Journal List > J Rheum Dis > v.27(2) > 1144362

Lee and Song: The Uric Acid and Gout have No Direct Causality With Osteoarthritis: A Mendelian Randomization Study



To examine whether uric acid level or gout is causally associated with the risk of osteoarthritis.


We performed a two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW), MR-Egger regression, and weighted median methods. We used the publicly available summary statistics datasets of uric acid level or gout genomewide association studies (GWASs) as the exposure, and a GWAS in 3,498 patients with osteoarthritis in the arcOGEN study and 11,009 controls of European ancestry as the outcome.


Six single nucleotide polymorphisms (SNPs) from the GWAS data on uric acid level and 12 SNPs from the GWAS data on gout were selected as instrumental variables (IVs). The IVW analysis did not support a causal association between uric acid level or gout and risk of osteoarthritis (beta=–0.026, standard error [SE]=0.096, p=0.789; beta=–0.018, SE=0.025, p=0.482). MR-Egger regression revealed no causal association between uric acid level or gout and risk of osteoarthritis (beta=0.028, SE=0.142, p=0.852; beta=–0.056, SE=0.090, p=0.548). Similarly, no evidence of a casual association was provided by the weighted median approach (beta=0.004, SE=0.064, p=0.946; beta=–0.005, SE=0.025, p=0.843).


The results of MR analysis demonstrates that uric acid level and gout may be not causally associated with the increased risk of osteoarthritis. Considering MR study is not susceptible to bias from unmeasured confounders or reverse causation, the epidemiological evidence for an association between uric acid level or gout and a higher risk of osteoarthritis may be due to residual confounding or reverse causation rather than direct causality.


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Figure 1.
Forrest plot of the causal effects of uric acid level (A) or gout (B)-associated SNPs on osteoarthritis. SNP: single nucleotide polymorphism, MR: Mendelian randomization, IVW: inverse-variance weighted, Na: not available.
Figure 2.
Scatter plots of genetic associations of uric acid level (A) or gout (B) against the genetic associations of osteoarthritis. The slopes of each line represent the causal association for each method. Blue line represents the IVW estimate, green line represents the weighted median estimate, and dark blue line represents the MR-Egger estimate. IVW: inverse-variance weighted, SNP: single nucleotide polymorphism, MR: Mendelian randomization, Na: not available.
Figure 3.
Funnel plot to assess the heterogeneity of the causal effects of uric acid level (A) or gout (B)-associated SNPs on osteoarthritis. Blue line represents the IVW estimate, and dark blue line represents the MR-Egger estimate. SNP: single nucleotide polymorphism, IVW: inverse-variance weighted, MR: Mendelian randomization, SE: standard error, β: beta coefficient.
Table 1.
Instrumental SNPs from uric acid level (A) or gout (B) and osteoarthritis GWASs
A. Uric acid levels
Instrumental SNP Effect allele Gene Exposure (uric acid) Outcome (osteoarthritis)
Beta SE p-value Case (n) Control (n) Beta SE p-value
rs12356193 A SLC16A9 0.080 0.014 1.00×10−8 3,498 11,009 0.010 0.029 0.657
rs17300741 A SLC22A11 0.060 0.008 7.00×10−14 3,498 11,009 −0.020 0.022 0.259
rs2231142 T ABCG2 0.140 0.022 1.00×10−10 3,498 11,009 −0.094 0.034 0.006
rs734553 T SLC2A9 0.400 0.013 1.00×10−192 3,498 11,009 0.010 0.026 0.679
rs742132 A SCGN 0.050 0.009 9.00×10−9 3,498 11,009 0.030 0.021 0.169
rs780094 T GCKR 0.050 0.008 1.00×10−9 3,498 11,009 −0.030 0.020 0.190
B. Gout
Instrumental SNP Effect allele Gene Exposure (gout) Outcome (osteoarthritis)
Beta SE p-value Case (n) Control (n) Beta SE p-value
rs1014290 T SLC2A9 0.451 0.042 7.00×10−26 3,498 11,009 0.041 0.024 0.075
rs10791821 G MAP3K11 0.451 0.084 1.00×10−7 3,498 11,009 0.000 0.026 0.973
rs1165176 G SLC17A1 0.351 0.057 1.00×10−9 3,498 11,009 0.010 0.021 0.717
rs11733284 A NIPAL1 0.215 0.045 9.00×10−7 3,498 11,009 −0.041 0.024 0.099
rs11758351 G HIST1H2BF 0.336 0.058 2.00×10−8 3,498 11,009 0.049 0.031 0.088
rs1260326 T GCKR 0.307 0.043 2.00×10−12 3,498 11,009 −0.041 0.024 0.089
rs2231142 T ABCG2 0.513 0.075 3.00×10−12 3,498 11,009 −0.094 0.034 0.006
rs2728125 C ABCG2 0.713 0.046 7.00×10−54 3,498 11,009 −0.073 0.036 0.043
rs3114020 C ABCG2 0.637 0.051 9.00×10−35 3,498 11,009 −0.030 0.021 0.193
rs4073582 G CNIH-2 0.507 0.086 6.00×10−9 3,498 11,009 0.020 0.024 0.259
rs4766566 T CUX2 0.412 0.046 4.00×10−20 3,498 11,009 0.030 0.026 0.201
rs734553 T SLC2A9 0.329 0.065 2.00×10−7 3,498 11,009 0.010 0.026 0.652

SNP: single nucleotide polymorphism, GWAS: genomewide association study, Beta: beta coefficient, SE: standard error, SLC16A9: Solute Carrier Family 16 Member 9, SLC22A11: Solute Carrier Family 22 Member 11, ABCG2: ATP Binding Cassette Subfamily G Member 2 (Junior Blood Group), SLC2A9: Solute Carrier Family 2 Member 9, SCGN: Secretagogin, EF-Hand Calcium Binding Protein, GCKR: Glucokinase Regulator, MAP3K11: Mitogen-Activated Protein Kinase Kinase Kinase 11, SLC17A1: Solute Carrier Family 17 Member 1, NIPAL1: NIPA-Like Domain Containing 1, HIST1H2BF: Histone Cluster 1 H2B Family Member F, CNIH-2: Cornichon Family AMPA Receptor Auxiliary Protein 2, CUX2: Cut-Like Homeobox 2.

Table 2.
The MR estimates of the causal effect of uric acid level (A) and gout (B) on osteoarthritis risk, derived using different methods
A. Uric acid level
MR method Number of SNP Beta SE Association p-value Cochran Q statistic Heterogeneity p-value
Inverse variance weighted 6 −0.026 0.096 0.789 13.02 0.232
MR-Egger 6 0.028 0.142 0.852 12.09 0.166
Weighted median 6 0.004 0.064 0.946 na na
B. Gout
MR method Number of SNP Beta SE Association p-value Cochran Q statistic Heterogeneity p-value
Inverse variance weighted 12 −0.018 0.025 0.482 26.53 0.005
MR-Egger 12 −0.056 0.090 0.548 26.03 0.004
Weighted median 12 −0.005 0.025 0.834 na na

MR: Mendelian randomization, SNP: single nucleotide polymorphism, Beta: beta coefficient, SE: standard error, na: not available.

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