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. 2024 Oct 22;22:961. doi: 10.1186/s12967-024-05737-z

Table 1.

Genetic studies of caffeine intake and metabolism

No Study design No. of participants Gene/Nearest gene SNP-effect allele/non-effect allele Genetic ancestry Mechanism of gene Result References
1 Case-control 39,196 individual participants aged more than 40 years, as part of the Korean Genome and Epidemiology Study GCKR rs126036-C/T Korean Caffeine metabolism Individuals with the GCKR C allele were more likely to consume more coffee than those with the T allele, in line with other studies where C allele was associated with higher caffeine consumption Kim et al. [141]
2 GWAS 130,153 23andMe participants of European Ancestry CYP1A1/2 rs2472297-C/T European Caffeine metabolism The study found 7 GWAS-significant loci that had strong associations with coffee intake Thorpe et al. [42]
AHR, AGR3 rs4410790-C/T European Caffeine metabolism
ADORA2A, UPB1 rs199612805-D/I European Caffeine metabolism
STYXL1 rs28634426-G/T European Exact role unknown
MMS22L, POU3F2 rs34645063-D/I European Exact role unknown
PCMTD2 rs11474881-D/I European Exact role unknown
CTC-490E21.12 rs117824460-A/G European Exact role unknown
3 GWAS 2830 participants through 2 cohorts recruited through Coriell Personalized Medicine Collaborative and United States Air Force CYP1A1/2 rs2472297-A American Caffeine metabolism Rs2472297’s association with caffeine consumption was replicated in this study Kusic et al. [142]
4 GWAS 336,517 individuals from the UK Biobank study CYP1A1/2 rs2472297-T European Caffeine metabolism rs4410790, and rs2472297, were found in associations with both cereal and coffee intake. Additionally, rs4410790 (the C-allele) and rs2472297 (the T-allele) were also strongly associated with higher intake of tea Kang et al. [143]
rs4410790-C European Caffeine metabolism
5 GWAS 370,193 individuals from the UK Biobank study 2p23.3 GCKR rs1260326-C/T European Caffeine reward All SNPs were associated with habitual coffee intake in both men (P < 0.002) and women (P < 0.0006). Similar patterns were observed for regular, instant, ground/filtered and decaffeinated coffee as well as tea Cornelis et al. [38]
4q22.1 ABCG2 rs1481012-A/G European Caffeine metabolism
7p21.1 AHR rs6968554-G/A European Caffeine metabolism
7q11.23 POR rs17685-A/G European Caffeine metabolism
15q24.1 CYP1A1-CYP1A2

