Connexin 37 and connexin 43 genotypes in correlation to cytokines in induced sputum and blood in cystic fibrosis (CF)

Aims: We have provided evidence in former studies that cytokines (IL-8, TNF alpha, LBP, TGFß) measured in blood correlate negatively with lung function in deltaF508 homozygous patients. GAP junction proteins might be of importance for the influx of blood cells into the lung. Our aim was to assess the relationship between connexin genotypes, cytokines (IL-8, TNF-alpha, LBP, TGFß) in induced sputum and serum, and lung disease. Methods: 36 patients homozygous for deltaF508 (median age 18 y, m/f 16/20, FEV 1 (%) 77) were examined. Sequence analysis was performed for GAP junction protein alpha 1 (GJA1/Connexin 43) and gap junction protein alpha 4 (GJA4/connexin 37). Cytokines were assessed in serum and induced sputum (IS) by chemiluminesence (DPC Biermann, Bad Homburg, Germany) as well as leukocyte counts. Results: 35 patients were sequenced. Whereas GJA1 showed only one rare heterozygous synonymous SNP (rs138386744) in one patient, four common SNPs were detected in GJA4. Two were synonymous changes, but the third variant (rs41266431) causes an amino acid substitution (GTA valine, ATA isoleucine) as well as the fourth SNP (rs1764391: CCC proline, TCCserine). For rs41266431 patients with homozygosity for the G variant had higher IL-8 levels (median: 13.3/8.0 pg/ml, p< 0.07) in serum as well as leukocytes in sputum (median: 2050/421 /µl p< 0.041) than those showing heterozygosity G/A. In individuals > 30 years lung function (FEV1 41.3/84.83 % predicted, p < 0.07) was worse. Conclusion: For GJA4 the SNP at rs41266431 seems a promising candidate for a disease modifying gene.