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Coffee and Caffeine Consumption and Risk of Kidney Stones: A Mendelian Randomization Study

  • Shuai Yuan
    Affiliations
    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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  • Susanna C. Larsson
    Correspondence
    Address for Correspondence: Susanna C. Larsson, PhD, Institute of Environmental Medicine, Karolinska Institutet, Nobelsväg 13, Stockholm, 17177, Sweden.
    Affiliations
    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Open AccessPublished:October 21, 2021DOI:https://doi.org/10.1053/j.ajkd.2021.04.018

      Rationale & Objective

      Coffee and caffeine consumption have been associated with a lower risk of kidney stones in observational studies. We conducted a Mendelian randomization study to assess the causal nature of these associations.

      Study Design

      Mendelian randomization analysis.

      Setting & Participants

      Independent genetic variants associated with coffee and caffeine consumption at the genome-wide significance level were selected from previously published meta-analyses as instrumental variables. Summary-level data for kidney stones were obtained from the UK Biobank study (6,536 cases and 388,508 noncases) and the FinnGen consortium (3,856 cases and 172,757 noncases).

      Exposure

      Genetically predicted coffee and caffeine consumption.

      Outcome

      Clinically diagnosed kidney stones.

      Analytical Approach

      Mendelian randomization methods were used to calculate causal estimates. Estimates from the 2 sources were combined using the fixed-effects meta-analysis methods.

      Results

      Genetically predicted coffee and caffeine consumption was associated with a lower risk of kidney stones in the UK Biobank study, and the associations were directionally similar in the FinnGen consortium. The combined odds ratio of kidney stones was 0.60 (95% CI, 0.46-0.79; P < 0.001) per a genetically predicted 50% increase in coffee consumption and 0.81 (95% CI, 0.69-0.94; P = 0.005) per a genetically predicted 80-mg increase in caffeine consumption.

      Limitations

      Genetic influence on kidney stone risk via pathways not involving coffee or caffeine.

      Conclusions

      Using genetic data, this study provides evidence that higher coffee and caffeine consumption may cause a reduction in kidney stones.

      Graphical abstract

      Index Words

      This Mendelian randomization study based on genetic data from 2 large studies found evidence to support causal associations between higher coffee and caffeine consumption and lower risk of kidney stones. Along with previous traditional epidemiological data, these findings suggest that coffee and caffeine consumption may prevent kidney stone disease.
      Editorial, p. 3
      Kidney stone disease is a common problem that afflicts up to around 15% of the population.
      • Romero V.
      • Akpinar H.
      • Assimos D.G.
      Kidney stones: a global picture of prevalence, incidence, and associated risk factors.
      Habitual coffee
      • Curhan G.C.
      • Willett W.C.
      • Rimm E.B.
      • Spiegelman D.
      • Stampfer M.J.
      Prospective study of beverage use and the risk of kidney stones.
      • Curhan G.C.
      • Willett W.C.
      • Speizer F.E.
      • Stampfer M.J.
      Beverage use and risk for kidney stones in women.
      • Goldfarb D.S.
      • Fischer M.E.
      • Keich Y.
      • Goldberg J.
      A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry.
      • Littlejohns T.J.
      • Neal N.L.
      • Bradbury K.E.
      • Heers H.
      • Allen N.E.
      • Turney B.W.
      Fluid intake and dietary factors and the risk of incident kidney stones in UK Biobank: a population-based prospective cohort study.
      • Barghouthy Y.
      • Corrales M.
      • Doizi S.
      • Somani B.K.
      • Traxer O.
      Tea and coffee consumption and pathophysiology related to kidney stone formation: a systematic review.
      • Barghouthy Y.
      • Corrales M.
      • Doizi S.
      • Somani B.K.
      • Traxer O.
      Tea and coffee consumption and the risk of urinary stones—a systematic review of the epidemiological data. World J Urol.
      • Ferraro P.M.
      • Taylor E.N.
      • Gambaro G.
      • Curhan G.C.
      Soda and other beverages and the risk of kidney stones.
      and caffeine
      • Ferraro P.M.
      • Taylor E.N.
      • Gambaro G.
      • Curhan G.C.
      Caffeine intake and the risk of kidney stones.
      consumption have been associated with a reduced risk of kidney stones in a large body of observational studies. Nevertheless, whether these associations are causal has not been established due to the possibility of confounding in observational studies and the lack of data from randomized controlled trials.
      Employing genetic variants as instrumental variables for an exposure (eg, coffee consumption), the Mendelian randomization design can strengthen the causal inference.
      • Burgess S.
      • Thompson S.G.
      Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation.
      The approach can minimize residual confounding because genetic variants are randomly allocated at conception and thus generally unrelated to confounders, such as environmental and self-adopted factors.
      • Burgess S.
      • Thompson S.G.
      Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation.
      The random allocation of effect allele in the Mendelian randomization design resembles the randomization process in randomized controlled trials. In addition, the method can diminish reverse causation because genetic variants used to proxy the effect of the exposure cannot be modified by the onset and progression of the outcome.
      • Burgess S.
      • Thompson S.G.
      Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation.
      Here, we conducted a Mendelian randomization (MR) study to determine the potential causal associations of coffee and caffeine consumption with risk of kidney stones.

