rs1051730

smoking and drinking

minus

Geno	Mag	Summary
(C;C)	2	Smokes normal (lower) number of cigarettes if a smoker.
(C;T)	2	1.3x increased risk of lung cancer
(T;T)	2.5	1.8x increased risk of lung cancer; reduced response to alcohol, therefore possibly increased risk of alcohol abuse

Reference

GRCh38 38.1/142

Chromosome

15

Position

78601997

Gene

CHRNA3

is a	snp
is	mentioned by
dbSNP	rs1051730
dbSNP (classic)	rs1051730
ClinGen	rs1051730
ebi	rs1051730
HLI	rs1051730
Exac	rs1051730
Gnomad	rs1051730
Varsome	rs1051730
LitVar	rs1051730
Map	rs1051730
PheGenI	rs1051730
Biobank	rs1051730
1000 genomes	rs1051730
hgdp	rs1051730
ensembl	rs1051730
geneview	rs1051730
scholar	rs1051730
google	rs1051730
pharmgkb	rs1051730
gwascentral	rs1051730
openSNP	rs1051730
23andMe	rs1051730
SNPshot	rs1051730
SNPdbe	rs1051730
MSV3d	rs1051730
GWAS Ctlg	rs1051730

GMAF

0.1933

Max Magnitude

2.5

?

(C;C) (C;T) (T;T)

28

rs1051730, also known as D398N, is a SNP in the nicotinic acetylcholine receptor alpha 3 subunit CHRNA3 gene.

In two recent (2008) studies, together comprising over 6,000 lung cancer patients of European ancestry, the rs1051730(T) allele was very significantly associated with increased risk. Having one copy (i.e. being a rs1051730(C;T) genotype) increased risk for lung cancer about 1.3x, and having two copies (rs1051730(T;T) individuals) represented 1.8x increased risk. Up to 14% of lung cancer incidence may be attributable to this allele.[PMID 18385738, PMID 18385676]

An independent study published at the same time concluded that (T) allele carriers for SNP rs1051730 are not at higher risk of becoming smokers compared to (C) carriers. However, if they do smoke, (T) carriers are quite likely to smoke more cigarettes than (C) carriers, and as an apparent consequence, they are at higher risk for lung cancer as reported in this and other studies. This study therefore links rs1051730 directly to nicotine dependence, and indirectly to lung cancer. [PMID 18385739 ]

According to DeCODE, the CC genotype at rs1051730 is associated with 0.88x risk of peripheral arterial disease (PAD). [PMID 18385739 ]

Note: publications tend to refer to the risk allele as "A", however, the orientation reported for rs1051730 in dbSNP is for the opposite strand, so in keeping with reporting all SNPs in the orientation published in dbSNP, SNPedia refers to this same risk allele as the (T) allele.

23andMe blog (T;T) once more smoke per day.

[PMID 19064933 ] rs1051730 influences how much alcohol it takes to have you feel a buzz. More professorially: rs1051730 influences the level of response to alcohol intake, as measured by body sway after having a 10am "3 drink challenge". rs1051730(T;T) individuals respond slower to alcohol, which generally is considered to actually increase their long-term risk of alcohol abuse.

23andMe blog (T;T) makes it harder to quit smoking

GWAS
SNP	rs1051730
PubMedID	[PMID 18385739 ]
Condition	Nicotine dependence
Gene	CHRNA3,CHRNA5,CHRNB4
Risk Allele	T
pValue	6.00E-020
OR	0.1
95% CI	0.08-0.12) increase in cigarettes per da

[PMID 19247474 ] Genome-wide and candidate gene association study of cigarette smoking behaviors.

[PMID 19300482 ] A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci.