rs2472297-T/C

rs762551-A

 European Caffeine metabolism
22q11.23 SPECC1L-ADORA2A rs2330783-G/T European Caffeine metabolism
22q11.23 ADORA2A rs5751876-T/C European Caffeine metabolism
7q11.23 MLXIPL rs7800944-C/T European Caffeine reward
6 GWAS 7868 Korean Individuals HECTD4 rs2074356 Korean Exact role unknown The significant SNPs discovered to be related to habitual coffee consumption in the Korean population in this GWAS were all introns. The strongest significant variant found in this study was rs2074356 Jin et al. [53]
ACAD10 rs11066015 Korean Exact role unknown
MYL2 rs12229654 Korean Exact role unknown
CUX2 rs12229654 Korean Caffeine metabolism
CUX2 rs12229654 Korean Caffeine metabolism
7 GWAS 165,084 Japanese individuals CYP1A2, CSK rs58806801-G/A Japanese Caffeine metabolism These loci were found to be associated with coffee consumption. Other loci nominally associated with caffeine consumption include ABCG2, MIR2113, MLXIPL, POR, APOE5 Matoba et al. [71]
ADORA2A-AS1 rs5760444-T/C Japanese Caffeine metabolism
AGR3-AHR rs4410790-T/C Japanese Caffeine metabolism
ABCG2 rs75544042-A/G Japanese Caffeine metabolism
POR rs3815455-C/T Japanese Caffeine metabolism
MCL1, ENSA rs6681426-G/A Japanese Exact role unknown
GCKR rs1260326-T/C Japanese Caffeine reward
ALDH2 rs671-G/A Japanese Exact role unknown
MLXIPL rs13234378-A/T Japanese Caffeine reward
APOE5 rs662799-G/A Japanese Exact role unknown
MIR2113 rs12189679-G/A Japanese Exact role unknown
8 GWAS 6264 individuals for GWAS discovery and 5975 for replication analysis 7p21 AHR rs10252701-A/C Japanese Caffeine metabolism 2 loci (7p21 and 12q24) were associated with habitual coffee consumption and achieved genome-wide significance (P < 5 × 10 −8) Jia et al. [55]
12q24 (ALDH2 and CUX) rs7910528-A/C Japanese Caffeine metabolism
9 GWAS 337 542 individuals from the UK Biobank Study 15q24.1 CYP1A1/2 rs2472297-T/C European Caffeine metabolism In this study, 5 loci that were associated with plasma caffeine metabolites in previous literature were replicated (CYP1A1/2, GCKR, ABCG2, AHR, POR). Other novel loci, SEC16B, TMEM18, OR8U8, AKAP6, MC4R, SPECC1L-ADORA2A were found to be associated with caffeine consumption Zhong et al. [47]
2p23.3 GCKR rs1260326-C/T European Caffeine reward
7p21.1 AHR rs117692895-C/G European Caffeine metabolism
rs4410790-C/T European
rs4719497-T/C European
4q22.1 ABCG2 rs1481012-A/G European Caffeine metabolism
7q11.23 POR rs1057868-T/C European Caffeine metabolism

22q11.23

SPECC1L-ADORA2A

 rs2330783-G/T European Caffeine metabolism
1q25.2 SEC16B rs574367-T/G European Exact role unknown
2p25.3 TMEM18 rs10866548-G/A European Exact role unknown
11q12.1 OR8U8 rs597045-A/T European Exact role unknown
14q12 AKAP6 rs1956218-G/A European Exact role unknown
18q21.32 MC4R rs66723169-A/C European Exact role unknown
10 GWAS Japanese population of 11,261 participants as part of the Japan Multi-Institutional Collaborative cohort ALDH2

rs4646776-C/G

rs671-A/G

 Japanese Exact role unknown 24 SNPS on the 12q24 locus were found to have genome-wide significance with habitual caffeine consumption. The lead variant for the 12q24.12-13 locus, rs2074356-A, had the strongest significance and its effect size was estimated at 0.20 Senda et al. [54]
ACAD10

rs60125993-C/CT

rs11066008-G/A

rs11066015-A/G

 Japanese Exact role unknown
BRAP

rs11065992-C/T

rs3782886-C/T

rs11066001-C/T

 Japanese Exact role unknown
NAA25

rs11066132-T/C

rs116873087-C/G

rs11066150-A/G

rs147992802-T/C

 Japanese Exact role unknown
TRAFD1 rs12231737-T/C Japanese Exact role unknown
MYL2-CUX2 (intergenic)

Rs12227162-T/C

rs149607519-G/C

rs148177611-T/TAGAA

 Japanese Exact role unknown
CUX2 (intron) rs3809297-T/G Japanese Caffeine metabolism
OAS2-DTX1 (intergenic) rs139144808-TA/T Japanese Exact role unknown
MAPKAPK5 rs78069066-A/G Japanese Exact role unknown
HECTD4

rs2074356-A

Rs144504271-A/G

rs77768175-G/A

rs11066280-A/T

 Japanese Exact role unknown
HECTD4-RPL6 (intergenic) rs11537471-G/A Japanese Exact role unknown
11 Meta-Analysis 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts CYP1A1/2 rs2472297-T/C European Caffeine metabolism CYP1A1/2, AHR showed the expected patterns with the T alleles for both genes being associated with higher habitual coffee consumption Zhou et al. [144]
AHR rs6968865-T European
12 GWAS 9876 individuals of European ancestry from 6 population-based studies 7p21 AHR