      Methods

       Study Design

      MR analysis is an instrumental variable analysis with the use of genetic variants as instrumental variables.
      • Burgess S.
      • Small D.S.
      • Thompson S.G.
      A review of instrumental variable estimators for Mendelian randomization.
      There are 3 important assumptions of MR analysis (Fig 1). The first assumption is that the genetic variants proposed as instrumental variables should be robustly associated with the exposure; the second assumption indicates that the used genetic variants should not be associated with any confounders; and the third assumption is that the selected genetic variants should affect the risk of the outcome merely through the risk factor, not via alternative pathways.
      • Burgess S.
      • Thompson S.G.
      Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation.
      The present study was based on publicly available summary-level data from large genome-wide association studies and consortia.
      Figure thumbnail gr1
      Figure 1Study design overview. Abbreviation: SNP, single-nucleotide polymorphism.

       Genetic Instrument Selection

      Fifteen single-nucleotide polymorphisms (SNPs) associated with coffee consumption at the genome-wide significance level (P < 5 × 10−8) were obtained from a meta-analysis of 4 genome-wide association studies (GWAS) on coffee consumption with up to 375,833 individuals of European ancestry (~89% from the UK Biobank study).
      • Zhong V.W.
      • Kuang A.
      • Danning R.D.
      • et al.
      A genome-wide association study of bitter and sweet beverage consumption.
      Twelve independent SNPs (r2 < 0.01 and clump distance > 10,000 kb) were used as instrumental variables for coffee consumption. The effect sizes for the SNP-coffee associations were scaled to a 50% increase (eg, an increase from 1 cup to 1.5 cups). Two variants associated with caffeine consumption at P < 5 × 10−8 were used as instrumental variables for caffeine consumption from a meta-analysis of 6 GWAS including 9,876 individuals of European ancestry.
      • Cornelis M.C.
      • Kacprowski T.
      • Menni C.
      • et al.
      Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.
      Summarized statistics (ie, beta coefficients and standard errors) for SNPs associated with caffeine consumption were derived from a GWAS on 4,460 women
      • McMahon G.
      • Taylor A.E.
      • Davey Smith G.
      • Munafò M.R.
      Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.
      and scaled to an 80-mg increase (equivalent to the caffeine dose from 1 cup of coffee). Caffeine consumption was measured from coffee, tea, and cola consumption via a self-reported questionnaire.
      • McMahon G.
      • Taylor A.E.
      • Davey Smith G.
      • Munafò M.R.
      Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.
      Selected SNPs explained around 0.5% and up to 1.3% phenotypic variance on average for coffee and caffeine consumption, respectively.
      • Zhong V.W.
      • Kuang A.
      • Danning R.D.
      • et al.
      A genome-wide association study of bitter and sweet beverage consumption.
      ,
      • McMahon G.
      • Taylor A.E.
      • Davey Smith G.
      • Munafò M.R.
      Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.
      Detailed information on SNPs for coffee and caffeine consumption is shown in Table 1.
      Table 1Associations of Single-Nucleotide Polymorphisms With Coffee or Caffeine Consumption and Kidney Stones
      SNPNearby GeneEANEAEAFCoffee or Caffeine ConsumptionKidney Stones in UKBBKidney Stones in FinnGen
      BetaSEPBetaSEPBetaSEP
      Coffee consumption
      rs2472297CYP1A1/2TC0.274.5400.1705.19 × 10−155−0.0250.0190.2−0.0150.0280.6
      rs4410790AHRCT0.633.9400.1505.59 × 10−141−0.0320.0180.07−0.0490.0250.05
      rs1057868PORTC0.291.9700.1605.26 × 10−33−0.0250.0190.20.0140.0240.6
      rs73073176LOC101927630CT0.872.3100.2205.56 × 10−25−0.0650.0250.01−0.0050.0420.9
      rs1260326GCKRCT0.611.3600.1502.62 × 10−19−0.0690.017<0.001−0.0810.0250.001
      rs34060476MLXIPLGA0.131.8900.2205.06 × 10−18−0.0240.0250.30.0790.0350.02
      rs66723169MC4RAC0.231.4700.1809.88 × 10−17−0.0110.0200.60.0160.0310.6
      rs10865548TMEM18GA0.831.5400.1904.46 × 10−15−0.0210.0230.4−0.0800.0320.01
      rs2330783SPECC1L-ADORA2AGT0.994.5300.6301.57 × 10−12−0.1580.0730.03−0.2080.1420.1
      rs597045OR8U8AT0.691.0700.1606.62 × 10−110.0060.0190.7−0.0210.0270.4
      rs574367SEC16BTG0.211.0500.1808.06 × 10−090.0130.0210.6−0.0330.0310.3
      rs1956218AKAP6GA0.560.8200.1503.62 × 10−08−0.0090.0170.6−0.0220.0240.4
      Caffeine consumption
      rs4410790AHRCT0.620.1500.0172.36 × 10−19−0.0210.0180.2−0.0490.0250.05
      rs2470893CYP1A1TC0.310.1200.0165.15 × 10−14−0.0320.0180.07−0.0180.0270.5
      Abbreviations: EA, effect allele; EAF, effect allele frequency; NEA, noneffect allele; SE, standard error; SNP, single-nucleotide polymorphism.

       Data Source for Kidney and Ureteral Stones

      Summary-level data for the associations of coffee- and caffeine-associated SNPs with kidney stones were derived from the UK Biobank study
      • Sudlow C.
      • Gallacher J.
      • Allen N.
      • et al.
      UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.
      and the FinnGen consortium.
      The FinnGen consortium
      The R4 release of FinnGen study.
      In UK Biobank, cases with kidney stones were defined by the International Classification of Diseases, 10th Revision (ICD-10), Office of Population and Censuses Surveys, and self-reported operation codes. GWAS was performed on 6,536 cases and 388,508 controls of European ancestry with the adjustment for sex, age, and the genotyping platform.
      • Howles S.A.
      • Wiberg A.
      • Goldsworthy M.
      • et al.
      Genetic variants of calcium and vitamin D metabolism in kidney stone disease.
      In FinnGen, cases were defined by N20 in ICD-10 and 592 in ICD-8 and ICD-9. The fourth release of the FinnGen consortium data was used with 3,856 cases and 172,757 noncases after the removal of individuals with ambiguous gender, high genotype missingness (>5%), excess heterozygosity (±4 SD), and non-Finnish ancestry. Association tests had been adjusted for age, sex, genetic principal components, and genotyping batch. Individuals who had withdrawn consent were excluded in both data sources.

