• Association of COL7A1 gene polymorphisms with risk of dystrophic epidermolysis bullosa. A systematic review and meta-analysis
  • Fatemeh Azarfar,1 Raheleh Bayatian,2 Paniz Ghasemian safaei,3 Fatemeh Hoseinzadeh,4 Amir Jalali,5,*
    1. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
    2. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
    3. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
    4. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
    5. Department of Biology, Faculty of Sciences, Arak University, Arak, Iran


  • Introduction: Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by minimal trauma (1). It has four major categories, based usually on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. The most feared of which — and also the leading cause of mortality — is squamous cell carcinoma (1). According to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intra epidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern) (2). Pathogenic variants in at least 16 genes that encode proteins vital for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa (2). The deficiency and/or dysfunction of type VII collagen leads to subepidermal blistering immediately below the lamina densa, resulting in mucocutaneous fragility and disease complications such as intractable ulcers, extensive scarring, malnutrition, and malignancy (3). The disease is predominantly diagnosed by immunofluorescence mapping and/or transmission electron microscopy and subsequently subclassified into one of 14 subtypes (3). Dystrophic epidermolysis bullosa (DEB) is inherited in both an autosomal dominant DEB and autosomal recessive manner RDEB, both of these result from mutations in the type VII collagen gene (COL7A1). Dominant dystrophic epidermolysis bullosa predominantly involves glycine substitutions within the triple helix of COL7A1 although other missense mutations, deletions or splice-site mutations may underlie some cases (4). In recessive dystrophic epidermolysis bullosa, the mutations include nonsense, splice site, deletions or insertions, ‘silent’ glycine substitutions within the triple helix and non-glycine missense mutations within the triple helix or non-collagenous NC-2 domain (4). Procollagen VII is a homotrimer composed of three proa1 (VII) chains which are encoded by the 32 kbCOL7A1gene located on chromosome 3p21. The mRNA transcript of approximately 8.9 kb is translated into a proa1 (VII) polypeptide containing 2944 amino acids (4). RDEB is caused by mutations to the COL7A1 gene located on chromosome three. A lack of type VII collagen protein at the dermal-epidermal junction (DEJ) results in a loss of structural integrity of the skin. Patients with RDEB exhibit incurable, often fatal, skin blistering, and have an increased risk for aggressive squamous cell carcinoma (5).
  • Methods: Study identification and selection: This meta-analysis conformed to the Preferred Reporting Items for and Meta-analyses criteria. Two investigators independently searched the databases MEDLINE (PubMed), Google Scholar, Web of Science (Thomson-Reuters), for eligible articles examining the association COL7A1 gene polymorphisms with risk of Dystrophic Epidermolysis Bullosa published up to August 4, 2023. The following terms were used: (“Dystrophic Epidermolysis Bullosa”) AND (“COL7A1” OR “Collagen alpha-1(VII) chain’’) AND (“rs2532848”) AND (“rs9878950”) AND (“rs9814951”) AND (“rs9871180”) AND (“rs9881877”) AND (“rs1264194”) AND (“rs2228561”) AND (“polymorphism”, OR “mutation” OR “variant” OR “gene” OR “genotype” OR “SNP” OR “allele”). Additionally, searching of the references of eligible studies, reviews and related meta-analyses, and the abstracts presented at relevant conferences was performed to identify potentially relevant studies. Inclusion and exclusion criteria: Studies were selected according to the following inclusion criteria: (1) full-text published studies up to August 4, 2023; (2) a case-control design or Clinical Trial; (3) the study goal was to evaluate the association of COL7A1 rs2532848, rs9878950, rs9814951, rs9871180, rs9881877, rs1264194, rs2228561 polymorphisms with risk of; Dystrophic Epidermolysis Bullosa, (4) sufficient data for estimating 95% confidence interval (CI) and odds ratio (OR). Data extraction: Information was extracted from all the eligible studies independently by 5 researchers using a pre-designed form according to the selection criteria listed above. For each study the following information was extracted: name of first author, publication year, country where the study was conducted, racial descent, polymorphisms, genotypic testing method, number of cases and controls, genotype frequency of cases and controls, and result of Hardy-Weinberg equilibrium test in control subjects.
  • Results: 10 records were found after examining online databases, references, and related articles; 9 of these records were subsequently eliminated as being unrelated. The current meta-analysis also included 1 eligible study. Spanish authors produced the included study. Table 1 provides basic data, including SNPs, Position, and Allele. Nine single nucleotide polymorphisms (SNPs) across the COL7A1 gene were genotyped to create haplotypes. Both control samples and RDEB patients, both of Hispanic ancestry, had their haplotypes identified. In this investigation, sixteen distinct haplotypes were found. an individual carrying the c.6527insC mutation. All bearers of the c.6527insC mutation shared the same haplotype (CCGCTCAAA_6527insC), according to haplotype analysis, pointing to a common ancestor. SNP Position Allele Ref rs2532848 Intron103 C > A (6) rs9878950 Intron93 A > G rs9814951 Intron85 A > G rs9871180 Intron 79 C>T rs9881877 Intron 70 C>T rs1264194 Exon 90 A > G rs2228561 Exon19 C>T
  • Conclusion: Several studies have examined associations between COL7A1 gene polymorphisms and risk of Dystrophic Epidermolysis Bullosa, but the results were controversial. Meta-analysis has been recognized as a prominent tool to exactly define the effect of genetic polymorphism on the risk of diseases. The present meta-analysis was carried out by critically reviewing 11 relevant and new recently published studies on COL7A1 polymorphisms with Dystrophic Epidermolysis Bullosa risk. Therefore, it may provide more information. The overall distribution of the estimated polymorphisms (Table1) were significantly different between patients and healthy controls.
  • Keywords: Epidermolysis bullosa, mutations, single nucleotide polymorphisms, COL7A1, type VII collagen