Description of the molecules encoded by the genes referenced in Table 2 and Figures 1 and 2
| Gene . | rs ID . | Function . |
|---|---|---|
| MAPK9 | rs4147385 | The molecule, also known as JNK2, belongs to a group of MAPKs that has been identified as a significant signaling pathway for the regulation of CD4+ T-cell differentiation. It also seems to influence the Th1/Th2 balance, providing protection against autoimmunity. Gene function has been associated with diabetes type 1 and malignancy.23,24 |
| PDGFRB | rs10072056 | The beta-type PDGF receptor gene encodes a cell-surface protein tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin, which may be of importance for the immune response and the pathophysiology of renal, vascular, and fibrotic disorders and malignancies.25 |
| PCGF2 | rs2879097 | The Polycomb group (PCG) gene products have been associated with a crucial role for the Th2-dependent immune response and Th2 differentiation by modifying the expression of different cytokines and chemokines and their receptors. Potential significance for various malignant diseases have also been reported.26,27 |
| DOCK2 | rs1863993 | The gene encodes a protein, which is a member of the DOCK family of guanine nucleotide exchange factors and activates the G-protein Rac in lymphocytes by promoting nucleotide exchange. The molecule is involved in cellular signaling and crucial for B- and T-lymphocyte chemotaxis and adhesion. In addition, the TCR seems to act through DOCK2. Deficiency causes a severe defect in lymphocyte responses to chemokines, peripheral T-cell distribution, and a deficiency in mature CD4 cells. A potential effect of the gene on various disorders such as autoimmune diseases, Alzheimer's disease, and malignancies have been described.28-30 |
| CD44 | rs927335 | This glycoprotein is expressed on the majority of immune cells and constitutes a cell-surface marker involved in cell-cell interaction, cell adhesion, and migration. Under inflammatory conditions, CD44 on endothelial cells presents hyaluronan on activated T cells and the pathway(s) by which the protein acts includes lymphocyte activation, recirculation, and homing of relevance for various inflammatory diseases and malignant processes31,32 |
| CD44 | rs10836342 | |
| IQGAP2 | rs17652304 | IQ-motif–containing GTPase-activating protein IQGAP2 is a family member of scaffolding proteins involved in a wide range of cellular processes. The protein interacts with components of the cytoskeleton and influences cell-cell interactions, cytokinesis, and apoptosis. An association with hepatocellular carcinoma has been described.33,34 |
| CSF1R | rs17725712 | Colony stimulating factor 1 receptor (CSF1R) encoded by this gene is also known as CD115. It is a cell-surface protein receptor that mediates the growth factor activity of CSF1 regulating differentiation of myeloid progenitors into various cell lines including monocytes, macrophages, and dendritic cells, as well as modulating the innate and adaptive immune systems. The gene product may influence a wide range of pathophysiological processes including inflammation, bone disease, and malignancy.35 |
| HSP90B1 | rs1882019 | Heat shock protein 90 kDA B1, also known as gp96, is a chaperone glycoprotein that has been suggested to play an essential role in regulating both the innate and adaptive immunity and modulate SLE, male fertility, and malignant processes,36,37 |
| F13A1 | rs13206518 | A transglutaminase with a well-known cross-linking function in the hemostatic process. Other biological processes unrelated to this have also been described and there is an increasing interest in the enzyme in the pathogenesis of inflammatory and autoimmune conditions such as celiac and inflammatory bowel disease and malignancies38,39 |
| IGSF2 | rs2296449 | Also previously known as V7 and CD101, a transmembrane glycoprotein expressed on monocytes, granulocytes, dendritic cells, and activated T cells including effector cells and CD4+CD25+Foxp3+ regulatory T cells. The biological functions of IGSF2 are largely unclear, but data suggest that this transmembrane glycoprotein modulates T-cell activation either directly or indirectly via dendritic cells, that it regulates T-cell proliferation via IL-10 production, and that it is involved in tolerance induction.40,41 |
| ALOX5AP | rs4075131 | The molecule encoded by this gene is involved in lipid and glucose metabolism and will potentially influence the synthesis of inflammatory mediators such as leukotrienes that are of importance for allergy and inflammatory processes.42 |
| MAP2K4 | rs3826392 | This gene encodes a kinase that is a direct activator of MAPKs, including MAPK9, in response to various environmental and stress stimulus. It is suggested to mediate survival signals in T-cell development and to influence inflammatory and malignant diseases.43,44 |
| PTPRN2 | rs12667537 | The transmembrane signaling molecules encoded by these genes are receptor-type tyrosine protein phosphatases. This family of proteins is known to be involved in and regulate a number of cellular processes such as cell growth and differentiation.45,46 |
| PTPRM | rs8086815 | |
| PTPRE | rs11015985 | |
| MSR1 | rs1564819 | This gene encodes a plasma membrane receptor, also named CD204, which belongs to a family of scavenger receptors. These receptors are suggested to be significantly involved in the formation of atherosclerotic lesions, but also other functions such as cell growth and interactions and host defense. An association with systemic inflammatory disorders has been suggested.47,48 |
| TNFRSF21 | rs10807350 | The protein encoded by this gene, also known as death protein 6 (DR6), is a member of the TNF-receptor superfamily and is considered to play an important regulatory role in the generation of adaptive immunity. Deficiencies seem to affect the Th2 response to both T-dependent and T-independent antigens and the marker has been suggested to be a potential therapeutic target for treating inflammatory and autoimmune diseases and malignancies.49,50 |
| Gene . | rs ID . | Function . |