       Statistical Analysis

      The inverse-variance weighted (IVW) method was used as the main statistical model.
      • Burgess S.
      • Butterworth A.
      • Thompson S.G.
      Mendelian randomization analysis with multiple genetic variants using summarized data.
      We used the IVW with random effects method to estimate the associations for genetically predicted coffee consumption and the IVW fixed-effects method (for analysis with <3 SNPs) to estimate the associations for genetically predicted caffeine consumption. The causal estimates were calculated by meta-analyzing SNP-specific Wald ratio estimates (ie, the beta coefficient for the effect of the SNP on the outcome divided by the beta coefficient for the effect of the SNP on the exposure) using a random- or fixed-effects inverse variance method that weights each ratio by its standard error.
      • Burgess S.
      • Small D.S.
      • Thompson S.G.
      A review of instrumental variable estimators for Mendelian randomization.
      The standard error of the ratio estimate is estimated using the delta method.
      • Burgess S.
      • Butterworth A.
      • Thompson S.G.
      Mendelian randomization analysis with multiple genetic variants using summarized data.
      Estimates from the UK Biobank and FinnGen were combined using the fixed-effect meta-analysis method.
      Three sensitivity analyses, including the weighted median,
      • Bowden J.
      • Davey Smith G.
      • Haycock P.C.
      • Burgess S.
      Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator.
      MR-Egger
      • Bowden J.
      • Davey Smith G.
      • Burgess S.
      Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.
      and MR-PRESSO
      • Verbanck M.
      • Chen C.Y.
      • Neale B.
      • Do R.
      Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.
      approaches, were performed. Assuming that at least 50% of the SNPs are valid, the weighted median method can generate consistent causal estimates.
      • Bowden J.
      • Davey Smith G.
      • Haycock P.C.
      • Burgess S.
      Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator.
      The MR-Egger regression can detect and correct for possible pleiotropy, and the P value of the intercept > 0.05 indicates no horizontal pleiotropic effects.
      • Bowden J.
      • Davey Smith G.
      • Burgess S.
      Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.
      The MR-PRESSO method can detect outliers and provide a causal estimate after the removal of corresponding outliers.
      • Verbanck M.
      • Chen C.Y.
      • Neale B.
      • Do R.
      Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.
      The F statistic was calculated to measure the strength of instrument in the analyses in the UK Biobank study given a large sample overlap between the exposure and outcome data.
      • Burgess S.
      • Davies N.M.
      • Thompson S.G.
      Bias due to participant overlap in two-sample Mendelian randomization.
      Cochrane Q value was used to assess the heterogeneity among estimates of SNPs in each analysis. All analyses were 2-sided and performed using the TwoSampleMR
      • Hemani G.
      • Zheng J.
      • Elsworth B.
      • et al.
      The MR-Base platform supports systematic causal inference across the human phenome.
      and MR-PRESSO
      • Verbanck M.
      • Chen C.Y.
      • Neale B.
      • Do R.
      Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.
      packages in R software (version 4.0.2).

       Ethics Approval

      All studies included in the GWAS cited here were approved by a relevant review board. The present MR analyses were approved by the Swedish Ethical Review Authority (2019-02793).

