Table 1.
Monogenic Diabetes Genes Associated With Common T1D and/or T2D
| Gene Name | Major Function | Monogenic Diabetes or Syndromes | Mutations or Variants Associated With Common T1D and/or T2D | Refs. |
|---|---|---|---|---|
| Monogenic Diabetes Genes Associated With T2D | ||||
| KCNJ11 | Encodes pore-forming inwardly-rectifying potassium channel subunits (Kir6.2) | PNDM (most common cause) and TNDM, CHI, MODY | E23K | 42–46 |
| ABCC8 | Encodes regulatory SUR1 subunits | PNDM and TNDM, CHI, MODY | A1369S, 1273AGA, R1420H | 46, 47, 52 |
| GCK | A key glucose-phosphorylating enzyme; a glucose sensor | GCK-MODY (MODY2), PNDM, CHI | rs1799884 (G/A), rs4607517 (A/G), 3′UTR SNP, chr7:44184184-G/A | 75, 78, 79 |
| SLC2A2 | Encodes GLUT2, a high-capacity facilitative glucose transporter | FBS | SNPs rs5393 (AA) and rs5394 (CC) in the promoter region and SNPs rs5400 (T110I) and rs5404 (T198T) | 93–100 |
| HNF1A/TCF1 | TF; regulator of pancreatic β-cell differentiation | HNF1A-MODY (MODY3), most common cause of MODY, CHI | G319S, c.1522G>A (p.E508K) | 114, 118, 119 |
| HNF4A | Key TF for early fetal development | HNF4A MODY (MODY1), CHI | SNPs rs2144908, rs3818247 and rs884614, rs4810424, rs1884613 | 121–124, 274 |
| HNF1B/TCF2 | TF; required for the generation of pancreatic and endocrine progenitors | RCAD syndrome, or MODY5; TNDM and PNDM (rare) | SNP rs757210 A, rs4430796 A, and rs7501939 C | 141, 144 |
| PDX1 | TF; required for pancreas development, β-cell differentiation and the maintenance of mature β-cell function | PNDM, MODY4 | C18R, Q59L, D76N, R197H, G212R, P239Q, InsCCG243, p.Gly218Alafs*12 | 163–165, 167 |
| PAX4 | Islet TF that functions mainly as a transcription repressor | MODY9 | R121W, R133W, R37W, rs10229583 G | 180, 181, 187 |
| NEUROD1/BETA2 | TF; required for the development of the endocrine pancreas; transactivates the INS gene | MODY6 and PNDM | R111L and 206 + C; A45T variant at rs1801262 (inconsistent) | 204–208 |
| WFS1 | A transmembrane protein; a negative regulator of ER stress | WFS1, sometimes referred to as DIDMOAD | R456 and H611, SNPs at rs10010131, rs6446482; variants rs10010131 G, 1801213 G, and rs734312 A | 223–225 |
| PPARG | TF; master regulator of adipogenesis, energy balance, lipid biosynthesis, and insulin sensitivity; cellular target of TZDs | Monogenic diabetes | Pro12Ala variant (rs1801282), SNP at rs4684847 | 240–243, 250 |
| Monogenic Diabetes Genes Associated With Both Common T1D and T2D | ||||
| INS | Predominant glucose-lowering hormone | PNDM (2nd most common cause), TNDM, MODY10 | Class I alleles of INS VNTR associated with T1D; Class III alleles of INS VNTR inconsistently associated with T2D | 273, 274, 276–281 |
| GLIS3 | TF; regulator of islet development, insulin gene transcription, and obesity-induced compensatory β-cell proliferation | Neonatal diabetes syndrome associated with congenital hypothyroidism, and polycystic kidneys | rs7020673 G associated with T1D; rs7034200 A and rs7041847 A associated with T2D | 78, 214, 289, 291, 292, 295–308 |
Abbreviation: TF, transcription factor.