Abstract
Objective: Cystic Fibrosis (CF) severity is determined by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, the environment and modifier genes. The adiponectin receptor 2 (ADIPOR2) gene is one of the potential modifier genes of CF and is responsible for expressing an anti-inflammatory protein. In this context, the 315 base deletion and the 134 base insertion polymorphisms in the ADIPOR2 gene are associated with CF severity. Methodology: A total of 169 CF patients were enrolled, and 27 CF clinical markers were analyzed. Results: The 315 base deletion and haplotypes analyses showed an association with the patient´s age and ethnicity. For the age, the deletion in both alleles was associated with a lower age in the patients without any identified CFTR mutations (OR= 7.257; 95%CI= 1.321-44.83) or disregarding CFTR mutations (OR= 2.394; 95%CI= 1.046- 5.721). For the ethnicity, the wild-type allele (315 base no deletion) showed lower risk of occurrence in Caucasians patients with two CFTR mutations identified (OR= 0.052; 95%CI= 0.002-0.382) or no CFTR mutations (OR= 0.154, 95%CI= 0.032-0.592). The same values were observed for the clustered analysis of the 315 base deletions. In the analysis of the haplotype, in the Caucasian group, the patients with two CFTR mutations were identified and demonstrated an OR of 0.076 (95%CI= 0.009-0.432) for wild-type alleles. The 134 base insertions were associated with the SpO2 [patients without considering the CFTR genotype (p-value= 0.034) and without any identified CFTR mutations (p-value= 0.034)] and the Kanga score (no CFTR mutations identified) (p-value= 0.008). The haplotype was associated with the forced vital capacity (disregarding CFTR genotype) (p-value= 0.028). Conclusion: The 315 base deletions and the insertion of 134 bases in the ADIPOR2 gene are potential modifiers of the severity of CF and should be considered during CFTR mutation screening.
Highlights
Cystic Fibrosis (CF) (MIM: 219700) presents as phenotypic heterogeneity of the clinical manifestations that are modulated by cystic fibrosis transmembrane regulator (CFTR) mutations [1,2], the environment and modifier genes [3,4,5]
The adiponectin receptor 2 (ADIPOR2) gene encodes an integral membrane protein, the adiponectin receptor, which regulates the expression of a diabetic hormone secreted by adipocytes and the absence of which is associated with insulin resistance [16]
Some of the functions of the ADIPOR2 protein are as follows: causing an increased expression of adiponectin, which is associated with increased insulin sensitivity; modulating inflammatory processes; modulating the fatty acid metabolism in the liver; downregulating the adiponectin receptor pathway, which could be causally implicated in decreased cardiovascular function; and reducing cancer with adiponectin/AdipoRs, at least in part, through ameliorating hyperinsulinemia, as well as through its direct effects on tumor cells via inhibition of the mammalian target of rapamycin pathway by activating AMP kinase [17]
Summary
Cystic Fibrosis (CF) (MIM: 219700) presents as phenotypic heterogeneity of the clinical manifestations that are modulated by cystic fibrosis transmembrane regulator (CFTR) mutations [1,2], the environment and modifier genes [3,4,5]. The adiponectin receptor 2 (ADIPOR2) gene, located in the region 12p13.3, was studied in CF and associated with the presence of meconium ileus [15]. The ADIPOR2 gene encodes an integral membrane protein, the adiponectin receptor, which regulates the expression of a diabetic hormone secreted by adipocytes and the absence of which is associated with insulin resistance [16]. Taking into account the expression of adiponectin receptor 2 in various tissues, especially the liver and the presence of circulating adiponectin hormone concentrations in blood that is associated with diseases, it is unclear how the signaling pathway of the adiponectin hormone can affect the meconium ileus and, in this study, the different clinical variables analyzed as CF severity. Regarding CF and meconium ileus, two mutations of copy number variation (the 315 base deletions and the insertion of 134 bases) in the ADIPOR2 gene were identified [15]
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