Table 2.
Characteristics of genetic variants and related genetic association study.
| Gene | SNP | Chromosome position | Variant type | Population | MAF:(case/ control) or population group | (P)*with HWE | Clinical effects | References |
|---|---|---|---|---|---|---|---|---|
| SLC22A1(OCT1) | rs622342 | chr6:160151834C>A | Intron variant | Chinese | 0.274 | - | Patients with the A/C genotype showed better response on ΔFPG (p = 0.008) and ΔHbA1c (P = 0.006) compared with the C/C genotype. No effect on metformin intolerance | Chen (12) |
| South Indian | 0.205/0.245 | >0.05 | Significant association with the metformin response [dominant:3.85 (1.61–9.19), P = 0.003)][recessive:3.56 (0.83–15.26), P = 0.09][over-dominant:0.35 (0.14–0.86), P = 0.03] | Umamaheswaran et al. (28) | ||||
| Mexican | 0.38 | >0.05 | Significant association with ΔHbA1c (P < 0.001) | Reséndiz-Abarca et al. (21) | ||||
| Lebanese | 0.175 | >0.05 | Significant relationship with ΔHbA1c after 6 months of metformin treatment (P = 0.03) significant relationship with ΔFBS after 3 months (P = 0.02) and 6 months (P = 0.001) of metformin treatment | Naja et al. (38) | ||||
| Chinese | - | 0.767 | Patients with the A/A genotype were significantly higher in FPG (P = 0.014), HbA1c (P = 0.046), and HOMA-IR (P = 0.004). | Wu et al. (37) | ||||
| Mexican | 0.358 | 0.188 | The interaction between rs72552763 and rs622342 was associated with the metformin response (P = 0.024) | Marta et al. (27) | ||||
| European | 0.050 | 0.95 | No significant relationship with HbA1c decrease (P = 0.95) | Tkáč et al. (11) | ||||
| South Indian | 0.463 | - | No significant association with the metformin response (P = 0.88) | Phani et al. (31) | ||||
| Jordanian | 0.23 | 0.04 | No significant relationship between glycemic control (P = 0.432) and HbA1c level (P = 0.277) | AL-Eitan et al. (26) | ||||
| South African | 0.259 | 0.218 | No significant relationship with the metformin response | Abrahams-October (33) | ||||
| rs12208357 | chr6:160122116C>T | Missense variant | South Indian | 0.89 | - | Patients with the C allele have higher FPG, PPG, and FINS (P < 0.05) | Koshy et al. (35) | |
| Bosnia and Herzegovina | - | - | Significant association with the incidence of gastrointestinal intolerance in haplotype analysis (P = 0.034) | Dujic et al. (24) | ||||
| Bosnia and Herzegovina | - | - | Significant association with the incidence of metformin intolerance in haplotype analysis (P < 0.001) | Dujic et al. (23) | ||||
| Egyptian | 0.75/0.275 | - | Patients with the C/G genotype showed lower RBS (P = 0.004) compared to patients with the C/C allele. | Mostafa-Hedeab et al. (20) | ||||
| Chinese | 0.067 | >0.05 | No significant association with ΔHbA1c (P = 0.470) | Zhou et al. (10) | ||||
| Latvian | 0.10 | 0.447 | No significant effect in metformin intolerance | Tarasova et al. (22) | ||||
| European | 0.071 | >0.05 | No significant influence on metformin intolerance | Dawed et al. (25) | ||||
| rs72552763 | chr6:160139849-160139853delGAT | Deletion variant | Bosnia and Herzegovina | - | - | Significant association with the incidence of gastrointestinal intolerance in haplotype analysis (P = 0.034) | Dujic et al. (24) | |
| Bosnia and Herzegovina | - | - | Significant association with the incidence of metformin intolerance in haplotype analysis (P < 0.001) | Dujic et al. (23) | ||||
| Mexican | 0.240 | < 0.001 | The interaction between rs72552763 and rs622342 was associated with metformin response (P = 0.024) | Marta et al. (27) | ||||
| Chinese | 0.198 | >0.05 | No significant association with HbA1c decrease (P = 0.919) | Zhou et al. (10) | ||||
