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RESEARCH PAPER
Association of metabotropic glutamate receptor 7 gene with nicotine dependence in a Chinese Han population: A cross-sectional candidate-gene association study
1
Faculty of Open Education,
Yunnan Open University,
Kunming, China
2
Yunnan Academy of
Tobacco Science, Kunming,
China
Submission date: 2025-12-01
Final revision date: 2026-03-11
Acceptance date: 2026-03-19
Publication date: 2026-08-01
Corresponding author
Tob. Induc. Dis. 2026;24(August):137
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Despite a global decline in prevalence, cigarette smoking remains a significant public health issue. Tobacco addiction is principally caused by nicotine dependence (ND). This study aimed to investigate the relationship between the metabotropic glutamate receptor 7 (GRM7) gene and ND in Chinese adults.
Methods:
This two-stage, cross-sectional, candidate-gene association study first enrolled a discovery cohort of 1609 participants from Kunming, Yunnan, China (2017–2019), followed by a replication stage involving 1329 individuals from Jincheng and Taiyuan, Shanxi, China (2012–2013). Association analysis between the GRM7 gene and ND was performed at individual SNP, haplotype, and wholegene levels. Logistic and linear regression models were employed for single-SNP association analyses. Heaviness of smoking index (HSI) and Fagerström test for nicotine dependence (FTND) were used to assess ND.
Results:
Rs77452956, rs74791991, and rs2176404 were significantly associated with ND proxied by HSI, with p-values of <0.001, 0.001, and 0.002, respectively. In the replication analysis, rs74791991 and rs2176404 showed associations with ND (p=0.006 and 0.082, respectively), while rs77452956 was linked to smoking status (p=0.014). Haplotype-based association analysis revealed that two haplotypes, C-C-T and T-G-C, comprising rs74791991, rs111848366, and rs7633313, were associated significantly with HSI, with p<0.001 and p=0.003, respectively. Gene-based analysis also revealed a significant association between GRM7 and HSI (p=0.006). Functional assessment suggested that rs77452956 and rs74791991 have regulatory capacity. Furthermore, the derived C alleles of rs74791991, rs2176404, and rs77452956 showed accelerated evolution.
Conclusions:
We identified three SNPs, rs74791991, rs2176404, and rs77452956, associated with ND in Han Chinese individuals. Our findings suggest a potential role of GRM7 in susceptibility to smoking-related behaviors and warrant further investigation to determine its relevance in smoking cessation.
Despite a global decline in prevalence, cigarette smoking remains a significant public health issue. Tobacco addiction is principally caused by nicotine dependence (ND). This study aimed to investigate the relationship between the metabotropic glutamate receptor 7 (GRM7) gene and ND in Chinese adults.
Methods:
This two-stage, cross-sectional, candidate-gene association study first enrolled a discovery cohort of 1609 participants from Kunming, Yunnan, China (2017–2019), followed by a replication stage involving 1329 individuals from Jincheng and Taiyuan, Shanxi, China (2012–2013). Association analysis between the GRM7 gene and ND was performed at individual SNP, haplotype, and wholegene levels. Logistic and linear regression models were employed for single-SNP association analyses. Heaviness of smoking index (HSI) and Fagerström test for nicotine dependence (FTND) were used to assess ND.
Results:
Rs77452956, rs74791991, and rs2176404 were significantly associated with ND proxied by HSI, with p-values of <0.001, 0.001, and 0.002, respectively. In the replication analysis, rs74791991 and rs2176404 showed associations with ND (p=0.006 and 0.082, respectively), while rs77452956 was linked to smoking status (p=0.014). Haplotype-based association analysis revealed that two haplotypes, C-C-T and T-G-C, comprising rs74791991, rs111848366, and rs7633313, were associated significantly with HSI, with p<0.001 and p=0.003, respectively. Gene-based analysis also revealed a significant association between GRM7 and HSI (p=0.006). Functional assessment suggested that rs77452956 and rs74791991 have regulatory capacity. Furthermore, the derived C alleles of rs74791991, rs2176404, and rs77452956 showed accelerated evolution.
Conclusions:
We identified three SNPs, rs74791991, rs2176404, and rs77452956, associated with ND in Han Chinese individuals. Our findings suggest a potential role of GRM7 in susceptibility to smoking-related behaviors and warrant further investigation to determine its relevance in smoking cessation.
CONFLICTS OF INTEREST
The authors have each completed and submitted an ICMJE form for
disclosure of potential conflicts of interest. The authors declare that
they have no competing interests, financial or otherwise, related to
the current work. J. Zhao reports that since the initial planning of the
work, received support from the Yunnan Provincial Department of
Education (Grant number: 2025J0733; payments were made to Yunnan
Open University). M. Li reports that in the past 36 months, received
support from the Yunnan Provincial Department of Education (Grant
number: 2024J0752; payments were made to Yunnan Open University)
and from the Yunnan Fundamental Research Projects (Grant number:
202501AU070093; payments were made to Yunnan Open University).
R. Wang reports that in the past 36 months, received support from the
Yunnan Provincial Department of Education (Grant number: 2025J2029;
payments were made to Yunnan Open University) and from the Yunnan
Fundamental Research Projects (Grant number: 202501AT070282;
payments were made to Yunnan Open University.) M. Li reports that
since the initial planning of the work received support from the Yunnan
Fundamental Research Projects (Grant number: 202001AU070044;
payments were made to Yunnan Academy of Tobacco Science), and that
in the past 36 months, has the following patents planned, issued or
pending: ZL 2020 1 0596317.1, primer sets, applications, products, and
methods for detecting nicotine dependence-related SNP loci. (Issued),
(In Chinese), this patent involves the PTPRT gene and does not relate to
GRM7. CN 116376842 A, a neural stem cell line for visual indication of
NF-κB signaling, and construction methods and applications thereof.
(Pending), (In Chinese), this patent relates to an NF-κB reporter neural
stem cell line and is unrelated to the GRM7 gene investigated here.
FUNDING
This research was supported by grants to M. Li from the Yunnan
Fundamental Research Projects (202001AU070044) and to Jinjie Zhao
from the Yunnan Provincial Department of Education (2025J0733).
ETHICAL APPROVAL AND INFORMED CONSENT
Ethical approval was obtained from the Institutional Review Board
of the Biomedical Ethics Committee of the Joint Institute of Tobacco
and Health on human studies (Approval number: JITH201801; Date:
November 2018). Participants provided informed consent.
DATA AVAILABILITY
The original datasets presented in this article are not readily available
due to China’s restriction, ‘Regulations on the Management of Human
Genetic Resources (HGR Regulations)’. Requests to access the variants
data should be directed to the corresponding author.
PROVENANCE AND PEER REVIEW
Not commissioned; externally peer reviewed.
SUPPLEMENTARY FILE DISCLAIMER
The content has been provided by the author(s) and has not been reviewed, verified, or endorsed by European Publishing. It may not have undergone peer review. The views, opinions, and recommendations expressed are solely those of the author(s) and do not necessarily reflect the position of European Publishing. European Publishing accepts no responsibility or liability for any consequences arising from the use of, or reliance on, this content.
The content has been provided by the author(s) and has not been reviewed, verified, or endorsed by European Publishing. It may not have undergone peer review. The views, opinions, and recommendations expressed are solely those of the author(s) and do not necessarily reflect the position of European Publishing. European Publishing accepts no responsibility or liability for any consequences arising from the use of, or reliance on, this content.
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