Background
Methods
Biochemical analyses
Study participants
Serum biomarker measurements
Statistical analyses
Mendelian randomization analysis
Selection of instrumental variable
Statistical analyses
Results
Biochemical observational association analysis
Association with serum urate concentration
Population |
n
a
| β (95% CI)b |
p
b
| β (95% CI)c |
p
c
|
---|---|---|---|---|---|
NZ European | 60 | 0.011 (− 0.006; 0.027) | 0.24 | 0.009 (− 0.009; 0.027) | 0.31 |
NZ Polynesian | 60 | 0.015 (0.007; 0.023) | 1.4E–04 | 0.014 (0.007; 0.022) | 2.5E–04 |
US | 60 | 0.048 (− 0.006; 0.102) | 0.079 | 0.041 (− 0.015; 0.097) | 0.15 |
JHS (males) | 567 | 0.008 (0.002; 0.014) | 9.6E–03 | 0.007 (0.002; 0.014) | 9.3E–03 |
JHS (females) | 693 | 0.023 (0.015; 0.032) | 1.6E–07 | 0.014 (0.005; 0.022) | 1.7E–03 |
JHS (combined) | 1260 | 0.027 (0.023; 0.033) | 1.8E–27 | 0.009 (0.005; 0.014) | 3.2E–05 |
NHANES III African American (males) | 1925 | 0.010 (0.007; 0.014) | 7.2E–09 | 0.006 (0.003; 0.009) | 5.1E–04 |
NHANES III African American (females) | 2430 | 0.028 (0.027; 0.032) | 1.3E–42 | 0.016 (0.012; 0.020) | 1.8E–15 |
NHANES III African American (combined) | 4355 | 0.029 (0.026; 0.031) | 2.0E–97 | 0.011 (0.008; 0.013) | 2.1E–16 |
NHANES III European (males) | 2460 | 0.006 (0.003; 0.009) | 1.0E–04 | 0.004 (0.001; 0.007) | 6.6E–03 |
NHANES III European (females) | 2652 | 0.019 (0.015; 0.023) | 1.3E–22 | 0.012 (0.008; 0.015) | 3.4E–10 |
NHANES III European (combined) | 5112 | 0.025 (0.023; 0.028) | 6.9E–84 | 0.007 (0.005; 0.009) | 5.1E–11 |
Meta-analyzed data | 10,907 | 0.025 (0.021; 0.028) | 9.3E–34 | 0.009 (0.007; 0.011) | 3.9E–32 |
Association with gout
Population | Comparison of average | Association analysis | ||||
---|---|---|---|---|---|---|
p
| (95% CI)for difference | OR (95% CI)a |
p
a
| OR (95% CI)b |
p
b
| |
NZ European | 0.21 | (−97.46; 22.02) | 1.01 (0.99; 1.03) | 0.22 | 1.00 (0.97; 1.02) | 0.84 |
NZ Polynesian | 2.3E–04 | (− 211.88; − 66.31) | 1.03 (1.01; 1.05) | 1.7E–03 | 1.03 (1.01; 1.06) | 1.8E–03 |
US | 6.6E–17 | (− 167.19; − 107.16) | 1.25 (1.07; 1.17) | 1.5E–06 | 1.11 (1.07; 1.17) | 7.4E–06 |
US no allopurinol | 6.6E–17 | (−167.19; − 107.16) | 1.11 (1.07; 1.16) | 4.5E–06 | 1.11 (1.06; 1.16) | 2.4E–05 |
Meta-analysisc | – | – | 1.04 (1.01; 1.08) | 0.02 | 1.04 (0.99; 1.09) | 0.09 |
Association of ferritin with flare frequency
Population | Ferritin (ng ml− 1) | C-reactive protein (mg dl− 1) | Serum urate (mg dl− 1) | |||||
---|---|---|---|---|---|---|---|---|
β (95% CI)a |
p
a
| β (95% CI)b |
p
b
| β (95% CI)a |
p
a
| β (95% CI)a |
p
a
| |
NZ European | 0.09 (0.003; 0.17) | 0.042 | 0.069 (− 0.01; 0.14) | 0.067 | 1.75 (− 3.85; 7.37) | 0.54 | − 0.61 (− 1.48; 0.25) | 0.16 |
NZ Polynesian | − 0.11 (− 0.24; 0.03) | 0.14 | −0.091 (− 0.22; 0.03) | 0.15 | −9.95 (− 23.75; 3.84) | 0.16 | −1.59 (− 3.88; 0.71) | 0.17 |
US | 0.02 (0.01; 0.04) | 0.002 | 0.018 (0.001; 0.04) | 0.043 | 0.10 (− 0.13; 0.35) | 0.38 | 0.13 (− 0.04; 0.30) | 0.13 |