      Results

      The F statistic was 159 for the association for coffee consumption in the UK Biobank. Genetically predicted coffee and caffeine consumption was inversely associated with a risk of kidney stones in the UK Biobank study, and the associations were directionally similar in the FinnGen consortium (Fig 2). After meta-analysis of the 2 data sources, the odds ratio of kidney stone disease was 0.57 (95% CI, 0.39-0.82; P = 0.003) per genetically predicted 50% greater coffee consumption and 0.86 (95% CI, 0.77-0.96; P = 0.008) per genetically predicted 80 mg greater caffeine consumption. The results for coffee consumption in relation to kidney stones remained consistent in sensitivity analyses (Table 2). We detected mild heterogeneity but no evidence of pleiotropy in the MR-Egger regression (P for the intercept > 0.2). MR-PRESSO analyses detected 2 outliers in the FinnGen consortium, respectively. The association remained after outlier removal (Table 2).
      Figure thumbnail gr2
      Figure 2Association of genetically predicted coffee and caffeine consumption with risk of kidney stones. Estimates were obtained from the inverse-variance weighted methods. ORs for kidney stone disease were scaled to genetically predicted 50% of increase in coffee consumption and 80-mg increase in caffeine consumption. Abbreviations: FinnGen, FinnGen Consortium; OR, odds ratio; UKBB, UK Biobank.
      Table 2Association of Genetically Predicted Coffee Consumption With Risk of Kidney Stones in Sensitivity Analyses
      MethodValueP
      Source: UKBB
       Weighted median methodOR, 0.68 (95% CI, 0.50-0.93)0.02
       MR-Egger regressionOR, 0.71 (95% CI, 0.38-1.34)0.3
       MR-PRESSO methodNANA
       Cochrane Q18
       Intercept in MR-Egger regression0.5
      Source: FinnGen
       Weighted median methodOR, 0.71 (95% CI, 0.44-1.15)0.2
       MR-Egger regressionOR, 0.96 (95% CI, 0.33-2.78)0.9
       MR-PRESSO methodOR, 0.65 (95% CI, 0.44-0.98)0.07
       Cochrane Q26
       Intercept in MR-Egger regression0.4
      Two outliers were detected in the MR-PRESSO analysis in FinnGen. No outlier was observed in the MR-PRESSO analysis in UKBB. Abbreviations: CI, confidence interval; FinnGen, FinnGen Consortium; OR, odds ratio; MR, Mendelian randomization; NA, not applicable; UKBB, UK Biobank.

