rs4410790

mixedMag 3.5

This is a intron variant variant in the AHR gene.

Key Literature Trait Associations

Coffee Consumption

rs4410790-C is one of the strongest common genetic determinants of daily coffee intake. A large-scale GWAS of coffee consumption (cups per day) in UK Biobank and other cohorts identified this variant at genome-wide significance (p=6e-70, beta~0.11 cups/day per C allele). The effect is driven by the AHR-CYP1A2 regulatory axis: higher CYP1A2 inducibility in C-allele carriers leads to faster caffeine metabolism and a compensatory increase in coffee consumption.

Cornelis MC et al. “Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.” Plos Genetics 7(4):e1002033 (2011)

Allele C

OR —

β -0.150

p 2.4e-19

N 47,341

Meta-analysisLarge 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 —

β 0.110

p 6.0e-70

Major Consortium StudyLarge GWAS

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 —

β -0.057

p 1.0e-150

N 448,204

Major Consortium StudyLarge GWAS

European

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 C

OR —

β -0.100 ±0.010

p 3.0e-17

N 91,462

Meta-analysisLarge GWAS

European

Caffeine Consumption

The C allele at rs4410790, located within an intron of the aryl hydrocarbon receptor gene (AHR), is robustly associated with higher habitual caffeine intake. AHR is a ligand-activated transcription factor that senses xenobiotics in roasted coffee and induces transcription of CYP1A1 and CYP1A2. Carriers of the C allele have enhanced AHR-driven CYP1A2 induction, accelerating caffeine clearance and reducing plasma caffeine levels, which in turn drives higher consumption to maintain preferred stimulant effects. The association was genome-wide significant (p=2.4e-19) in a meta-analysis of 47,341 individuals.

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 —

β -0.052

p 3.0e-104

N 407,072

Large GWAS

European

Cornelis MC et al. “Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.” Plos Genetics 7(4):e1002033 (2011)

Allele C

OR —

β 0.150

p 2.4e-19

Meta-analysis

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 C

OR 1.41

p —

N 168

Candidate gene study

Costa Rican

Bitter beverage consumption

The T allele of rs4410790 is paradoxically associated with higher total bitter beverage consumption (coffee + tea + alcohol combined) in a large GWAS of beverage preferences (Zhong et al. 2019, n~370,000 European-ancestry participants). This seemingly contradicts the coffee finding but reflects that T-allele carriers who drink less coffee may compensate with tea or other bitter beverages, or that the aggregated bitter-beverage phenotype captures different biology than coffee alone. The AHR locus (alongside ABCG2 and CYP1A1/2) was one of five genome-wide significant loci for total bitter beverage consumption, highlighting the pleiotropic influence of caffeine-metabolism genes on beverage choice broadly.

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 —

β 0.027

p 5.0e-58

N 370,000

Large GWAS

European

HDL cholesterol

The T allele of rs4410790 shows a modest positive association with HDL cholesterol levels (β≈+0.011 units, p=2×10⁻⁸) in large-scale metabolic GWAS. This association may reflect the lower caffeine intake of T-allele carriers, since caffeine acutely affects lipid metabolism, or it may represent an independent pleiotropic effect of AHR pathway activity on lipid homeostasis. The effect is small in absolute terms but consistently observed in biobank-scale analyses. Counterbalancing associations with triglyceride:HDL ratio and VLDL cholesterol have also been reported for the opposite (C) allele, suggesting complex lipid pleiotropy at this locus.

Zoodsma M et al. “A genetic map of human metabolism across the allele frequency spectrum.” Nature Genetics 57(10):2445-2455 (2025)

Allele T

OR —

β 0.011 ±0.002

p 2.0e-8

N 450,000

Large GWAS

multi-ancestry

Urinary albumin-creatinine ratio

The C allele at rs4410790 is associated with higher urinary albumin-creatinine ratio (ACR), a marker of early kidney injury, in a large GWAS of UK Biobank participants (Casanova et al. 2019, n=437,027 discovery). The effect size is modest (β=+0.024, p=2×10⁻³⁰) but well-powered and genome-wide significant. Taken together with the eGFR association, rs4410790 appears to have mild pleiotropic effects on renal filtration and tubular function, potentially mediated via AHR's role in renal xenobiotic detoxification pathways. Absolute clinical impact for individual carriers is minimal given the small effect size.

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 C

OR —

β 0.024

p 2.0e-30

N 437,027

Large GWAS

European

Estimated glomerular filtration rate

The C allele of rs4410790 shows a small but genome-wide significant association with reduced estimated glomerular filtration rate (eGFR) in the largest kidney function GWAS to date (Wuttke et al. 2019, n≈567,000 discovery, 216,000 replication). The effect size is very small (β≈−0.002 eGFR units), but the high statistical significance and replication in independent cohorts establish this as a true association. The underlying mechanism may involve AHR-mediated regulation of renal CYP enzymes or indirect effects of higher caffeine consumption on kidney perfusion. Clinical significance is low given the minimal effect size.

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 C

OR —

β -0.002

p 1.0e-13

N 567,460

Large GWAS

European

IgG levels

A small cross-sectional study in 168 Korean adults (Khil et al. 2023) found the TT genotype at rs4410790 was associated with significantly elevated serum IgG levels — a marker used as a proxy for chronic low-grade inflammation — compared to TC/CC genotypes. The effect was modified by alcohol consumption and BMI, being strongest in frequent drinkers and overweight individuals. Coffee consumption did not modify the genotype-IgG relationship. This finding requires replication in larger, independent cohorts before clinical conclusions can be drawn, and the sample size is far too small to establish reliable effect estimates.

Khil J et al. “AHR rs4410790 genotype and IgG levels: Effect modification by lifestyle factors.” Plos One (2023)

Allele T

OR —

p —

N 168

Candidate gene study

Korean

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GWAS Catalog Trait Associations (44)

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

rs4410790

Key Literature Trait Associations

Coffee Consumption

Caffeine Consumption

Bitter beverage consumption

HDL cholesterol

Urinary albumin-creatinine ratio

Estimated glomerular filtration rate

IgG levels

GWAS Catalog Trait Associations (44)

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