| Latvian | 0.18 | 1 | No significant effect in metformin intolerance | Tarasova et al. (22) | ||||
| - | 0.188/0.288 | 0.088 | No significant association with the metformin response (P = 0.069) | Mahrooz et al. (29) | ||||
| European | 0.186 | >0.05 | No significant influence on metformin intolerance | Dawed et al. (25) | ||||
| rs628031 | chr6:160139813A>G | Missense variant | Latvian | 0.39 | 0.785 | The A allele was significantly associated with the decrease of metformin intolerance (P = 0.012) | Tarasova et al. (22) | |
| Chinese | 0.207 | - | Patients with the G/G genotype showed worse response on ΔFPG (P = 0.019) | Chen (12) | ||||
| Chinese | 0.10/0.262 | 0.49 | Patients with the G/G genotype have shown greater reductions in the FPG level (P < 0.01) | Zhou et al. (10) | ||||
| Chinese | 0.463/0.306 | 0.88 | Patients with the G/G genotype have shown greater reductions in the FPG level (P = 0.001) The A allele was significantly associated with the increase in metformin intolerance (P < 0.05) | Fu (17) | ||||
| Chinese | 0.325/0.307 | >0.05 | Patients with A/G (P1 = 0.038, P2 = 0.007) and G/G (P1 = 0.011, P2 = 0.022) genotypes showed better response on ΔFPG (1) and ΔHbA1c (2) | Liu et al. (16) | ||||
| Mexican | 0.275 | 0.046 | Significant association with ΔHbA1c (P = 0.016) | Reséndiz-Abarca et al. (21) | ||||
| Iranian | 0.317/0.331 | - | No significant effect in metformin response (P = 0.47) | Shokri et al. (30) | ||||
| rs594709 | chr6:160134722 G>A | Intron variant | Chinese | 0.268/0.286 | >0.05 | No significant association with ΔFPG (P = 0.112), ΔPPG (P = 0.171), and ΔHbA1c (P = 0.227) | Xiao et al. (18) | |
| Mexican | 0.18 | >0.05 | Significant association with ΔHbA1c (P = 0.032) | Reséndiz-Abarca et al. (21) | ||||
| Chinese | 0.268/0.29 | >0.05 | No significant association with Δ FPG (P = 0.835), ΔPPG (P = 0.520), and ΔHbA1c (P = 0.977) | Bao (39) | ||||
| rs1867351 | chr6:160122091T>C | Missense variant | Chinese | 0.50/0.38 | 0.44/0.53 | Patients with the T/T genotype have shown greater reductions in PPG (P = 0.06) and HbA1c (P = 0.02) levels | Zhou et al. (13) | |
| Jordanian | 0.19 | 0.85 | No significant relationship with glycemic control (P = 0.187) and HbA1c level (P = 0.136) | AL-Eitan et al. (26) | ||||
| rs2297374 | chr6:160154953C>T | Intron variant | Chinese | 0.40/0.343 | 0.53/0.43 | Patients with the C/T genotype have shown greater reductions in FPG (P = 0.002) and HbA1c (p =0.039) levels | Zhou et al. (13) | |
| Jordanian | 0.46 | 0.79 | No significant relationship with glycemic control (P = 0.285) and HbA1c level (P = 0.180) | AL-Eitan et al. (26) | ||||
| rs683369 | chr6:160130172G>C | Missense variant | Chinese | 0.138/0.194 | 0.11 | No significant association with change of FPG, PPG, HbA1c | Fu (17) | |
| Jordanian | 0.13 | 0.37 | No significant relationship with glycemic control (P = 0.146) and HbA1c level (P = 0.072) | AL-Eitan et al. (26) | ||||
| rs34059508 | chr6:160154805G>A | Missense variant | Bosnia and Herzegovina | - | - | Significant association with the incidence of metformin intolerance in haplotype analysis (P < 0.001) | Dujic et al. (23) | |
| Latvian | 0.04 | 1 | No significant effect in metformin intolerance | Tarasova et al. (22) | ||||
| rs34130495 | chr6:160139792 G>A | Missense variant | Bosnia and Herzegovina | - | - | Significant association with the incidence of metformin intolerance in haplotype analysis (P < 0.001) | Dujic et al. (23) | |
| - | 0.031 | >0.05 | No significant influence on metformin intolerance | Dawed et al. (25) | ||||
