rs2472297

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This is a intergenic variant variant in the CYP1A1 gene.

Key Literature Trait Associations

Clozapine metabolism

rs2472297, located between CYP1A1 and CYP1A2, is the top genome-wide significant variant for clozapine concentration-to-dose (C/D) ratio, reflecting CYP1A2's central role in clozapine N-demethylation. In a GWAS of 2,989 clozapine-treated patients, the T (minor) allele was associated with a reduction in steady-state clozapine plasma levels roughly equivalent to a 50 mg/day dose decrease — a clinically meaningful effect. A subsequent three-cohort meta-analysis (n=3,643) confirmed rs2472297 as the lead variant for clozapine C/D ratio. Fast metabolizers carrying the T allele may require dose adjustments to achieve therapeutic plasma concentrations.

Pardiñas AF et al. “Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism.” The American Journal of Psychiatry 176(6):477-486 (2019)
Allele T
OR —
p —
N 2,989
Preliminary work
European
Rask SM et al. “Meta-analyses of clozapine, norclozapine levels and their ratio across three genome wide association studies.” Translational Psychiatry (2025)
Allele T
OR —
p —
N 3,643
Preliminary work
European

Caffeine Metabolism (Plasma Caffeine Level)

The 15q24 locus containing rs2472297 was one of two genome-wide significant loci identified for plasma caffeine levels and caffeine metabolite ratios. The T allele is associated with lower plasma caffeine and a higher paraxanthine-to-caffeine ratio, indicating faster CYP1A2-mediated 3-demethylation of caffeine to paraxanthine. Together with the AHR locus, these two loci explain ~1% of variance in coffee intake.

Cornelis MC et al. “Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.” Human Molecular Genetics 25(24):ddw334 (2016)
Allele T
OR —
p 5.2e-14
Large GWAS
Larsson SC et al. “Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study.” Bmj Medicine (2023)
Allele T
OR —
p —
Candidate gene study
European

Coffee Consumption

rs2472297 lies in the 23-kb intergenic region shared between the 5' ends of CYP1A1 and CYP1A2 on chromosome 15q24. The T allele is associated with increased coffee consumption (~0.2 cups/day per allele) in a meta-analysis of 10,661 coffee drinkers. This intergenic region contains regulatory elements for both CYP1A1 and CYP1A2; the T allele enhances CYP1A2 transcriptional inducibility, accelerating caffeine metabolism and driving higher consumption. The T allele shows striking population stratification: ~21% in Europeans but essentially absent in East Asians.

Cornelis MC et al. “Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.” Molecular Psychiatry 20(5):647-656 (2015)
Allele T
OR —
β 0.140 ±0.010
p 2.0e-24
N 91,462
Meta-analysisLarge GWAS
European
Sulem P et al. “Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption.” Human Molecular Genetics 20(10):2071-2077 (2011)
Allele T
OR —
β 0.200
p 5.4e-14
Large GWAS
Amin N et al. “Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.” Molecular Psychiatry 17(11):1116-29 (2012)
Allele T
OR —
β 0.310
p 2.7e-11
N 26,105
Large GWAS
European
Josse AR et al. “Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption.” The American Journal of Clinical Nutrition (2012)
Allele T
OR 1.55
p —
Candidate gene study
Costa Rican

Type 2 diabetes mellitus

Mendelian randomization studies using rs2472297 as a genetic instrument for plasma caffeine level have found that higher genetically predicted plasma caffeine is associated with lower type 2 diabetes risk (combined OR=0.81, 95% CI: 0.74–0.89), with approximately 43% of the effect mediated through BMI reduction. Because rs2472297's T allele lowers plasma caffeine, T-allele carriers carry slightly higher genetically predicted diabetes risk in this MR framework — the C allele (associated with higher plasma caffeine) is protective. The evidence is indirect (MR design) and effect sizes from MR studies may differ from direct genetic associations; no direct GWAS of T2D has identified rs2472297 at genome-wide significance.

Larsson SC et al. “Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study.” Bmj Medicine (2023)
Allele C
OR 0.81
p 1.0e-3
Candidate gene study
European

Inflammatory bowel disease

Mendelian randomization using rs2472297 and rs4410790 as instruments for plasma caffeine concentration found that higher genetically predicted plasma caffeine was associated with reduced overall IBD risk (OR=0.78, 95% CI: 0.66–0.91) as well as reduced risk of ulcerative colitis (OR=0.79) and Crohn's disease (OR=0.78) separately. As the C allele is associated with higher plasma caffeine levels, C-allele homozygotes have the most favorable predicted risk profile. This MR evidence supports a potential causal anti-inflammatory role of caffeine, though biological mechanisms remain to be fully elucidated.

