508del (mean age, 27.6 years; m/f, 61/51) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. A sequence analysis was performed for GJA4 and MBL. The clinical phenotype was assessed over three years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, and inflammatory markers. Results: A clinically relevant SNP of GJA4 was identified by sequence analysis. Pulmonary function (FVC% pred, mean 78/85; p < 0.055) and survival to end-stage lung disease were lower (p < 0.043) for this variant (rs41266431) in carriers homozygous for the G variant (n = 82/112; 73%) than in other carriers. Serum MBL (820/372 ng/mL, p < 0.001) was significantly higher in “MBL-sufficient” genotypes (n = 79/112; 71%) than in “MBL-insufficient” genotypes, and a trend for a significant difference in BMI percentiles (35.2/23.8; p < 0.059) was observed. For the MBL-sufficient genotype (median age at death, 38/26 years), there was a trend for better survival (p < 0.076). There was no augmentation by gene-gene interaction between MBL and GJA4 variants for any outcome parameter. Conclusions: The clinical disease phenotype associated with GJA4 variants is independent of MBL variants. MBL-sufficient variants were associated with superior BMI and a trend for better survival than MBL insufficient variants.

cystic fibrosis
mannose-binding lectin
gap junction protein alpha 4 (GJA4)
bronchial inflammation
delta F 508 homozygous
gene-gene interaction
Fig. 1.
Back to top