| rs461473 | chr6:160122530G>A | Intron variant | Jordanian | 0.10 | 0.44 | No significant relationship with glycemic control (P = 0.311) and HbA1c level (P = 0.253) | AL-Eitan et al. (26) | |
| South African | 0.011 | 0.898 | No significant relationship with the metformin response | Abrahams-October et al. (33) | ||||
| rs4709400 | chr6:160122578C>G | Intron variant | Chinese | 0.30/0.468 | 0.45/0.88 | Patients with the G/G genotype have shown greater reductions in FPG (P = 0.046) and PPG (P = 0.07) levels | Zhou et al. (13) | |
| rs36056065 | G160560908delinsGT AAGTTG | Insertion variant | Latvian | 0.39 | 0.686 | Significant association with metformin intolerance (P = 0.002) | Tarasova et al. (22) | |
| rs55918055 | chr6:160122197T>C | Missense variant | Scotland | - | - | Significant association with the incidence of metformin intolerance in haplotype analysis (P < 0.001) | Dujic et al. (23) | |
| SLC22A2(OCT2) | rs316019 | chr6:160249250A>C | Missense variant | Chinese | 0.22 | - | Patients with the C/C genotype showed better response on ΔFINS (P = 0.034) compared to patients with the A/C allele | Chen (12) |
| South Indian | 0.112 | - | Significant association with the metformin response [dominant:0.35 (0.16-0.77), P = 0.0064)] | Phani et al. (31) | ||||
| Chinese | 0.153 | - | Significant association with ΔHbA1c (P = 0.04) | Hou et al. (14) | ||||
| European | 0.065 | - | No significant influence on ΔHbA1c (P = 0.15) | Tkáč et al. (11) | ||||
| Chinese | 0.075/0.128 | 0.5 | No significant influence on metformin intolerance (P = 0.445) | Fu (17) | ||||
| Latvian | 0.08 | 0.203 | No significant influence on metformin intolerance | Tarasova et al. (22) | ||||
| Mexican | 0.047 | P > 0.05 | No significant influence on ΔHbA1c (P = 0.368) | Reséndiz-Abarca et al. (21) | ||||
| rs316009 | chr6:160254732T>C | Intron variant | South African | 0.039 | 0.595 | Patients with the allele T show a better response for metformin (P = 0.044), but after Bonferroni correction, P = 0.088 | Abrahams-October et al. (33) | |
| rs145450955 | chr6:160250619C>T | Missense variant | Iranian | - | - | Patients with minor alleles had higher HbA1c level (P = 0.019), FPG (P = 0.023), and HOMA-IR (P = 0.03) | Kashi et al. (36) | |
| SLC22A3(OCT3) | rs3088442 | chr6:160451620 G>A | Non-coding transcript variant | Iranian | 0.31 | P > 0.05 | No significant association between ΔHbA1c and ΔFPG | Ghaffari-Cherati et al. (15) |
| Pakistani | 0.153 | P > 0.05 | The allele A may act as a protective allele for metformin response [0.56 (0.40–0.80), P < 0.05] | Moeez et al. (32) | ||||
| rs2292334 | chr6:160437156G>A | Synonymous variant | Iranian | 0.35 | 0.544 | The mean reduction in HbA1c levels following 3 months was higher in patients with the A allele than in those with the homozygous G allele | Hosseyni-Talei et al. (19) | |
| rs12194182 | chr6:160413483T>C | Intron variant | Jordanian | 0.09 | 0.29 | Significant association with HbA1c levels (P = 0.007) | Al-Eitan et al. (26) | |
| rs543159 | chr6:160354985C>A | Intron variant | Iranian | 0.39/0.48 | 0.051/0.67 | Significant association with the metformin response [Dominant:2.48(1.28–4.78), P = 0.0057] | Taheri et al. (34) | |
| rs1317652 | chr6:160386129C>T | Intron variant | Iranian | 0.38/0.49 | 0.03/0.83 | Significant association with the metformin response [Dominant:2.49(1.32–4.70), P = 0.0043] | Taheri et al. (34) | |
| rs2048327 | chr6:160442500T>C | Intron variant | Chinese | 0.162/0.122 | 0.29 | No significant influence on metformin intolerance (P = 0.813) | Fu (17) |