MTHFR and risk of stroke and heart disease in a low-folate population: a prospective study of 156 000 Chinese adults
Authors: Bennett Derrick A , Parish Sarah , Millwood Iona Y , Guo Yu , Chen Yiping , Turnbull Iain , Yang Ling , Lv Jun , Yu Canqing , Davey Smith George , Wang Yongjun , Wang Yilong , Peto Richard , Collins Rory , Walters Robin G , Li Liming , Chen Zhengming , Clarke Robert ,   the China Kadoorie Biobank (CKB) Study Collaborative Group, Chen Junshi , Chen Zhengming , Clarke Robert , Collins Rory , Li Liming , Wang Chen , Lv Jun , Peto Richard , Walters Robin , Avery Daniel , Barnard Maxim , Bennett Derrick , Boxall Ruth , Chan Ka Hung , Chen Yiping , Chen Zhengming , Clarke Johnathan , Clarke Robert , Du Huaidong , Mohamed Ahmed Edris , Fry Hannah , Gilbert Simon , Im Pek Kei , Iona Andri , Kakkoura Maria , Kartsonaki Christiana , Lam Hubert , Lin Kuang , Liu James , Mazidi Mohsen , Millwood Iona , Morris Sam , Nie Qunhua , Pozarickij Alfred , Ryder Paul , Said Saredo , Schmidt Dan , Stevens Becky , Turnbull Iain , Walters Robin , Wang Baihan , Wang Lin , Wright Neil , Yang Ling , Yang Xiaoming , Yao Pang , Han Xiao , Hou Can , Xia Qingmei , Liu Chao , Lv Jun , Pei Pei , Sun Dianjianyi , Chen Canqing Yu Naying , Liu Duo , Chen Zhenzhu Tang Ningyu , Jiang Qilian , Lan Jian , Li Mingqiang , Liu Yun , Meng Fanwen , Meng Jinhuai , Pan Rong , Qin Yulu , Wang Ping , Wang Sisi , Wei Liuping , Dong Liyuan Zhou Caixia , Ge Pengfei , Li Xiaolan Ren Zhongxiao , Mao Enke , Wang Tao , Zhang Hui , Zhang Xi , Chen Jinyan , Hu Ximin , Guo Xiaohuan Wang Zhendong , Li Huimei , Li Yilei , Weng Min , Yan Shukuan Wu Shichun , Zou Mingyuan , Guo Xue Zhou Ziyan , Kang Quan , Li Yanjie , Yu Bo , Chang Qinai Xu Liang , Fan Lei , Feng Shixian , Zhang Ding , Gao Gang Zhou Yulian , He Tianyou , He Pan , Hu Chen , Sun Huarong , Chen Xukui Zhang Biyun , Fu Zhongxi , Huang Yuelong , Liu Huilin , Xu Qiaohua , Long Li Yin Huajun , Xu Xin , Zhang Hao , Zhang Libo , Su Jian , Tao Ran , Wu Ming , Yang Jie , Zhou Jinyi , Hu Yonglin Zhou Yihe , Hua Yujie , Jin Jianrong , Liu Fang , Liu Jingchao , Lu Yan , Ma Liangcai , Tang Aiyu , Zhang Jun , Cheng Liang , Du Ranran , Gao Ruqin , Li Feifei , Li Shanpeng , Liu Yongmei , Ning Feng , Pang Zengchang , Sun Xiaohui , Tian Xiaocao , Wang Shaojie , Zhai Yaoming , Zhang Hua , Hou Wei , Lv Silu , Wang Junzheng , Chen Xiaofang , Wu Xianping , Zhang Ningmei , Chang Xiaoyu , Chen Xiaofang , Li Jianguo , Liu Jiaqiu , Luo Guojin , Sun Qiang , Zhong Xunfu , Gong Weiwei , Hu Ruying , Wang Hao , Wang Meng , Yu Min , Chen Lingli , Gu Qijun , Pan Dongxia , Wang Chunmei , Xie Kaixu , Zhang Xiaoyi 
Published: October 2023

Abstract

Background
The relevance of folic acid for stroke prevention in low-folate populations such as in China is uncertain. Genetic studies of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which increases plasma homocysteine (tHcy) levels, could clarify the causal relevance of elevated tHcy levels for stroke, ischaemic heart disease (IHD) and other diseases in populations without folic acid fortification.

Methods
In the prospective China Kadoorie Biobank, 156 253 participants were genotyped for MTHFR and 12 240 developed a stroke during the 12-year follow-up. Logistic regression was used to estimate region-specific odds ratios (ORs) for total stroke and stroke types, IHD and other diseases comparing TT genotype for MTHFR C677T (two thymine alleles at position 677 of MTHFR C677T polymorphism) vs CC (two cytosine alleles) after adjustment for age and sex, and these were combined using inverse-variance weighting.

Results
Overall, 21% of participants had TT genotypes, but this varied from 5% to 41% across the 10 study regions. Individuals with TT genotypes had 13% (adjusted OR 1.13, 95% CI 1.09–1.17) higher risks of any stroke [with a 2-fold stronger association with intracerebral haemorrhage (1.24, 1.17–1.32) than for ischaemic stroke (1.11, 1.07–1.15)] than the reference CC genotype. In contrast, MTHFR C677T was unrelated to risk of IHD or any other non-vascular diseases, including cancer, diabetes and chronic obstructive lung disease.

Conclusions
In Chinese adults, the MTHFR C677T polymorphism was associated with higher risks of stroke. The findings warrant corroboration by further trials of folic acid and implementation of mandatory folic acid fortification programmes for stroke prevention in low-folate populations.