rs4410790-C/T

rs6968554-G/A

rs10275488-C/T

rs2892838-A/C

rs11400459-A/AT

rs10683220 –G/GTTAACA

 European Caffeine metabolism AHR and CYP1A2 variants were associated with higher plasma caffeine, slow caffeine metabolism and low caffeine consumption. CYP2A6 variants was associated with lower caffeine consumption Cornelis et al. [30]
15q24 CYP1A2

rs12909047-A/G

rs35107470-G/A

rs62005807-C/G

rs2470893-T/C

rs2472297-T/C

 European Caffeine metabolism
19q13.2 CYP2A6

rs66500423-T/C

rs4803373-C/G

rs78011401-C/T

rs11668399-C/G

rs56113850-T/C

rs56267346-G/A

rs28399442-A/C

rs67210567-T/G

rs7260629-T/G

rs5828081-A/AT

rs200292835-TTTTG/T

rs28602288-C/T

rs79600176-C/T

rs184589612-C/T

rs72480748-G/A

rs10425738-G/A

rs56881024-T/A

 European Caffeine metabolism
6p23 CD83 rs62391270-C/T European Exact role unknown
13 Meta analysis 7 studies (N = 6778) included subjects of Caucasian ethnicity and 3 studies (N = 1750) included subjects of Asian ethnicity CYP1A2 rs762551-A Association was significant in Caucasian subjects but not Asian subjects Caffeine metabolism CYP1A2 rs762551 AA genotype may lead to higher coffee intake, especially in males, younger age groups, and individuals of Caucasian ethnicity Denden et al. [145]
14 GWAS 2938 Italian individuals PDSS2

rs2216084-T/C

rs6942255-A/G

rs7745311-C/T

rs7754744-G/A

rs9386630-G/T

 Italian Caffeine metabolism Conditional knockout of PDSS2 in the liver has been shown to increase the expression of the genes of the caffeine metabolism pathway. It was thus hypothesized that higher PDSS2 expression would inhibit the expression of the genes in the caffeine metabolism pathway thus inhibiting caffeine degradation Pirastu et al. [52]
15 Genome-wide (GW) meta-analysis 30 062 and 7964 coffee consumers of European and African American ancestry respectively CYP1A1/2

rs2472297-T/C

rs2470893-T/C

 European Caffeine metabolism Eight loci met GW significance with per-allele effect sizes of 0.03–0.14 cups per day. 4 genes, ABCG2, AHR, POR and CYP1A2, are involved in pharmacokinetics and 2 genes are involved in pharmacodynamics (BDNF and SLC6A4) of caffeine. GCKR and MLXIPL genes are related to metabolic traits but lack roles in coffee consumption Cornelis et al. [1]
AHR

rs4410790-C/T

rs6968554-G/A

 European Caffeine metabolism
POR rs17685-A/G European Caffeine metabolism
ABCG2 rs1481012-A/G European Caffeine metabolism
BDNF rs6265-C/T European Caffeine reward
SLC6A4, EFCAB5 rs9902453-G/A European Caffeine reward
GCKR rs1260326-C/T European Caffeine reward
MLXIPL rs7800944-C/T European Caffeine reward
16 GWAS 10,015 Individuals from the Avon Longitudinal Study of Parents and Children 15q24 CYP1A1/2 rs2472297 European Caffeine metabolism Both genotypes were individually associated with total caffeine consumption, and with coffee and tea consumption McMahon et al. [43]
7p21 AHR rs6968865 European Caffeine metabolism
17 Cross sectional 4066 individuals from different parts of Europe and Central Asia TAS2R43

rs71443637-T (H212R)

rs35720106 (synonymous variant)

rs68157013-C (W35S)