      Discussion

      The present MR study revealed inverse associations of genetically predicted coffee and caffeine consumption with risk of kidney stones in a combined sample of 7,396 cases and 530,411 noncases, which supported findings from most but not all observational studies.
      • Curhan G.C.
      • Willett W.C.
      • Rimm E.B.
      • Spiegelman D.
      • Stampfer M.J.
      Prospective study of beverage use and the risk of kidney stones.
      • Curhan G.C.
      • Willett W.C.
      • Speizer F.E.
      • Stampfer M.J.
      Beverage use and risk for kidney stones in women.
      • Goldfarb D.S.
      • Fischer M.E.
      • Keich Y.
      • Goldberg J.
      A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry.
      • Littlejohns T.J.
      • Neal N.L.
      • Bradbury K.E.
      • Heers H.
      • Allen N.E.
      • Turney B.W.
      Fluid intake and dietary factors and the risk of incident kidney stones in UK Biobank: a population-based prospective cohort study.
      ,
      • Barghouthy Y.
      • Corrales M.
      • Doizi S.
      • Somani B.K.
      • Traxer O.
      Tea and coffee consumption and the risk of urinary stones—a systematic review of the epidemiological data. World J Urol.
      ,
      • Ferraro P.M.
      • Taylor E.N.
      • Gambaro G.
      • Curhan G.C.
      Caffeine intake and the risk of kidney stones.
      In a recent systematic review, large-scale, population-based studies found that coffee consumption was associated with a lower risk of urinary stones, with similar associations for caffeinated and decaffeinated coffee consumption.
      • Barghouthy Y.
      • Corrales M.
      • Doizi S.
      • Somani B.K.
      • Traxer O.
      Tea and coffee consumption and the risk of urinary stones—a systematic review of the epidemiological data. World J Urol.
      Caffeine intake showed an independent association with a lower risk of incident kidney stones in an analysis including 217,883 individuals from 3 studies.
      • Ferraro P.M.
      • Taylor E.N.
      • Gambaro G.
      • Curhan G.C.
      Caffeine intake and the risk of kidney stones.
      Furthermore, a cohort study including 194,095 participants reported an approximately 26% lower risk of developing kidney stones in individuals who consumed ≥1 serving per day of caffeinated coffee compared with those who consumed <1 serving per week.
      • Ferraro P.M.
      • Taylor E.N.
      • Gambaro G.
      • Curhan G.C.
      Soda and other beverages and the risk of kidney stones.
      However, in a case-control study including 39 patients with calcium stones, caffeine intake showed a positive association with calcium oxalate stone formation.
      • Massey L.K.
      • Sutton R.A.
      Acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers.
      A cross-sectional study in US adults also found caffeine intake mostly derived from coffee consumption was linearly associated with an increased risk of recurrent kidney stones.
      • Sun Y.
      • Wang D.
      • Zhou Q.
      Caffeine intake and the risk of recurrent kidney stones in adults, an analysis of 2007-2014 National Health and Nutrition Examination Surveys.
      The discrepancy across these studies might be caused by residual confounding, such as coffee-correlated traits and recall bias.
      There are several underlying mechanisms supporting inverse associations of coffee and caffeine consumption with kidney stones. Caffeine exerts diuretic properties by adenosine receptors in the kidney.
      • Rieg T.
      • Steigele H.
      • Schnermann J.
      • Richter K.
      • Osswald H.
      • Vallon V.
      Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine.
      Adequately compensated by water intake, the caffeine contained in coffee beverages results in an increase in urine flow, which represents an important protective factor against the development of kidney stones. Caffeine can also reduce calcium oxalate crystal adhesion on the apical surface of renal tubular epithelial cells.
