Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis
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 man...
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IMR Press
2022-05-01
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| Series: | Frontiers in Bioscience-Landmark |
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| Online Access: | https://www.imrpress.com/journal/FBL/27/6/10.31083/j.fbl2706168 |
| _version_ | 1811236387562717184 |
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| author | Joern Pascal Laubach Michael Ludwig Tabea Horn Olaf Eickmeier Christina Smaczny Ralf Schubert Stefan Zielen Christof Majoor Malik Aydin Sabina Schmitt-Grohé |
| author_facet | Joern Pascal Laubach Michael Ludwig Tabea Horn Olaf Eickmeier Christina Smaczny Ralf Schubert Stefan Zielen Christof Majoor Malik Aydin Sabina Schmitt-Grohé |
| author_sort | Joern Pascal Laubach |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:09:23Z |
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| institution | Directory Open Access Journal |
| issn | 2768-6701 |
| language | English |
| last_indexed | 2024-04-12T12:09:23Z |
| publishDate | 2022-05-01 |
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| spelling | doaj.art-bddf1121be364e7b93eb602a821f79852022-12-22T03:33:38ZengIMR PressFrontiers in Bioscience-Landmark2768-67012022-05-0127616810.31083/j.fbl2706168S2768-6701(22)00527-5Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic FibrosisJoern Pascal Laubach0Michael Ludwig1Tabea Horn2Olaf Eickmeier3Christina Smaczny4Ralf Schubert5Stefan Zielen6Christof Majoor7Malik Aydin8Sabina Schmitt-Grohé9University Children's Hospital Bonn, 53127 Bonn, GermanyDepartment of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, GermanyUniversity Children's Hospital Bonn, 53127 Bonn, GermanyDepartment for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, GermanyChristiane-Herzog CF-Ambulanz, Goethe-University, 60590 Frankfurt, GermanyDepartment for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, GermanyDepartment for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, GermanyDepartment of Respiratory Medicine, Amsterdam University Medical Centers (UMC), 1100 Amsterdam, The NetherlandsLaboratory 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, GermanyUniversity Children's Hospital Bonn, 53127 Bonn, GermanyBackground: 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.https://www.imrpress.com/journal/FBL/27/6/10.31083/j.fbl2706168cystic fibrosismannose-binding lectingap junction protein alpha 4 (gja4)bronchial inflammationdelta f 508 homozygousgene-gene interaction |
| spellingShingle | Joern Pascal Laubach Michael Ludwig Tabea Horn Olaf Eickmeier Christina Smaczny Ralf Schubert Stefan Zielen Christof Majoor Malik Aydin Sabina Schmitt-Grohé Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis Frontiers in Bioscience-Landmark cystic fibrosis mannose-binding lectin gap junction protein alpha 4 (gja4) bronchial inflammation delta f 508 homozygous gene-gene interaction |
| title | Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis |
| title_full | Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis |
| title_fullStr | Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis |
| title_full_unstemmed | Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis |
| title_short | Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis |
| title_sort | mannose binding lectin mbl and gap junction protein alpha 4 gja4 gene heterogeneity in relation to severity of clinical disease in cystic fibrosis |
| topic | cystic fibrosis mannose-binding lectin gap junction protein alpha 4 (gja4) bronchial inflammation delta f 508 homozygous gene-gene interaction |
| url | https://www.imrpress.com/journal/FBL/27/6/10.31083/j.fbl2706168 |
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