 Europeans and Central Asians Caffeine reward rs71443637 -T and rs68157013-C, both wild type alleles, were found to be associated with higher caffeine liking Pirastu et al. [78]
18 Cross sectional 158 women and 59 men (n = 217) between the ages of 24 and 47 years of Caucasian and African descent living in North America ANKK1 Taq1 (rs1800497) 80% Caucasian, 15% African Caffeine reward A multilocus genetic profile score reflecting the additive effects of alleles known to confer relatively increased dopamine signaling in the ventral striatum was related to more frequent engagement in addictive behaviours, including caffeine Davis et al. [61]
DRD2

rs12364283

rs6277 (C957T)

rs1799732 (141C Ins/Del)

 80% Caucasian, 15% African Caffeine reward
DAT1 NA 80% Caucasian, 15% African Caffeine reward
COMT Rs4680 (Val158Met) 80% Caucasian, 15% African Caffeine reward
19 GWAS  > 18 000 individuals of Northern European ancestry CYP1A1/2

rs2470893

rs2472296

 Caucasian Caffeine metabolism Genome-wide significant association was observed for two SNPs in the 15q24 region, rs2470893 and rs2472297, which were also in strong linkage disequilibrium. They have a commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. Significant evidence of association was also detected at rs382140 near NRCAM-a gene implicated in vulnerability to addiction Amin et al. [33]
NRCAM rs382140 Caucasian Addiction
NA rs6495122 Caucasian Independent Hit
20 Case-control Hispanic Americans living in the Central Valley of Costa Rica CYP1A1/1A2 rs2472297 (n = 2570) Costa Rican Caffeine metabolism Subjects who drank more caffeine were more likely to be carriers of the T, C, or T allele for rs6968865, rs4410790, and rs2472297, respectively Josse et al. [40]
AHR

rs6968865

rs4410790

 Costa Rican Caffeine metabolism
21 Cohort 6288 participants from the Rotterdam Study (RS), a cohort study of inhabitants of Ommoord, Rotterdam, Netherlands with age more than 55 years old CYP1A1/2

rs2472297-A

rs2470893-A

 Dutch Caffeine metabolism rs2472297G > A, the female sex, and non-smoking habits were significantly inversely related to coffee intake Rodenburg et al. [39]
22 Genome-wide association study (GWAS) 47,341 individuals of European descent CYP1A1/2 (15q24) rs2470893-T/C European Caffeine metabolism 2 Loci received genome-wide significance: 7p21 near AHR and 15q24, between CYP1A1 and CYP1A2. CYP1A2 metabolizes caffeine and AHR regulates CYP1A2 Cornelis et al. [41]
AHR (7p21) rs4410790-C/T European Caffeine metabolism
23 Meta analysis of 4 genome wide association studies 5110 individuals from Iceland, 2791 individuals from the Netherlands, 1620 Danish women, 771 individuals from the Sorbs Slavonic populate in Germany, 369 individuals from the USA CYP1A1/2 rs2472297-T European Caffeine metabolism Two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21. An effect of ∼0.2 cups a day per allele was observed for both SNPs Sulem et al. [36]
AHR rs6968865-T European Caffeine metabolism
24 Randomized, double-blind, parallel groups design 379 predominantly white Europeans ADORA2A

rs5751876-T

rs3761422-T

 European Caffeine metabolism In the participants who habitually consumed at least moderate amounts of caffeine, caffeine intake from coffee was higher in the TT genotype group compared with the combined CC and CT group. Results were similar for rs3761422, including higher habitual coffee consumption in the TT genotype group Rogers et al. [46]
25 Cross-sectional study 2873 Hispanic Americans living in Costa Rica ADORA2A rs5751876 Costa Rican Caffeine metabolism Persons with the ADORA2A TT genotype were significantly more likely to consume less caffeine (ie. < 100 mg/day) than were carriers of the C allele Cornelis et al. [48]