Table 2.
List of genes that could mediate the potential correlation between keratoconus and diabetes.
| Gene | Functions | CHR | KC/CCT effects | DM effects | References |
|---|---|---|---|---|---|
|
Cornea biomechanics and collagen crosslinking | |||||
| LOX | Lysyl oxidase, participates in collagen crosslinking | 5q23.2 | Reduced LOX expression in corneal stroma and reduced activity in KC-derived corneal fibroblasts | Increased LOX expression and activity in retinal endothelial cells; unclear effect in DM cornea | 33,45,47,58 |
|
COL5A1 |
Collagen type V, alpha-1 chain |
9q34.2-q34.3 |
COL5A1 haploinsufficiency results in corneal stroma thinning, reduced collagen fibers |
Possible interaction between COL5A1 and HbA1c in DR study; no known direct effect on COL5A1 in cornea |
65,66,72,81 |
|
ECM remodeling | |||||
| FOXO1 | Transcription factor | 13q14.1 | SNP in FOXO1 linked to CCT, FOXO1 expression/activity unknown in cornea | FOXO1 linked to AGE-mediated disruption of autophagic flux and vascular endothelial cell autophagic apoptosis, role in cornea unknown | 66,85,90 |
| SMAD3 | Transcription factor | 15q22.23 | SNP in SMAD3 linked to CCT, Increased pSMAD3 and increased TGFβ signaling in KC cells | SMAD3 linked to ECM remodeling in DN; role in cornea unclear | 49,98,100,106 |
| TGFBI | Transforming growth factor beta induced | 5q31.1 | SNP in TGFBI linked to KC with decreased levels of TGFBIp in KC cornea | Unknown effect in DM cornea, shown to be upregulated in response to high glucose and TGFβ in DM proximal tubules | 124, 125, 126,132 |
| ZEB1 | Zinc finger transcription factor | 10p11.22 | Mutations in ZEB1 associated with KC and PPCD; possible genotype/phenotype correlation | Unknown effect in DM cornea, implicated in epithelial-to-mesenchymal transition under hyperglycemic conditions | 152,154,155,158 |
| MMP-9 | Matrix metalloproteinase- 9 | 20q11.2-q13.1 | Increased MMP-9 activity noted in tear sample with corresponding upregulation in MMP-9 mRNA; SNP identified in MMP-9 | Increased MMP-9 activity in tears from DM patients; SNP identified in MMP-9 associated with T2DM susceptibility | 170,173,176,181,185 |
| TIMP-1 | Tissue inhibitor of metalloproteinases-1 | Xp11.23 | Decreased TIMP-1 levels detected in KC patients, SNP in TIMP-1 associated with increased KC risk | Increased TIMP-1 levels in tears of pediatric T1DM patients, but overall role of TIMP-1 in DM remains inconclusive | 83,178,182,185 |
|
MIR184 |
microRNA |
15q22-q25 |
Mutations in miR-184 implicated in KC pathogenesis, but extent of association with KC alone remains unclear |
miR-184 expression decreased in pancreatic β –cells in response to extracellular glucose; decreased in islet cells of T2DM patients |
187,196,200,201,310,311 |
|
Inflammation and ROS production | |||||
| HGF | Hepatocyte growth factor | 7q21.1 | Increased HGF protein in KC corneal epithelium; increased HGF and c-Met mRNA in corneal wound healing | Increased HGF with decreased HGF receptor c-Met expression in DM cornea | 3,214,217,220 |
| CAST | Calpain/calpastatin, proteolytic degradation | 5q15 | SNP in CAST strongly linked to KC; CAST expression/activity unclear | High glucose induces calpain activity, increasing ROS production and vascular endothelial dysfunction; unknown effect in cornea | 226,229,230 |
| SOD1 | Superoxide dismutase 1 cytoplasmic antioxidant enzyme | 21q22.11 | Deletion mutation in SOD1 in several cohorts; decreased SOD1 expression in KC corneal fibroblast cultures | Associated polymorphisms in SOD1 identified; decreased SOD1 expression in DM cornea with associated increase in RAGE | 238, 239, 240, 241,254,256 |
|
IL1A/IL1B |
Interleukin 1alpha/beta, inflammatory cytokine |
2q13 |
Increased IL-1α expression in KC corneas, SNPs identified in IL1A and IL1B |
Imbalance in IL-1β to IL-1Ra in DM cornea, SNPs identified in IL1A, IL1B, and IL1RN in DM patients |
119,162,203,262,268 |
|
Additional genes of interest | |||||
| SPRY2 | Sprouty 2 | 13q31.1 | SNP in SPRY2 linked to CCT and corneal epithelium proliferation; SPRY2 expression activity in KC cornea unknown | SNP near SPRY2 linked to increase DM susceptibility; unclear effect in SPRY2 cornea | 49,278,280, 281, 282 |
| COL4A3, COL4A4 | Collagen type IV, alpha-3/4 chain, structural portion of corneal membranes | 2q36.3 | Alterations in collagen type IV reported in KC, but unclear if genetic polymorphisms play a role | Alterations in collagen type IV reported in DN and in the cornea under hypoxic conditions, unknown genetic association with DM cornea | 48,283,290,291 |