GWAS snp
PMID	[PMID 18978790 ]
Trait	Lung cancer
Title	Lung cancer susceptibility locus at 5p15.33
Risk Allele	A
P-val	1E-15
Odds Ratio	1.35 [1.25-1.45]

[PMID 19465454] The TERT-CLPTM1L lung cancer susceptibility variant associates with higher DNA adduct formation in the lung

OMIM	612052
Desc	LUNG CANCER SUSCEPTIBILITY 2; LNCR2
Variant
Related	also

OMIM	188890
Desc	TOBACCO ADDICTION, SUSCEPTIBILITY TO
Variant
Related	also

OMIM	118503
Desc	CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 3; CHRNA3
Variant
Related	also

[PMID 19641473 ] Racial Differences in the Association Between SNPs on 15q25.1, Smoking Behavior, and Risk of Non-small Cell Lung Cancer

[PMID 19733931] Blood-based CHRNA3 single nucleotide polymorphism and outcome in advanced non-small-cell lung cancer patients

GWAS snp
PMID	[PMID 19836008 ]
Trait	Lung adenocarcinoma
Title	A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma
Risk Allele	T
P-val	2E-51
Odds Ratio	1.31 [1.27-1.36]

[PMID 19132693 ] Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence

[PMID 20068085 ] Analysis of Genetic Variants in Never-Smokers with Lung Cancer Facilitated by an Internet-Based Blood Collection Protocol: A Preliminary Report

[PMID 20418890 ] Genome-wide meta-analyses identify multiple loci associated with smoking behavior

GWAS snp
PMID	[PMID 20418889 ]
Trait	Smoking behavior
Title	Meta-analysis and imputation refines the association of 15q25 with smoking quantity
Risk Allele	G
P-val	2E-66
Odds Ratio	0.08 [0.07-0.09] unit decrease

GWAS snp
PMID	[PMID 20418888 ]
Trait	Smoking behavior
Title	Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior
Risk Allele	A
P-val	2E-69
Odds Ratio	0.80 [0.70-0.90] CPD increase

[PMID 20554942 ] Nicotinic Acetylcholine Receptor Region on Chromosome 15q25 and Lung Cancer Risk Among African Americans: A Case-Control Study

[PMID 20564069 ] Mediating effects of smoking and chronic obstructive pulmonary disease on the relation between the CHRNA5-A3 genetic locus and lung cancer risk

[PMID 20393456 ] Sensorimotor gating is associated with CHRNA3 polymorphisms in schizophrenia and healthy volunteers

[PMID 21248747 ] Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population

OMIM	118503
Desc
Variant	0001
Related	also

[PMID 21511889] Variant Within the Promoter Region of the CHRNA3 Gene Associated With FTN Dependence Is Not Related to Self-reported Willingness to Quit Smoking

[PMID 21646606] Nicotinic Acetylcholine Receptor Polymorphism, Smoking Behavior, and Tobacco-Related Cancer and Lung and Cardiovascular Diseases: A Cohort Study

[PMID 21645942 ] Association of smoking with tumor size at diagnosis in non-small cell lung cancer

[PMID 21685187 ] Genome-wide association study of smoking behaviours in patients with COPD

[PMID 21858091 ] In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression

[PMID 22441734] CHRNA3 genotype, nicotine dependence, lung function and disease in the general population

[PMID 22687325] The causal role of smoking in anxiety and depression: a Mendelian randomization analysis of the HUNT study

[PMID 18385721] With a coarse-tooth comb

[PMID 22534784 ] Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure.

[PMID 17135278 ] Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

[PMID 18519524 ] Variants in nicotinic receptors and risk for nicotine dependence.

[PMID 18565990 ] Systematic biological prioritization after a genome-wide association study: an application to nicotine dependence.

[PMID 18571741 ] Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research.

[PMID 18759969 ] In search of causal variants: refining disease association signals using cross-population contrasts.

[PMID 18780872 ] Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer.

[PMID 18957677 ] The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.

[PMID 19005185] Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese.

[PMID 19010884 ] Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine.

[PMID 19029397 ] Nicotinic receptor gene variants influence susceptibility to heavy smoking.

[PMID 19259974 ] Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes.

[PMID 19300500 ] A genome-wide association study of pulmonary function measures in the Framingham Heart Study.

[PMID 19423719 ] Update in lung cancer 2008.

[PMID 19429911 ] A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy.

[PMID 19436041 ] Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes.

[PMID 19443489 ] Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5.

[PMID 19569043 ] Genome-wide association studies and the genetic dissection of complex traits.

[PMID 19628476 ] Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15.

[PMID 19639606 ] Correcting "winner's curse" in odds ratios from genomewide association findings for major complex human diseases.

[PMID 19706762 ] The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans.

[PMID 19750184 ] Genome-wide association studies for atherosclerotic vascular disease and its risk factors.

[PMID 19800047 ] Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene.

[PMID 20007924] The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema.

