Table 3.

Risk or comorbidity associated with hyperuricemia and gout: Evaluated by recent mendelian randomization studies

Author/year/reference number	Dominant ancestry	Number of study participants	Exposure	Outcome	Conclusions
Hyperuricemia or gout as an outcome
Kobylecki et al., 2018 [64]	EA	106,147 from CGPS (24.099 with HUA)	Plasma Vitamin C	SUA	No causal relationships detected
Larsson and Carlström, 2018 [65]	EA	110,347 from GUGC	Coffee	SUA	OR=−0.15 mg/dl (95% CI−0.22-−0.09, P=7.9×10−6) for SUA, for 1 cup/day coffee consumption
Larsson and Carlström, 2018 [65]	EA	2115 gout and 110,347 controls, from GUGC	Coffee	Gout	OR=0.56 (95% CI 0.38-0.84; P=0.005) for gout, for 1 cup/day coffee consumption
Larsson et al., 2018 [66]	EA	110,347 from GUGC	Adiposity	SUA	OR=0.30 mg/dl (95% CI 0.25-0.35, P=1.6×10−36) for SUA, for each SD increase of BMI
Larsson et al., 2018 [66]	EA	2115 gout and 67,259 controls from GUGC	Adiposity	Gout	OR=2.24 (95% CI 1.70-2.95; P=8.4×10−9) for gout, for each SD increase of BMI
Lee, 2018 [67]	EA	Exposure dataset: 85,997 Outcome dataset: 2115 gout and 67,259 controls	Smoking	Gout	No causal relationships detected
Nicolopoulos et al., 2020 [68]	EA	333,214 from UKB	Coffee	MR-PheWAS for 1117 phecodes	Association with gout was due to pleiotropy. Causal association for increased odds of osteoarthrosis, other arthropathies, and overweight, and lower odds of postmenopausal bleeding
Yuan and Larsson, 2020 [69]	EA	140,000 (2115 gout) from GUGC	Iron status*	Gout, rheumatoid arthritis and inflammatory bowel disease	Genetically high iron status was positively associated with gout and inversely associated with rheumatoid arthritis
Topless et al., 2021 [70]	EA	419,060 (ARIC, FHS, CARDIA, CHS) and UKB	Diet	Hyperuricemia	Weak causal effect of four dietary habits, such as preferentially drinking skim milk, consuming tub margarine, preferentially drinking milk with a higher fat content and dried fruit, on SUA levels, which were mediated by BMI
Hyperuricemia or gout as an exposure
Li et al., 2018 [71]	EA	120,091 from UKB	SUA	MR-PheWAS for 568 phecodes	OR=4.58 (95% CI 2.72-7.72) for gout OR=1.15 (95% CI 1.01-1.31) for inflammatory polyarthropathies
Jordan et al., 2019 [72]	EA	110,347–335,212 (from GUGC, EMR-linked UKB, ARIC, FHS, CARDIA, CHS)	SUA	CKD, eGFR, Gout	OR=3.41-6.04 for gout, per 1 mg/dl increase in SUA, all P<0.001
Biradar et al., 2020 [15]	Taiwan	10,000 TWB participants	SUA	MetS components	SUA increment may augment the risk of MetS through increase blood pressure and triglyceride levels and decrease high-density lipoprotein cholesterol levels
Chiang et al., 2019 [16]	Taiwan	10,000 TWB participants	SUA	CVD	OR=1.62 (95% CI 1.17-2.23), P=0.003 for high versus. low SUA WGRS group
Li et al., 2019 [73]	EA	339,256 from UKB	SUA	MR-PheWAS for 1431 disease outcomes	Associations with circulatory and metabolic disorders were due to pleiotropy. For the association with inflammatory polyarthropathies, only gout had a significant association in PheWAS analysis
Lee and Song, 2019 [74]	EA	Exposure dataset: 28,141 Outcome dataset: 4807 gout, 332,352 controls	SUA, gout	Bone mineral density	No causal relationships detected
Hyperuricemia or gout as an exposure
Lee, 2019 [75]	EA	17,008 Alzheimer’s disease and 37,154 controls	Gout	Alzheimer’s disease	No causal relationships detected
Narang et al., 2021 [76]	EA	359,827 (6398 urolithiasis) from UKB	SUA	Urolithiasis	No causal relationships detected

*Including serum iron, ferritin, transferrin saturation, and transferrin levels. ARIC: Atherosclerosis risk in communities, CARDIA: Coronary artery risk development in young adults, CGPS: Copenhagen general population study, CHS: Cardiovascular health study, CI: Confidence interval, CKD: Chronic kidney disease, CVD: Cardiovascular disease, EA: European ancestry, eGFR: Estimated glomerular filtration rate, EMR: Electronic medical record, FHS: Framingham heart study, GUGC: Global urate genetics consortium, HUA: Hyperuricemia, MetS: Metabolic syndrome, OR: Odds ratio, PheWAS: Phenome-wide association study, SD: Standard deviation, SUA: Serum uric acid, TWB: Taiwan Biobank, UKB: UK Biobank, WGRS: Weighted genetic risk score, MR: Mendelian randomization, BMI: Body mass index