Polymorphism of methylenetetrahydrofolate reductase gene in patients with T2DM combined with NAFLD and the relationship with hepatic fat content and insulin resistance

Abstract

Abstract: Objective To analyze the polymorphism of methylenetetrahydrofolate reductase gene and the relationship with hepatic fat content and insulin resistance in patients with type 2 diabetes mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD). Methods A total of 120 patients with T2DM complicated by NAFLD admitted to our hospital from January 2021 to December 2022 were selected. Patients carrying the CC genotype at the C677T locus were classified as the wild-type group, while those with the CT or TT genotype were assigned to the mutation group. The clinical characteristics of the two groups were compared, and multivariate logistic regression analysis was performed to identify independent risk factors influencing methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in T2DM patients with NAFLD. Results Among the 120 patients, 50 were in the mutation group and 70 in the wild-type group. Compared to the wild-type group, the mutation group exhibited significantly higher serum homocysteine levels (P<0.05). No statistically significant differences were observed in fasting blood glucose, fasting insulin, or HOMA-IR between the two groups (P>0.05). The mutation group showed significantly lower HDL levels (P<0.05). In terms of liver fat content, the mutation group had 30 cases with <240 dB/m and 20 cases with >240 dB/m, while the wild-type group had 25 cases and 45 cases, respectively, with a statistically significant difference (P<0.05). Elevated serum homocysteine, reduced HDL, and liver fat content >240 dB/m were identified as independent risk factors for MTHFR gene polymorphism in these patients (OR=5.078, 4.918, 4.963; P<0.05). Conclusion Serum Hcy, high-density lipoprotein cholesterol, and hepatic fat content above 240 dB/m were independent risk factors affecting methylenetetrahydrofolate reductase gene polymorphisms in patients with T2DM combined with NAFLD, and mutations in the C677T locus of the methylenetetrahydrofolate reductase gene usually resulted in abnormal lipid metabolism but had no effect on hepatic fat content.

Key words: Type 2 diabetes mellitus, Nonalcoholic fatty liver, Methylenetetrahydrofolate reductase gene polymorphism, Hepatic fat content, Insulin resistance

CHENG Xiao-he, ZHAI Chun-ying, KE Xiao-li, TIAN Nan. Polymorphism of methylenetetrahydrofolate reductase gene in patients with T2DM combined with NAFLD and the relationship with hepatic fat content and insulin resistance[J]. Chinese Hepatolgy, 2026, 31(2): 253-256.

References

[1] Tanase D M, Gosav E M, Costea C F, et al. The intricate relationship between type 2 diabetes mellitus (T2DM), insulin resistance (IR), and nonalcoholic fatty liver disease (NAFLD)[J]. J Diabetes Res, 2020, 2020:3920196.
[2] Caussy C, Aubin A, Loomba R. The relationship between type 2 diabetes, NAFLD, and cardiovascular risk[J]. Curr Diab Rep, 2021, 21(5):15.
[3] Yan J, Yao B, Kuang H, et al. Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease[J]. Hepatology, 2019, 69(6): 2414-2426.
[4] Zarembska E, Ślusarczyk K, Wrzosek M. The implication of a polymorphism in the methylenetetrahydrofolate reductase gene in homocysteine metabolism and related civilisation diseases[J]. Int J Mol Sci, 2023, 25(1):193.
[5] Wang Z, Li K, Ouyang L, et al. Effects of methylenetetrahydrofolate reductase single-nucleotide polymorphisms on breast, cervical, ovarian, and endometrial cancer susceptibilities[J]. Chronic Dis Transl Med, 2021, 7(3):169-181.
[6] 中华医学会糖尿病分会. 2007年版中国2型糖尿病防治指南[J]. 中华内分泌代谢杂志, 2008, 24(2) :1-26.
[7] Pouwels S, Sakran N, Graham Y, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss[J]. BMC Endocr Disord, 2022, 22(1):63.
[8] Cao Y, Du Y, Jia W, et al. Identification of biomarkers for the diagnosis of chronic kidney disease (CKD) with non-alcoholic fatty liver disease (NAFLD) by bioinformatics analysis and machine learning[J]. Front Endocrinol (Lausanne), 2023, 14:1125829.
[9] De Vincentis A, Mancina R M, Pihlajamäki J, et al. Genetic variants in the MTHFR are not associated with fatty liver disease[J]. Liver Int, 2020, 40(8):1934-1940.
[10] Wang X, Zhou Y, Zhang M, et al. The methylenetetrahydrofolate reductase genotype 677CT and non-alcoholic fatty liver disease have a synergistic effect on the increasing homocysteine levels in subjects from Chongqing, China[J]. Genes Dis, 2018, 6(1):88-95.
[11] Sun M Y, Zhang L, Shi S L, et al. Associations between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and non-alcoholic fatty liver disease (NAFLD) risk: a meta-analysis[J]. PLoS One, 2016, 11(4):e0154337.
[12] Kasapoglu B, Turkay C, Yalcin K S, et al. MTHFR 677C/T and 1298A/C mutations and non-alcoholic fatty liver disease[J]. Clin Med (Lond), 2015, 15(3):248-251.
[13] Serin E, Güçlü M, Ataç F B, et al. Methylenetetrahydrofolate reductase C677T mutation and nonalcoholic fatty liver disease[J]. Dig Dis Sci, 2007, 52(5):1183-1186.
[14] Chen P, Yang Z, Guo L, et al. Effects of homocysteine on nonalcoholic fatty liver related disease: a mendelian randomization study[J]. Front Mol Biosci, 2022, 9:1083855.
[15] Araszkiewicz A F, Jańczak K, Wójcik P, et al. MTHFR gene polymorphisms: a single gene with wide-ranging clinical implications-A review[J]. Genes (Basel), 2025, 16(4):441.