|---|---|---|
| MAPK9 | rs4147385 | The molecule, also known as JNK2, belongs to a group of MAPKs that has been identified as a significant signaling pathway for the regulation of CD4+ T-cell differentiation. It also seems to influence the Th1/Th2 balance, providing protection against autoimmunity. Gene function has been associated with diabetes type 1 and malignancy.23,24 |
| PDGFRB | rs10072056 | The beta-type PDGF receptor gene encodes a cell-surface protein tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin, which may be of importance for the immune response and the pathophysiology of renal, vascular, and fibrotic disorders and malignancies.25 |
| PCGF2 | rs2879097 | The Polycomb group (PCG) gene products have been associated with a crucial role for the Th2-dependent immune response and Th2 differentiation by modifying the expression of different cytokines and chemokines and their receptors. Potential significance for various malignant diseases have also been reported.26,27 |
| DOCK2 | rs1863993 | The gene encodes a protein, which is a member of the DOCK family of guanine nucleotide exchange factors and activates the G-protein Rac in lymphocytes by promoting nucleotide exchange. The molecule is involved in cellular signaling and crucial for B- and T-lymphocyte chemotaxis and adhesion. In addition, the TCR seems to act through DOCK2. Deficiency causes a severe defect in lymphocyte responses to chemokines, peripheral T-cell distribution, and a deficiency in mature CD4 cells. A potential effect of the gene on various disorders such as autoimmune diseases, Alzheimer's disease, and malignancies have been described.28-30 |
| CD44 | rs927335 | This glycoprotein is expressed on the majority of immune cells and constitutes a cell-surface marker involved in cell-cell interaction, cell adhesion, and migration. Under inflammatory conditions, CD44 on endothelial cells presents hyaluronan on activated T cells and the pathway(s) by which the protein acts includes lymphocyte activation, recirculation, and homing of relevance for various inflammatory diseases and malignant processes31,32 |
| CD44 | rs10836342 | |
| IQGAP2 | rs17652304 | IQ-motif–containing GTPase-activating protein IQGAP2 is a family member of scaffolding proteins involved in a wide range of cellular processes. The protein interacts with components of the cytoskeleton and influences cell-cell interactions, cytokinesis, and apoptosis. An association with hepatocellular carcinoma has been described.33,34 |
| CSF1R | rs17725712 | Colony stimulating factor 1 receptor (CSF1R) encoded by this gene is also known as CD115. It is a cell-surface protein receptor that mediates the growth factor activity of CSF1 regulating differentiation of myeloid progenitors into various cell lines including monocytes, macrophages, and dendritic cells, as well as modulating the innate and adaptive immune systems. The gene product may influence a wide range of pathophysiological processes including inflammation, bone disease, and malignancy.35 |
| HSP90B1 | rs1882019 | Heat shock protein 90 kDA B1, also known as gp96, is a chaperone glycoprotein that has been suggested to play an essential role in regulating both the innate and adaptive immunity and modulate SLE, male fertility, and malignant processes,36,37 |
| F13A1 | rs13206518 | A transglutaminase with a well-known cross-linking function in the hemostatic process. Other biological processes unrelated to this have also been described and there is an increasing interest in the enzyme in the pathogenesis of inflammatory and autoimmune conditions such as celiac and inflammatory bowel disease and malignancies38,39 |
| IGSF2 | rs2296449 | Also previously known as V7 and CD101, a transmembrane glycoprotein expressed on monocytes, granulocytes, dendritic cells, and activated T cells including effector cells and CD4+CD25+Foxp3+ regulatory T cells. The biological functions of IGSF2 are largely unclear, but data suggest that this transmembrane glycoprotein modulates T-cell activation either directly or indirectly via dendritic cells, that it regulates T-cell proliferation via IL-10 production, and that it is involved in tolerance induction.40,41 |
| ALOX5AP | rs4075131 | The molecule encoded by this gene is involved in lipid and glucose metabolism and will potentially influence the synthesis of inflammatory mediators such as leukotrienes that are of importance for allergy and inflammatory processes.42 |
| MAP2K4 | rs3826392 | This gene encodes a kinase that is a direct activator of MAPKs, including MAPK9, in response to various environmental and stress stimulus. It is suggested to mediate survival signals in T-cell development and to influence inflammatory and malignant diseases.43,44 |
| PTPRN2 | rs12667537 | The transmembrane signaling molecules encoded by these genes are receptor-type tyrosine protein phosphatases. This family of proteins is known to be involved in and regulate a number of cellular processes such as cell growth and differentiation.45,46 |
| PTPRM | rs8086815 | |
| PTPRE | rs11015985 | |
| MSR1 | rs1564819 | This gene encodes a plasma membrane receptor, also named CD204, which belongs to a family of scavenger receptors. These receptors are suggested to be significantly involved in the formation of atherosclerotic lesions, but also other functions such as cell growth and interactions and host defense. An association with systemic inflammatory disorders has been suggested.47,48 |
| TNFRSF21 | rs10807350 | The protein encoded by this gene, also known as death protein 6 (DR6), is a member of the TNF-receptor superfamily and is considered to play an important regulatory role in the generation of adaptive immunity. Deficiencies seem to affect the Th2 response to both T-dependent and T-independent antigens and the marker has been suggested to be a potential therapeutic target for treating inflammatory and autoimmune diseases and malignancies.49,50 |
Shown here are the genes on which SNPs most strongly associated with inhibitor development in the Combined Cohort and the discordant pairs are located.