Table 5.

List of Major Candidate Genes Involved in the Inflammation Pathway

Gene Symbol	Gene Name	Chromosomal Location	Transcript information	Justification
TNF-α	tumor necrosis factor receptor superfamily	chr3:156092602–156107426	Exons: 9 Transcript length: 1,247 bps Protein length: 289 residues	TNF-α, a potential mediator of insulin resistance, promotes serine phosphorylation of IRS-1 and -2, impairs the ability of IRS-1 and -2 to associate with the insulin receptor and inhibits insulin-stimulated tyrosine phosphorylation [54–56]. TNF-α is upregulated in Dahl S rats [52].
NF-kappa-B-activating protein	Nuclear factor kappa-B-activating protein	chr X: 7,762,299–7,781,765.	Exons: 9 Transcript length: 1,248 bps Protein length: 415 residues	Renal NF-{kappa}B is significantly upregulated in high-salt-fed Dahl S rats [58].
NF-IKBKB	Nuclear factor kappa-B kinase subunit beta	chr16: 73,805,082–73,858,088.	Exons: 21 Transcript length: 3,022 bps Protein length: 757 residues	Inhibition of IKBKB with salicylates or through targeted gene disruption causes a dramatic improvement of insulin sensitivity in animal models of insulin resistance such as ob/ob mice and obese Zucker fatty rats [59,60].
IL1β	Interleukin-1β receptor accessory protein precursor	chr11: 76,092,840–76,222,495.	Exons: 11 Transcript length: 1,862 bps Protein length: 570 residues	IL1β activates jnk which is upregulated in high-salt-fed Dahl S rats [57].
IL17d	interleukin 17D	chr 15: 36,566,307–36,583,168.	Exons: 9 Transcript length: 621 bps Protein length: 206 residues	IL-17 D, a proinflammatory cytokine that enhances T cell priming and stimulates the production of proinflammatory molecules such as IL-1, IL-6, TNF-alpha, NOS-2, and chemokines resulting in inflammation.
IL10	Interleukin-10 precursor (IL-10) (Cytokine synthesis inhibitory factor) (CSIF).	chr 13: 43.95m	Exons: 5 Transcript length: 1,289 bps Protein length: 178 residues	IL-10, also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. It is capable of inhibiting synthesis of pro-inflammatory cytokines like Interferon-gamma, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and the Type 1 T helper cells.
Crp	C-reactive protein precursor	chr 13: 88,674,743–88,715,585.	Exons: 2 Transcript length: 1,655 bps Protein length: 230 residues	Insulin resistance and C-reactive protein (CRP) levels are strongly correlated in adults [110].
Ratsg2	Selenoprotein S (VCP-interacting membrane protein) (Sg2).	chr 1: 120,509,128–120,518,322.	Exons: 6 Transcript length: 573 bps Protein length: 190 residues	In humans, polymorphisms in the encoded plama membrane selenoprotein (SEPS1, or SELS gene) correlate to diabetes mellitus and coronary heart diseases. The selenoprotein regulate red-ox balance and clear cells of misfolded proteins. Gene polymorphisms result in accumulation of these proteins even higher under cell stress. Carriers have higher IL1, -6, -10, and TNF [111].
Ptpn22_predicted	protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (predicted)	chr 2: 199,083,234–199,132,761	Exons: 22 Transcript length: 2,476 bps Protein length: 803 residues	Tyrosine phosphatase gene (PTPN22) prevents spontaneous T-cell activation. In humans, mutations (C1858T, R620W) was associated with type 1 diabetes [112–114].
Crhr1	Corticotropin-releasing factor receptor 1 precursor (CRF-R) (CRF1) (Corticotropin-releasing hormone receptor 1) (CRH-R 1).	chr 10: 93.31 m	Exons: 12 Transcript length: 1,218 bps Protein length: 405 residues	Crhr1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine release.
IL6	Interleukin-6 precursor	chr 4: 456,799–461,376.	Exons: 6 Transcript length: 1,042 bps Protein n length: 210 residues	Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 [115].
IL15	Interleukin-15 precursor.	chr 19: 27,482,376–27,499,255.	Exons: 6 Transcript length: 768 bps Protein length: 161 residues	IL-15 increases insulin sensitivity therefore increasing glucose transport and utilization in muscles [116].
IL18	interleukin 18	chr 9: 39,676,026–39,698,748.	Exons: 10 Transcript length: 1,884 bps Protein length: 604 residues	Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans [117,118].
Map2k7	Dual specificity mitogen-activated protein kinase kinase 7	chr 12: 1,543,467–1,552,353.	Exons: 13 Transcript length: 1,407 bps Protein length: 468 residues	MAP2K7 selectively activates the JNKs which suppresses insulin signaling [57].
Mapk6	Mitogen-activated protein kinase 6 or (Extracellular signal-regulated kinase 3) (ERK-3) (p55-MAPK).	chr 8: 80,212,726–80,236,362	Exons: 6 Transcript length: 4,180 bps Protein length: 720 residues	ERK3 associates with MAP2 and is involved in glucose-induced insulin secretion [119].
