Table 5.
Example of possible multifaceted therapy derived from post CPB-based functional genomic analysis.
| SNP | Symbol (regression coefficient) | Gene name | Gene function | Plausible therapeutic strategy |
|---|---|---|---|---|
| pCPB | ||||
| rs6917589 | SOD2 (−0.20) | Superoxide dismutase 2 | This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen [provided by RefSeq, Apr 2016] | •Antioxidant drugs |
| rs3749166 | CAPN10 (+0.55) | Calpain 10 | Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. [provided by RefSeq, Sep 2010] | •Calpain inhibitor drugs •Tight glucose control |
| rs198388 | NPPB (−0.50) | Natriuretic peptide B | This gene is a member of the natriuretic peptide family and encodes a secreted protein which functions as a cardiac hormone. The protein undergoes two cleavage events, one within the cell and a second after secretion into the blood. The protein's biological actions include natriuresis, diuresis, vasorelaxation, inhibition of renin and aldosterone secretion, and a key role in cardiovascular homeostasis. A high concentration of this protein in the bloodstream is indicative of heart failure. The protein also acts as an antimicrobial peptide with antibacterial and antifungal activity. [provided by RefSeq, Nov 2014] | •Natriuretic hormones •Angiotensin converting enzyme inhibitors •Angiotensin receptor blockers |
| rs2227631 | SERPINE1 (+0.43) | Serpin family E member 1 | This gene encodes a member of the serine proteinase inhibitor (serpin) superfamily. This member is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), and hence is an inhibitor of fibrinolysis. [provided by RefSeq, Sep 2009] | •Anticoagulation |
| rs237025 | SUMO4 (+0.17) | Small ubiquitin-like modifier 4 | This gene is a member of the SUMO gene family. This family of genes encode small ubiquitin-related modifiers that are attached to proteins and control the target proteins' subcellular localization, stability, or activity. The protein described in this record is located in the cytoplasm and specifically modifies IKBA, leading to negative regulation of NF-kappa-B-dependent transcription of the IL12B gene. The RefSeq contains this polymorphism. [provided by RefSeq, Jul 2008] | •Anti-inflammatory? |
| 24H | ||||
| rs553668 | ADRA2A (+0.28) | Adrenoceptor alpha 2A | Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. They include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. [provided by RefSeq, Jul 2008] | •Alpha-2 receptor drugs •Yohimbine •dexmedetomidine |
| rs5361 | SELE (−0.21) | Selectin E | The protein encoded by this gene is found in cytokine-stimulated endothelial cells and is thought to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. These proteins are part of the selectin family of cell adhesion molecules. Adhesion molecules participate in the interaction between leukocytes and the endothelium and appear to be involved in the pathogenesis of atherosclerosis. [provided by RefSeq, Jul 2008] | •Anti-inflammatory drugs with interfere with leukocyte adhesion •glucocorticoids |
| rs1805419 | BAX (+0.21) | BCL2 associated X, apoptosis regulator | The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. [provided by RefSeq, Jul 2008] | •Anti-apoptotic drugs •Drugs with affect mitochondrial permeability pore, e.g., cyclosporine |
| rs4973768 | SLC4A7 (+0.57) | Solute carrier family 4 member 7 | This locus encodes a sodium bicarbonate cotransporter. The encoded transmembrane protein appears to transport sodium and bicarbonate ions in a 1:1 ratio, and is thus considered an electroneutral cotransporter. The encoded protein likely plays a critical role in regulation of intracellular pH involved in visual and auditory sensory transmission. [provided by RefSeq, Apr 2012] | •Drugs increasing intracellular pH •THAM, tromethamine •Citrate •Hyperventilation |
| rs2763979 | HSPA1B (+0.55) | Heat shock protein family A (Hsp70) member 1B | This intronless gene encodes a 70 kDa heat shock protein which is a member of the heat shock protein 70 family. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. [provided by RefSeq, Jul 2008] | •Heat shock protein supporting therapy •Ischemic preinduction |
| rs2070011 | FGA (−0.50) | fibrinogen alpha chain | This gene encodes the alpha subunit of the coagulation factor fibrinogen, which is a component of the blood clot. Following vascular injury, the encoded preproprotein is proteolytically processed by thrombin during the conversion of fibrinogen to fibrin. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia and renal amyloidosis [provided by RefSeq, Jan 2016] | •Anticoagulation |
Data from Table 4 with regression coefficients with P < 0.05 were included in this table indicating how such information might be used to develop a multifaceted neuroprotection strategy in cardiac surgery. The drugs and therapies suggested are based on an association with noted genes but without regard to the whether the coefficient is positive or negative. A high and statistically significant coefficient was used to indicate importance of a pathway. Therapies suggested were then made based on prior knowledge or data indicating a neuroprotective potential. Notably this table supports the importance of a potential therapy with regard to time after CPB.