      • Peerapen P.
      • Thongboonkerd V.
      Caffeine prevents kidney stone formation by translocation of apical surface annexin A1 crystal-binding protein into cytoplasm: in vitro evidence.
      In addition, coffee plants are rich in citric acid; urinary citrate is a known inhibitor of renal stone formation.
      • Phillips R.
      • Hanchanale V.S.
      • Myatt A.
      • Somani B.
      • Nabi G.
      • Biyani C.S.
      Citrate salts for preventing and treating calcium containing kidney stones in adults.
      Other bioactive compounds in decaffeinated coffee, such as trigonelline, may generate similar protective effects like caffeine.
      • Arai K.
      • Terashima H.
      • Aizawa S.
      • et al.
      Simultaneous determination of trigonelline, caffeine, chlorogenic acid and their related compounds in instant coffee samples by HPLC using an acidic mobile phase containing octanesulfonate.
      There are strengths and limitations in this study. The major merit is the MR design, which strengthened the causal inference in the associations of coffee and caffeine consumption with risk of kidney stones. Additionally, we examined these associations in 2 independent populations, and the consistent results guaranteed the robustness of findings. We confined the studied population to individuals of European ancestry, which limited the population bias, whereas this might on the other side limit the generalizability of our findings to other populations. There was a large overlap in sample between exposure and outcome data, which might make the model overfitting and the causal estimates toward observational associations.
      • Burgess S.
      • Davies N.M.
      • Thompson S.G.
      Bias due to participant overlap in two-sample Mendelian randomization.
      However, the F statistic > 10 indicated that the bias caused by sample overlap was likely to be minimal.
      The important limitation is possible horizontal pleiotropy, which means that genetic instruments influence risk of kidney stones not via coffee or caffeine consumption but via other pathways. However, traits that are genetically correlated with coffee consumption, such as obesity and smoking, appear to increase risk of kidney stone disease
      • Jones P.
      • Karim Sulaiman S.
      • Gamage K.N.
      • Tokas T.
      • Jamnadass E.
      • Somani B.K.
      Do lifestyle factors including smoking, alcohol, and exercise impact your risk of developing kidney stone disease? Outcomes of a systematic review.
      ,
      • Taylor E.N.
      • Stampfer M.J.
      • Curhan G.C.
      Obesity, weight gain, and the risk of kidney stones.
      and are therefore unlikely to bias inverse associations between coffee consumption and kidney stone formation. Another pleiotropic factor may be daily fluid intake, which is likely to be positively correlated with coffee and caffeine consumption and inversely associated with risk of kidney stone disease.
      • Littlejohns T.J.
      • Neal N.L.
      • Bradbury K.E.
      • Heers H.
      • Allen N.E.
      • Turney B.W.
      Fluid intake and dietary factors and the risk of incident kidney stones in UK Biobank: a population-based prospective cohort study.
      The genetic variants selected for caffeine consumption are involved in caffeine metabolism and have been shown to be associated with caffeine metabolites in previous studies.
      • Cornelis M.C.
      • Kacprowski T.
      • Menni C.
      • et al.
      Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.
      ,
      • Cornelis M.C.
      • Monda K.L.
      • Yu K.
      • et al.
      Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.
      In conclusion, this MR study provides genetic evidence in support of causal inverse associations of coffee and caffeine consumption with kidney stones. Increasing coffee and caffeine consumption may be a prevention strategy for kidney stones.