Map4k4	Mitogen-activated protein kinase 4-isoform4	chr 9: 39,070,845–39,211,446.	Exons: 34 Transcript length: 4,401 bps Translation length: 1,232 residues	Map4k4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance [120].
Map2k1	Dual specificity mitogen-activated protein kinase kinase 1 or (MAP kinase kinase 1) (MAPKK 1) (ERK activator kinase 1) (MAPK/ERK kinase 1) (MEK1).	chr 8: 68,379,077–68,451,583.	Exons: 11 Transcript length: 2,120 bps Protein length: 393 residues	MAP2K1 restored insulin action on glucose uptake by cells [120,121].
Jnk	C-Jun amino terminal kinase	chr 3: 76.78 m	Exons: 12 Transcript length: 2,992 bps Protein length: 699 residues	JnK is activated by TNF-α and IL-β. Jnk forms a stable complex with IRS-1 and phosphorylates Ser307 that inhibits insulin stimulated tyrosine phosphorylation of IRS-1 [57].
Cx3cr1	CX3C chemokine receptor 1	chr 8: 125.03 m	Exons: 2 Transcript length: 1,326 bps Protein length: 354 residues	Modulators of CX3CR1 can be used to treat diabetes, as well as diagnose diabetes by measuring the levels of CX3CR1 in a patient (US patents 2006).
Ccr3	C-C chemokine receptor type 3	chr 8: 128.76 m	Exons: 2 Transcript length: 1,315 bps Protein length: 359 residues	CCL3was reported to be increased in obese mice and to contribute to insulin resistance and macrophage recruitment [122].
Ccr2	C-C chemokine receptor type 2	chr 8: 128.89 m	Exons: 1 Transcript length: 1,122 bps Protein length: 373 residues	CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance [123].
Ccr5	C-C chemokine receptor type 5	chr 8: 128.91 m	Exons: 2 Transcript length: 2,495 bps Protein length: 354 residues	CCR5 polymorphisms in children with insulin-dependent diabetes mellitus [124].
Nox3	NADPH oxidase 3	chr 1: 38.64 m	Exons: 14 Transcript length: 1,761 bps Protein length: 586 residues	NOX3, a ROS generating NADPH oxidase, plays an integral role in insulin-induced signal transmission [125].
Nox4	NADPH oxidase 4	chr 1: 143.42 m	Exons: 18 Transcript length: 2,176 bps Protein length: 578 residues	The NAD(P)H Oxidase Homolog Nox4 Modulates Insulin-Stimulated Generation of H2O2 and Plays an Integral Role in Insulin Signal Transduction [126].
Ptgs2	Prostaglandin G/H synthase 2 precursor (Cyclooxygenase-2) (COX-2) (Prostaglandin H2 synthase 2) (PGH synthase 2) (PGHS-2) (PHS II).	chr 13: 64,427,282–64,432,982.	Exons: 10 Transcript length: 1,825 bps Protein length: 604 residues	PTGS2 generates prostaglandins, which negatively modulate glucose-stimulated insulin secretion, and functions as a mediator of the inflammatory response [127].
Alox5	Arachidonate 5-lipoxygenase (5-lipoxygenase) (5-LO)	chr 4: 152.61 m	Exons: 14 Transcript length: 2,450 bps Protein length: 674 residues	The epidemiologic data suggest that subjects with two variant alleles will have greater ALOX5 gene expression, greater production of arachidonic acid-derived leukotrienes and a more "proinflammatory phenotype than subjects with two common alleles.
Alox5ap	Arachidonate 5-lipoxygenase-activating protein (FLAP) (MK-886-binding protein).	chr 12: 6.25 m	Exons: 5 Transcript length: 937 bps Protein length: 161 residues	ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance [128].
Nos3	Nitric-oxide synthase, endothelial (NOSIII) (Endothelial NOS) (eNOS)	chr 4: 6.16 m	Exons: 26 Transcript length: 3,953 bps Protein length: 1,202 residues	The (-)786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients [129]
Nos2	Nitric oxide synthase, inducible (NOS type II) (Inducible NO synthase) (Inducible NOS) (iNOS)	chr 10: 65.04 m	Exons: 27 Transcript length: 4,106 bps Protein length: 1,147 residues	obese Nos2 -/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles [130].
Cpr	NADPH-cytochrome P450 reductase (CPR) (P450R).	chr 12: 22.08 m	Exons: 16 Transcript length: 2,438 bps Protein length: 678 residues	NADPH-cytochrome P450 reductase (CPR) plays a role in type II diabetes [131]
Pla2g1b	Phospholipase A2 precursor	chr 12: 42.41 m	Exons: 4 Transcript length: 543 bps Protein length: 146 residues	Mice with targeted inactivation of the group 1B phospholipase A [2] (Pla2glb) gene displayed lower postprandial glycemia than that observed in wild-type mice after being fed a glucose-rich meal [132].