The extracellular matrix (ECM) consists of a network of proteins, glycoproteins, and proteoglycans. Mutations in genes coding for ECM are known to lead to numerous diseases (1). Heparan sulfate (HS) glycosaminoglycan chains are components of HS proteoglycans (HSPG) that mediate interactions between the cell and the ECM. HS chains mediate signaling by binding a multitude of growth factors, but also cell adhesion proteins such as fibronectin and fibrillin 2, which are unique in having cell surface integrin- and HS-binding regions (2). An alteration in cross talk between ECM and cells is most likely linked to development of diseases (1).

Fibronectin is a major glycoprotein component of the ECM. It plays an important part in cell adhesion, migration and differentiation (3). The single pre-mRNA is alternatively spliced, and fibronectin has at least 20 different isoforms in humans (4). Fibronectin is upregulated in atherosclerosis (5). Mutations in the fibronectin gene are known to be associated with human glomerulopathy (6). Fibrillin 2 is a widely distributed major component of extracellular microfibrils throughout the body. Mutations in the fibrillin 2 (FBN2) gene cause congenital contractural arachnodactyly (CCA), which is phenotypically similar to the Marfan syndrome (MFS) (7). However, in contrast to MFS, CCA does not affect the aorta or the eyes. All the identified disease-causing mutations in FBN2 cluster in a limited region between exons 23 and 34 (8).

The authors have previously observed in the present study population an association between the HSPG gene syndecan-4 SNP rs1981429 variant with BMI and coronary artery disease (9). Previous findings have indicated that variation in genes involved in the maintenance of the integrity of the ECM of the arterial wall, including serpine1, transforming growth factor β induced, perlecan, fibronectin, fibrillin 2 and alpha 1 type IV collagen, serve a role in susceptibility to intracranial aneurysms (10). For these reasons, the authors sought to assess whether there was an association between clinical characteristics of the subjects and the gene polymorphisms of HS-binding ECM proteins fibronectin and fibrillin 2.

The authors previously observed in the present TAMRISK study population an association between a HSPG gene syndecan-4 SNP rs1981429 variant with BMI and coronary artery disease (9). Cell surface HSPGs such as syndecans serve an important role in the organization of the ECM. Fibrillin and fibronectin are ECM proteins that bind to HS chains in HSPGs and consequently also convey information to the cell (2). Therefore, they wanted to assess whether these HS-binding ECM proteins are associated with clinical characteristics such as BMI and cardiovascular diseases in this middle-aged cohort followed up to 60 years of age.

Subjects with fibronectin rs2289202 (G>A) minor genotype AA had significantly more cerebrovascular disease than those with the G allele. This difference remained following adjustments for BMI and sex. This was in accordance with the previous study addressing the association of this polymorphism with intracranial aneurysms, where the OR was 1.35 for the minor allele (10). Fibronectin (FN1) is an ECM glycoprotein that is important for cell adhesion and also migration. As the ECM affects cell growth, motility and differentiation, its modifications in the arterial wall may lead to cerebrovascular complications (10).

The authors identified that subjects with fibrillin rs331069 (T>C) minor genotype CC had more myocardial infarction and TIA than those with the T allele. Patients younger than 60 years old at the time of a TIA may have an especially high age-adjusted risk for future MI (13). The minor allele has previously been associated with intracranial aneurysm with an OR of 1.29 (10). However, there was no association of this variation with cerebrovascular disease as such. The fibrillins FBN1 and FBN2 polymerize to a scaffold for the assembly of elastin that provides architectural framework for tissues (14). Fibrillin is present in blood vessels to convey elasticity and flexibility to resist stretch and pressure forces. Disease-causing mutations in FBN2 result in CCA, which unlike the MFA does not affect the aorta (7). However, the results for thrombotic complications such as MI and TIA, together with the earlier observation for intracranial aneurysm indicate that the FBN2 gene may be involved in cardiovascular pathology as well.

FBN2 rs331069 is an intron variant and FN1 rs2289202 is a synonymous codon. Up to date there is only one report on their association with intracranial aneurysms, and the functional importance of these variations has not been elucidated (10). On the other hand, it is known that few SNPs are exonic and cause non-synonymous missense substitutions that would alter the amino acid protein sequence. Most of the genetic risk variants for cardiovascular disease are located in DNA sequence that do not code for protein. In fact, >85% of SNPs for CAD/AMI are located either in introns or intergenic regions (15).

FBN2 rs331069 and FN1 rs2289202 appear to have biological relevance in human pathophysiology, possibly through interference with vascular ECM composition.