Dong H et al. “Unraveling the link between plasma caffeine concentrations and inflammatory bowel disease risk through Mendelian randomization.” The American Journal of Clinical Nutrition (2024)
Allele C
OR 0.78
p 4.0e-3
Candidate gene study
European
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GWAS Catalog Trait Associations (41)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

coffee consumption measurement

Cole JB et al. “Comprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic associations.” Nature Communications 11(1):1467 (2020)
Allele C
OR 0.07
p 1.0e-182
N 448,204
Major Consortium StudyLarge GWAS
European
Said MA et al. “Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus.” Journal of the American Heart Association 9(24):e016808 (2020)
Allele C
OR 0.07
p 3.0e-140
N 373,522
Large GWAS
European
Zhong VW et al. “A genome-wide association study of bitter and sweet beverage consumption.” Human Molecular Genetics 28(14):2449-2457 (2019)
Allele C
OR 0.04
p 9.0e-157
N 335,909
Large GWAS
European

tea consumption measurement

Said MA et al. “Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus.” Journal of the American Heart Association 9(24):e016808 (2020)
Allele C
OR 0.05
p 3.0e-102
N 395,866
Large GWAS
European
Pirastu N et al. “Using genetic variation to disentangle the complex relationship between food intake and health outcomes.” Plos Genetics 18(6):e1010162 (2022)
Allele C
OR 0.02
p 2.0e-36
N 434,171
Large GWAS
European
Zhong VW et al. “A genome-wide association study of bitter and sweet beverage consumption.” Human Molecular Genetics 28(14):2449-2457 (2019)
Allele C
OR 0.02
p 1.0e-45
N 336,898
Large GWAS
European

bitter non-alcoholic beverage consumption measurement

Zhong VW et al. “A genome-wide association study of bitter and sweet beverage consumption.” Human Molecular Genetics 28(14):2449-2457 (2019)
Allele T
OR 0.04
p 1.0e-97
N 85,852
Large GWAS
European

cups of coffee per day measurement

Kennedy OJ et al. “Coffee Consumption and Kidney Function: A Mendelian Randomization Study.” American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation 75(5):753-761 (2020)
Allele T
OR 0.14
p 2.0e-95
N 227,666
Large GWAS
European

bitter beverage consumption measurement

Zhong VW et al. “A genome-wide association study of bitter and sweet beverage consumption.” Human Molecular Genetics 28(14):2449-2457 (2019)
Allele T
OR 0.03
p 4.0e-74
N 85,852
Large GWAS
European

glomerular filtration rate

Liu H et al. “Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease.” Nature Genetics 54(7):950-962 (2022)
Allele T
OR 14.75
p 3.0e-49
N 1,508,659
Large GWAS
multi-ancestry
Stanzick KJ et al. “Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.” Nature Communications 12(1):4350 (2021)
Allele T
OR 0.00
p 6.0e-24
N 1,004,040
Large GWAS
European
Wuttke M et al. “A catalog of genetic loci associated with kidney function from analyses of a million individuals.” Nature Genetics 51(6):957-972 (2019)
Allele T
OR 0.00
p 1.0e-34
N 765,348
Large GWAS
multi-ancestry
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele T
OR 0.03
p 8.0e-23
N 571,227
Major Consortium StudyLarge GWAS
multi-ancestry
Sinnott-Armstrong N et al. “Genetics of 35 blood and urine biomarkers in the UK Biobank.” Nature Genetics 53(2):185-194 (2021)
Allele T
OR 0.03
p 2.0e-32
N 355,731
Major Consortium StudyLarge GWAS
multi-ancestry
Hellwege JN et al. “Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.” Nature Communications 10(1):3842 (2019)
Allele T
OR 0.00
p 8.0e-20
N 280,722
Major Consortium StudyLarge GWAS
multi-ancestry

serum creatinine amount

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele T
OR 0.02
p 7.0e-37
N 394,642
Large GWAS
European
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele T
OR 0.03
p 6.0e-19
N 600,139
Major Consortium StudyLarge GWAS
multi-ancestry
Sinnott-Armstrong N et al. “Genetics of 35 blood and urine biomarkers in the UK Biobank.” Nature Genetics 53(2):185-194 (2021)
Allele T
OR 0.03
p 4.0e-26
N 345,913
Major Consortium StudyLarge GWAS
multi-ancestry

caffeine metabolite measurement

Yin X et al. “Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.” Nature Communications 13(1):1644 (2022)
Allele T
OR 0.25
p 1.0e-32
N 6,136
Large GWAS
European
Cornelis MC et al. “Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.” Human Molecular Genetics 25(24):ddw334 (2016)
Allele T
OR 9.58
p 9.0e-22
N 5,323
Large GWAS
European

urinary albumin to creatinine ratio

Casanova F et al. “A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.” Human Molecular Genetics 28(24):4197-4207 (2019)
Allele T
OR 0.03
p 2.0e-32
N 437,027
Large GWAS
European
Zanetti D et al. “Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion.” Kidney International 95(5):1197-1208 (2019)
Allele T
OR 0.03
p 3.0e-16
N 218,759
Large GWAS
European
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Research that mentions this SNP (1)

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Interaction between genetic variants ofDLGAP3andSLC1A1Affecting the Risk of Atypical Antipsychotics‐Induced Obsessive–Compulsive Symptoms
AssociationN=91Seunghyong Ryu et al.(2011)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

This proof-of-concept study examined polygenetic risk scores (PRS) in 91 clozapine-treated schizophrenia patients with obsessive-compulsive symptoms/disorder (OCS/OCD). OCS prevalence was 39.6% and OCD prevalence was 27.5%. A significant correlation was found between OCD occurrence and PRS for CLZ metabolism (p=0.010 at pd=0.001), though this did not survive multiple testing correction. OCS severity positively correlated with clozapine treatment duration and PANSS general psychopathology subscale scores, but no associations were found with PRS for OCD, schizophrenia, or cross-disorder phenotypes.

Traits studied:CLZ/NorCLZ ratioClozapine metabolismNorclozapine metabolismObsessive-compulsive disorderObsessive-compulsive symptomsSchizophrenia
PubMedDOIMetascience Observatory

Gene information from NCBI Gene. Variant classifications from ClinVar.

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