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

Young Ho Lee; Gwan Gyu Song

doi:10.4078/jrd.2020.27.2.88

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

Original Article

J Rheum Dis 2020;27(2):88-95.

Published online: 31 October 2020

DOI: https://doi.org/10.4078/jrd.2020.27.2.88

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

Young Ho Lee, M.D., Ph.D., Gwan Gyu Song, M.D., Ph.D.

Department of Rheumatology, Korea University College of Medicine, Seoul, Korea

Corresponding to: Young Ho Lee http://orcid.org/0000-0003-4213-1909 Department of Rheumatology, Korea University Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. E-mail: lyhcgh@korea.ac.kr

Received 20 August 201924 October 2019 Accepted 15 November 2019

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

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

Methods

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.

Results

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).

Conclusion

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.

Keywords: Uric acid, Gout, Osteoarthritis, Mendelian randomization analysis

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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)
Instrumental SNP	Effect allele	Gene	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)
Instrumental SNP	Effect allele	Gene	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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