Association of MTHFR C677T, MTHFRA1298C and MTRRA66G gene polymorphisms with hyperhomocysteinemia and its modulation by the combined effect of vitamin B12 and folate in a hypertensive Chinese population

Sultan Mehmood Siddiqi; Lishun Liu; Yiming Du; Yun Song; Ping Chen; Shuqun Li; Qiangqiang He; Ziyi Zhou; Jiafeng Xu; Jie Bai; Binyan Wang; Xianhui Qin; Anam Mehmood; Liu Xiuqing; Xiaoxu Cheng; Han-Ping Shi

doi:10.1016/j.tjnut.2024.09.003

Association of MTHFR C677T, MTHFRA1298C and MTRRA66G gene polymorphisms with hyperhomocysteinemia and its modulation by the combined effect of vitamin B12 and folate in a hypertensive Chinese population

J Nutr. 2024 Sep 17:S0022-3166(24)01014-9. doi: 10.1016/j.tjnut.2024.09.003. Online ahead of print.

Authors

Sultan Mehmood Siddiqi¹, Lishun Liu², Yiming Du³, Yun Song⁴, Ping Chen⁵, Shuqun Li⁶, Qiangqiang He¹, Ziyi Zhou⁷, Jiafeng Xu⁸, Jie Bai⁴, Binyan Wang⁴, Xianhui Qin⁹, Anam Mehmood¹⁰, Liu Xiuqing¹¹, Xiaoxu Cheng¹², Han-Ping Shi¹³

Affiliations

¹ Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
² Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Guangdong Key Laboratory of H-type Hypertension and Stroke Precision Prevention Research and Development Enterprise, Shenzhen AUSA Pharmaceutical Co. Ltd, Shenzhen 518057, China.
³ State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China.
⁴ Shenzhen Evergreen Medical Institute, Shenzhen 518057, China.
⁵ College of Pharmacy, Jinan University, Guangzhou 510630, China; Inspection and Testing Center, Key Laboratory of Cancer FSMP for State Market Regulation, Shenzhen 518057, China.
⁶ Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University; Beijing 100038, China.
⁷ Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China; Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ Shenzhen Evergreen Medical Institute, Shenzhen 518057, China; Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
⁹ National Clinical Research Study Center for Kidney Disease, The State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
¹⁰ Department of Applied Psychology, Bahauddin Zakariya University, Multan, Pakistan.
¹¹ Department of Laboratory Medicine, Shenzhen Second People's Hospital, Shenzhen 518057, China.
¹² Department of Cardiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330031 China.
¹³ Key Laboratory of Cancer FSMP for State Market Regulation; Beijing 100038, China. Electronic address: 15919737331@163.com.

PMID: 39299473
DOI: 10.1016/j.tjnut.2024.09.003

Abstract

Background: In China, the MTHFR 677T allele, unlike in most Western populations, is a rare genetic variant linked to various disorders. The contributing nutritional and genetic factors to this genetic risk remain unclear.

Objective: This study aimed to elucidate the interactions between genetic variations in total homocysteine (tHcy) pathway genes, serum tHcy levels, and nutritional factors in a hypertensive Chinese population.

Methods: This study analyzed 1,304 hypertensive Chinese adults aged 18 years and older enrolled in the China Precision Nutrition and Health KAP Real World Study (CPNAS). Serum levels of vitamin B12 and folate were measured using the magnetic microparticle chemiluminescence method, and tHcy levels were measured using Hcy Assay kits. Identification of the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms was performed via time-of-flight nucleic spectrometry.

Results: Our findings revealed significant sex differences in tHcy levels, with males exhibiting higher tHcy levels than females (13.95 μmol/L vs. 11.15 μmol/L, p < 0.001). Individuals deficient in both vitamin B12 and folate had an increased risk of H-Hcy (57.4%). In contrast, the prevalence of H-Hcy was lower among those deficient in either vitamin B12 (31.1%) or folate (23.2%) alone. Significant associations were identified between the MTHFR C677T and A1298C polymorphisms and elevated serum tHcy levels, particularly in individuals homozygous for the T allele. Conversely, the MTRR A66G genotype did not show a significant correlation with tHcy levels. Optimal vitamin B12 concentrations significantly modulated the genotypic effect on tHcy levels, with individuals having adequate vitamin B12 and folate exhibiting low tHcy levels, even among high-risk genotypes (TT).

Conclusions: Adequate levels of folate and vitamin B12 significantly reduce serum tHcy concentrations and mitigate the genotypic impact on tHcy levels, highlighting the potential for targeted nutritional interventions to manage cardiovascular risks associated with hyperhomocysteinemia.

Trial registration: The Clinical Study Protocol for the Trial (CPNAS) has been officially registered at ClinicalTrials.gov under the identification number ChiCTR2100051983.

Keywords: Genetic polymorphisms; Hyperhomocysteinemia; MTHFR A1298C; MTHFR C677T; Vitamin B12; folate.