Association of ferritin levels with allopurinol use
Population/marker | No allopurinol | Allopurinol |
p
| (95% CI)for difference |
---|---|---|---|---|
NZ European (n) | 23 | 66 | – | |
Serum iron (μmol L−1) | 100.44 | 98.65 | 0.77 | (− 10.661; 14.258) |
Serum ferritin (ng ml− 1) | 253.71 | 284.31 | 0.48 | (− 115.787; 54.597) |
NZ Polynesian (n) | 22 | 74 | ||
Serum iron (μmol L−1) | 91.21 | 85.08 | 0.26 | (− 4.592; 16.816) |
Serum ferritin (ng ml−1) | 373.81 | 494.32 | 0.005 | (− 204.466; − 36.548) |
US (n) | 155 | 34 | ||
Serum ferritin (ng ml− 1) | 158.57 | 248.21 | 0.02 | (− 164.816; 14.451) |
Analysis with log-transformed ferritin
Mendelian randomization analysis
Iron biomarkers as exposures for urate as outcome
MR analysis | Phenotype | Gene/locus | Genetic variant | estimate | SE | (95% CI) | p-causal |
Q–p
| MR Egger_HP | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Exposure | Outcome | intercept | p value | ||||||||
Wald ratio | Iron | Urate |
TF
|
rs1525892
| 0.127 | 0.076 | (− 0.02; 0.28) | 0.093 | – | – | – |
– | Iron | Urate |
HFE
|
rs1800562
| 0.107 | 0.032 | (0.04; 0.17) | 0.0008 | – | – | – |
– | Iron | Urate |
TMPRSS6
|
rs855791
| − 0.001 | 0.031 | (− 0.06; 0.06) | 0.99 | – | – | – |
IVW | Iron | Urate | – | All | 0.056 | 0.039 | (− 0.02; 0.13) | 0.15 | 0.179 | – | – |
MR Egger | Iron | Urate | – | All | 0.064 | 0.109 | (− 0.15; 0.28) | 0.61 | 0.011 | − 0.0016 | 0.95 |
Wald ratio | Log ferritin | Urate |
SLC40A1
|
rs12693541
| − 0.068 | 0.076 | (− 0.22; 0.08) | 0.37 | – | – | – |
– | Log ferritin | Urate |
HFE
|
rs1800562
| 0.190 | 0.057 | (0.08; 0.30) | 0.0002 | – | – | – |
– | Log ferritin | Urate |
TMPRSS6
|
rs2413450
| 0.011 | 0.106 | (− 0.20; 0.22) | 0.92 | – | – | – |
– | Log ferritin | Urate |
TEX14
|
rs411988
| − 0.048 | 0.123 | (− 0.29; 0.19) | 0.70 | – | – | – |
– | Log ferritin | Urate |
ABO
|
rs651007
| 0.320 | 0.140 | (0.05; 0.59) | 0.022 | – | – | – |
IVW | Log ferritin | Urate | – | All | 0.089 | 0.066 | (− 0.04; 0.22) | 0.18 | 0.063 | – | – |
MR Egger | Log ferritin | Urate | – | All | 0.160 | 0.134 | (− 0.10; 0.42) | 0.32 | 0.014 | − 0.0067 | 0.58 |
Phenotype | Instrumental variant excluded from IVW analysis | β estimate | (95% CI) | p-causal | |
---|---|---|---|---|---|
Exposure | Outcome | ||||
Iron | Urate |
TF rs1525892
| 0.050 | (− 0.06; 0.16) | 0.35 |
Iron | Urate |
HFE rs1800562
| 0.017 | (− 0.07; 0.10) | 0.70 |
Iron | Urate |
TMPRSS6 rs855791
| 0.110 | (0.05; 0.17) | 2.0E–04 |
Iron | Urate | All | 0.050 | (− 0.02; 0.13) | 0.15 |
Log ferritin | Urate |
SLC40A1 rs12693541
| 0.141 | (0.02; 0.27) | 0.027 |
Log ferritin | Urate |
HFE rs1800562
| 0.007 | (− 0.14; 0.15) | 0.93 |
Log ferritin | Urate |
TMPRSS6 rs2413450
| 0.101 | (− 0.05; 0.26) | 0.20 |
Log ferritin | Urate |
TEX14 rs411988
| 0.103 | (− 0.04; 0.25) | 0.17 |
Log ferritin | Urate |
ABO rs651007
| 0.070 | (− 0.06; 0.20) | 0.30 |
Log ferritin | Urate | All | 0.089 | (− 0.04; 0.22) | 0.18 |