      Article Information

      Authors’ Full Names and Academic Degrees

      Shuai Yuan, BMed, MMedSc, and Susanna C. Larsson, PhD.

      Authors’ Contributions

      Study design: SCL; data analysis: SY. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

      Support

      This study is supported by the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018-00123) and the Swedish Research Council (Vetenskapsrådet; grant no. 2019-00977). The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Acknowledgements

      Genetic instruments for coffee consumption and caffeine were obtained from the cited meta-analyses of genome-wide association studies. Genetic association estimates for kidney stones were obtained from the UK Biobank study and the FinnGen consortium. The authors thank all investigators for sharing these data.

      Data Sharing

      All data analyzed in this study are listed in Table 1.

      Peer Review

      Received March 12, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form April 26, 2021.

      References

        • Romero V.
        • Akpinar H.
        • Assimos D.G.
        Kidney stones: a global picture of prevalence, incidence, and associated risk factors.
        Rev Urol. 2010; 12: e86-96
        • Curhan G.C.
        • Willett W.C.
        • Rimm E.B.
        • Spiegelman D.
        • Stampfer M.J.
        Prospective study of beverage use and the risk of kidney stones.
        Am J Epidemiol. 1996; 143: 240-247
        • Curhan G.C.
        • Willett W.C.
        • Speizer F.E.
        • Stampfer M.J.
        Beverage use and risk for kidney stones in women.
        Ann Intern Med. 1998; 128: 534-540
        • Goldfarb D.S.
        • Fischer M.E.
        • Keich Y.
        • Goldberg J.
        A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry.
        Kidney Int. 2005; 67: 1053-1061
        • Littlejohns T.J.
        • Neal N.L.
        • Bradbury K.E.
        • Heers H.
        • Allen N.E.
        • Turney B.W.
        Fluid intake and dietary factors and the risk of incident kidney stones in UK Biobank: a population-based prospective cohort study.
        Eur Urol Focus. 2020; 6: 752-761
        • Barghouthy Y.
        • Corrales M.
        • Doizi S.
        • Somani B.K.
        • Traxer O.
        Tea and coffee consumption and pathophysiology related to kidney stone formation: a systematic review.
        World J Urol. 2020; 39: 2417-2426
        • Barghouthy Y.
        • Corrales M.
        • Doizi S.
        • Somani B.K.
        • Traxer O.
        Tea and coffee consumption and the risk of urinary stones—a systematic review of the epidemiological data. World J Urol.
        (Published online January 17, 2021, doi:)
        • Ferraro P.M.
        • Taylor E.N.
        • Gambaro G.
        • Curhan G.C.
        Soda and other beverages and the risk of kidney stones.
        Clin J Am Soc Nephrol. 2013; 8: 1389-1395
        • Ferraro P.M.
        • Taylor E.N.
        • Gambaro G.
        • Curhan G.C.
        Caffeine intake and the risk of kidney stones.
        Am J Clin Nutr. 2014; 100: 1596-1603
        • Burgess S.
        • Thompson S.G.
        Mendelian Randomization: Methods for Using Genetic Variants in Causal Estimation.
        Chapman & Hall/CRC Press, 2015
        • Burgess S.
        • Small D.S.
        • Thompson S.G.
        A review of instrumental variable estimators for Mendelian randomization.
        Stat Methods Med Res. 2017; 26: 2333-2355
        • Zhong V.W.
        • Kuang A.
        • Danning R.D.
        • et al.
        A genome-wide association study of bitter and sweet beverage consumption.
        Hum Mol Genet. 2019; 28: 2449-2457
        • Cornelis M.C.
        • Kacprowski T.
        • Menni C.
        • et al.
        Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.
        Hum Mol Genet. 2016; 25: 5472-5482
        • McMahon G.
        • Taylor A.E.
