PMID- 34707639
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211030
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 12
DP  - 2021
TI  - Exome-Wide Association Study Identifies East Asian-Specific Missense Variant 
      MTHFR C136T Influencing Homocysteine Levels in Chinese Populations RH: ExWAS of 
      tHCY in a Chinese Population.
PG  - 717621
LID - 10.3389/fgene.2021.717621 [doi]
LID - 717621
AB  - Plasma total homocysteine (tHCY) is a known risk factor of a wide range of 
      complex diseases. No genome scans for tHCY have been conducted in East Asian 
      populations. Here, we conducted an exome-wide association study (ExWAS) for tHCY 
      in 5,175 individuals of Chinese Han origin, followed by a replication study in 
      668 Chinese individuals. The ExWAS identified two loci, 1p36.22 (lead 
      single-nucleotide polymorphism (SNP) rs1801133, MTHFR C677T) and 16q24.3 
      (rs1126464, DPEP1), showing exome-wide significant association with tHCY (p < 
      5E-7); and both loci have been previously associated with tHCY in non-East Asian 
      populations. Both SNPs were replicated in the replication study (p < 0.05). 
      Conditioning on the genotype of C677T and rs1126464, we identified a novel East 
      Asian-specific missense variant rs138189536 (C136T) of MTHFR (p = 6.53E-10), 
      which was also significant in the replication study (p = 9.8E-3). The C136T and 
      C677T variants affect tHCY in a compound heterozygote manner, where compound 
      heterozygote and homozygote genotype carriers had on average 43.4% increased tHCY 
      than had other genotypes. The frequency of the homozygote C677T genotype showed 
      an inverse-U-shaped geospatial pattern globally with a pronounced frequency in 
      northern China, which coincided with the high prevalence of hyperhomocysteinemia 
      (HHCY) in northern China. A logistic regression model of HHCY status considering 
      sex, age, and the genotypes of the three identified variants reached an area 
      under the receiver operating characteristic curve (AUC) value of 0.74 in an 
      independent validation cohort. These genetic observations provide new insights 
      into the presence of multiple causal mutations at the MTHFR locus, highlight the 
      role of genetics in HHCY epidemiology among different populations, and provide 
      candidate loci for future functional studies.
CI  - Copyright (c) 2021 Liu, Momin, Zhou, Zheng, Fan, Jia, Liu, Bao, Li, Huo, Liu, 
      Zhang, Mao, Han, Hu, Zeng, Liu and Zhang.
FAU - Liu, Tianzi
AU  - Liu T
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
FAU - Momin, Mohetaboer
AU  - Momin M
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Zhou, Huiyue
AU  - Zhou H
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
FAU - Zheng, Qiwen
AU  - Zheng Q
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
FAU - Fan, Fangfang
AU  - Fan F
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Jia, Jia
AU  - Jia J
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Liu, Mengyuan
AU  - Liu M
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Bao, Minghui
AU  - Bao M
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Li, Jianping
AU  - Li J
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Huo, Yong
AU  - Huo Y
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
FAU - Liu, Jialin
AU  - Liu J
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Zhang, Yaning
AU  - Zhang Y
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Mao, Xuemei
AU  - Mao X
AD  - Beijing P4 Healthcare Institute, Beijing, China.
FAU - Han, Xiao
AU  - Han X
AD  - Beijing P4 Healthcare Institute, Beijing, China.
FAU - Hu, Zhiyuan
AU  - Hu Z
AD  - Beijing P4 Healthcare Institute, Beijing, China.
AD  - CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key 
      Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for 
      Excellence in Nanoscience, National Center for Nanoscience and Technology of 
      China, Beijing, China.
AD  - School of Nanoscience and Technology, Sino-Danish College, University of Chinese 
      Academy of Sciences, Beijing, China.
FAU - Zeng, Changqing
AU  - Zeng C
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Liu, Fan
AU  - Liu F
AD  - CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of 
      Genomics, Chinese Academy of Sciences, Beijing, China.
AD  - China National Center for Bioinformation, Beijing, China.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Zhang, Yan
AU  - Zhang Y
AD  - Department of Cardiology, Peking University First Hospital, Beijing, China.
AD  - Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, 
      China.
LA  - eng
PT  - Journal Article
DEP - 20211011
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC8542906
OTO - NOTNLM
OT  - MTHFR C136T
OT  - MTHFR C677T
OT  - coding variants
OT  - homocysteine
OT  - hyperhomocysteinemia
OT  - population heterogeneity
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/10/29 06:00
MHDA- 2021/10/29 06:01
PMCR- 2021/10/11
CRDT- 2021/10/28 06:37
PHST- 2021/06/02 00:00 [received]
PHST- 2021/09/02 00:00 [accepted]
PHST- 2021/10/28 06:37 [entrez]
PHST- 2021/10/29 06:00 [pubmed]
PHST- 2021/10/29 06:01 [medline]
PHST- 2021/10/11 00:00 [pmc-release]
AID - 717621 [pii]
AID - 10.3389/fgene.2021.717621 [doi]
PST - epublish
SO  - Front Genet. 2021 Oct 11;12:717621. doi: 10.3389/fgene.2021.717621. eCollection 
      2021.