[PMID 20010834 ] Genome-wide association study identifies five loci associated with lung function.

[PMID 20010835 ] Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.

[PMID 20395203 ] A second genetic variant on chromosome 15q24-25.1 associates with lung cancer.

[PMID 20700436 ] Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

[PMID 20808433 ] Associations of variants in CHRNA5/A3/B4 gene cluster with smoking behaviors in a Korean population.

[PMID 20886544] Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance.

[PMID 21081471 ] Genetic variations on chromosomes 5p15 and 15q25 and bladder cancer risk: findings from the Los Angeles-Shanghai bladder case-control study.

[PMID 21168125 ] TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood.

[PMID 21232152 ] Epidemiology, radiology, and genetics of nicotine dependence in COPD.

[PMID 21268243] Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy.

[PMID 21320324 ] The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case-control study.

[PMID 21385908 ] Association of the nicotine metabolite ratio and CHRNA5/CHRNA3 polymorphisms with smoking rate among treatment-seeking smokers.

[PMID 21690317 ] CHRNA3 rs1051730 genotype and short-term smoking cessation.

[PMID 21697764 ] Susceptibility locus for lung cancer at 15q25.1 is not associated with risk of pancreatic cancer.

[PMID 21747048 ] Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk.

[PMID 22071378 ] Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis.

[PMID 22544838 ] From Men to Mice: CHRNA5/CHRNA3, Smoking Behavior and Disease.

[PMID 22701590 ] Strong association between two polymorphisms on 15q25.1 and lung cancer risk: a meta-analysis

Peripheral Artery Disease

[PMID 23196875 ] Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder

[PMID 23249876 ] Nicotinic acetylcholine receptor variation and response to smoking cessation therapies

[PMID 23056235 ] Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese

[PMID 24254305] Quantitative assessment of the influence of common variations (rs8034191 and rs1051730) at 15q25 and lung cancer risk

[PMID 22914670] Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population.

[PMID 22956269 ] Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.

[PMID 23299987 ] Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility.

[PMID 23604333] The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism.

[PMID 25051068 ] Four SNPs in the CHRNA3/5 Alpha-Neuronal Nicotinic Acetylcholine Receptor Subunit Locus Are Associated with COPD Risk Based on Meta-Analyses

[PMID 25073350] [Genetic aspects of occupational chronic obstructive lung disease under exposure to various risk factors]

[PMID 25293386 ] Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

ClinVar
Risk	Rs1051730(T;T)
Alt	Rs1051730(T;T)
Reference	Rs1051730(C;C)
Significance	Other
Disease	Lung cancer susceptibility 2 Smoking as a quantitative trait locus 3 nicotine response - Toxicity/ADR
Variation	info
Gene	CHRNA3
CLNDBN	Lung cancer susceptibility 2 Smoking as a quantitative trait locus 3 nicotine response - Toxicity/ADR
Reversed	1
HGVS	NC_000015.9:g.78894339G>A
CLNSRC	OMIM Allelic Variant PharmGKB Clinical Annotation
CLNACC	RCV000019055.2, RCV000033204.2, RCV000211282.1,

[PMID 25806352 ] CHRNA3 rs1051730 polymorphism and lung cancer susceptibility in Asian population: a meta-analysis

[PMID 25950378] Effect of the rs1051730-rs16969968 variant and smoking cessation treatment: a meta-analysis

[PMID 26054357] Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression

[PMID 25154699 ] Phenotypic and genetic heterogeneity among subjects with mild airflow obstruction in COPDGene

[PMID 26264275 ] Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium

[PMID 25632390 ] Association between genetic variants on chromosome 15q25 locus and several nicotine dependence traits in Polish population: a case-control study

[PMID 26508385 ] Analyzing large-scale samples confirms the association between the rs1051730 polymorphism and lung cancer susceptibility

[PMID 26538566 ] Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomisation Meta-Analysis in the CARTA Consortium

[PMID 26751916] CHRNA5/CHRNA3 Locus Associates with Increased Mortality among Smokers.

[PMID 28533558 ] Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.

[PMID 29052254] Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease.

[PMID 29747220] The causal role of smoking on the risk of headache. A Mendelian randomization analysis in the HUNT Study.

[PMID 30003442] Assessing the causal association between smoking behavior and risk of gout using a Mendelian randomization study.