        • Davey Smith G.
        • Munafò M.R.
        Phenotype refinement strengthens the association of AHR and CYP1A1 genotype with caffeine consumption.
        PLoS One. 2014; 9e103448
        • Sudlow C.
        • Gallacher J.
        • Allen N.
        • et al.
        UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.
        PLoS Med. 2015; 12e1001779
        • The FinnGen consortium
        The R4 release of FinnGen study.
        (Accessed January 15, 2021)
        • Howles S.A.
        • Wiberg A.
        • Goldsworthy M.
        • et al.
        Genetic variants of calcium and vitamin D metabolism in kidney stone disease.
        Nat Commun. 2019; 10: 5175
        • Burgess S.
        • Butterworth A.
        • Thompson S.G.
        Mendelian randomization analysis with multiple genetic variants using summarized data.
        Genet Epidemiol. 2013; 37: 658-665
        • Bowden J.
        • Davey Smith G.
        • Haycock P.C.
        • Burgess S.
        Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator.
        Genet Epidemiol. 2016; 40: 304-314
        • Bowden J.
        • Davey Smith G.
        • Burgess S.
        Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.
        Int J Epidemiol. 2015; 44: 512-525
        • Verbanck M.
        • Chen C.Y.
        • Neale B.
        • Do R.
        Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases.
        Nat Genet. 2018; 50: 693-698
        • Burgess S.
        • Davies N.M.
        • Thompson S.G.
        Bias due to participant overlap in two-sample Mendelian randomization.
        Genet Epidemiol. 2016; 40: 597-608
        • Hemani G.
        • Zheng J.
        • Elsworth B.
        • et al.
        The MR-Base platform supports systematic causal inference across the human phenome.
        Elife. 2018; 7e34408
        • Massey L.K.
        • Sutton R.A.
        Acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers.
        J Urol. 2004; 172: 555-558
        • Sun Y.
        • Wang D.
        • Zhou Q.
        Caffeine intake and the risk of recurrent kidney stones in adults, an analysis of 2007-2014 National Health and Nutrition Examination Surveys.
        Eur J Nutr. 2020; 59: 2683-2692
        • Rieg T.
        • Steigele H.
        • Schnermann J.
        • Richter K.
        • Osswald H.
        • Vallon V.
        Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine.
        J Pharmacol Exp Ther. 2005; 313: 403-409
        • Peerapen P.
        • Thongboonkerd V.
        Caffeine prevents kidney stone formation by translocation of apical surface annexin A1 crystal-binding protein into cytoplasm: in vitro evidence.
        Sci Rep. 2016; 6: 38536
        • Phillips R.
        • Hanchanale V.S.
        • Myatt A.
        • Somani B.
        • Nabi G.
        • Biyani C.S.
        Citrate salts for preventing and treating calcium containing kidney stones in adults.
        Cochrane Database Syst Rev. 2015; 10: CD010057
        • Arai K.
        • Terashima H.
        • Aizawa S.
        • et al.
        Simultaneous determination of trigonelline, caffeine, chlorogenic acid and their related compounds in instant coffee samples by HPLC using an acidic mobile phase containing octanesulfonate.
        Anal Sci. 2015; 31: 831-835
        • Jones P.
        • Karim Sulaiman S.
        • Gamage K.N.
        • Tokas T.
        • Jamnadass E.
        • Somani B.K.
        Do lifestyle factors including smoking, alcohol, and exercise impact your risk of developing kidney stone disease? Outcomes of a systematic review.
        J Endourol. 2021; 35: 1-7
        • Taylor E.N.
        • Stampfer M.J.
        • Curhan G.C.
        Obesity, weight gain, and the risk of kidney stones.
        JAMA. 2005; 293: 455-462
        • Cornelis M.C.
        • Monda K.L.
        • Yu K.
        • et al.
        Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.
        PLoS Genet. 2011; 7e1002033