Session Information
Session Type: Abstract Submissions (ACR)
Background: Gout is the most common inflammatory arthritis and is caused by hyperuricemia. The Global Urate Genetics Consortium (GUGC) has recently validated 28 SNP associations in serum urate. However, most corresponding data for the risk of gout have been based on suboptimal definitions (e.g., self-report, by the presence of hyperuricemia, or by anti-gout drug use) and prevalent cases (thus potentially selecting survivors given the risk of premature death associated with gout). To address these issues, we examined two large prospective cohorts and estimated the impact of the GUGC urate genetic loci on the risk of incident gout, which was ascertained by a widely-used standard definition.
Methods: The Health Professionals Follow-up Study (HPFS) and Nurses’ Health Study (NHS) have systematically collected a wide range of exposures and health outcome data, including incident cases of gout, regularly for several decades. We ascertained incident gout cases using the American College of Rheumatology survey criteria. Using GWAS data from the two cohorts (4223 men from the HPFS and 6850 women from the NHS), we calculated a weighted genetic risk score (GRS) based on GUGC urate loci (possible range 0 to 58). Cox proportional hazards models were used to examine the association of GRS as well as individual urate loci with the risk of incident gout in these cohorts separately and together.
Results: Over a total of 262,805 person years, we documented 1081 confirmed cases of incident gout (727 in the HPFS and 354 in the NHS). The GRS ranged from 12.2 to 44.5 among our study participants. Increasing GRS scores were associated with an increasing risk of incident gout in both cohorts (P for heterogeneity > 0.17), and the pooled relative risks (RRs) for incident gout according to increasing GRS categories were 0.34, 0.66, 1.00 (referent), 1.37, 2.01, and 3.48 (P for trend < 0.001) (Table 1). Our analyses for individual loci (Table 2) showed that SLC2A9, ABCG2, and GCKR were significantly associated with the risk of incident gout in each cohort as well as in the pooled cohort. TMEM171, SLC17A1, INHBC, VEGFA, and UBE2Q2 were modestly associated only in men (HPFS), and PRKAG2, B4GALT1, MAF, and HLF were modestly associated only in women (NHS). Heterogeneity between the sexes of these loci was significant for INHBC, PRKAG2, B4GALT1, and HLF.
Conclusion: These two large prospective cohort studies confirm that the urate GRS scores are strongly associated with the risk of incident cases of confirmed gout among men as well as among women. SLC2A9, ABCG2, and GCKR were most strongly associated with the risk of incident gout, and nine additional urate loci are more modestly associated with the risk as well.
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Table 1. Relative risks (RRs) of Incident Gout According to Genetic Risk Score |
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Genetic Risk Score |
<20.5 |
20.5 – <25.5 |
25.5 – <30.5 |
30.5 – <35.5 |
35.5 – <40.5 |
≥40.5 |
Ptrend |
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HPFS (Men) |
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No. of Cases/Person Years |
11/3025 |
83/14241 |
232/29717 |
316/26820 |
79/4866 |
6/208 |
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RR (95% CI) |
0.47 (0.25-0.85) |
0.75 (0.58-0.96) |
1.00 (referent) |
1.51 (1.27-1.78) |
2.08 (1.61-2.68) |
3.68 (1.64-8.28) |
<0.001 |
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NHS (Women) |
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2/6344 |
34/32605 |
133/70479 |
143/62986 |
40/11148 |
2/366 |
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RR (95% CI) |
0.17 (0.04-0.67) |
0.55 (0.38-0.80) |
1.00 (referent) |
1.20 (0.95-1.52) |
1.90 (1.33-2.70) |
2.93 (0.73-11.83) |
<0.001 |
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Pooled Cohort |
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RR (95% CI) |
0.34 (0.14-0.86) |
0.66 (0.50-0.89) |
1.00 (referent) |
1.37 (1.10-1.70) |
2.01 (1.64-2.48) |
3.48 (1.72-7.00) |
<0.001 |
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Pheterogeneity |
0.19 |
0.19 |
— |
0.13 |
0.68 |
0.78 |
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Table 2. RR of Incident Gout According to Individual Urate Loci (Limited to 12 Loci with Significance in at Least One or the Pooled Cohort) |
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SNP |
Gene |
Risk allele |
HPFS |
NHS |
Pooled |
Pheterogeneity |
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RR (95% CI) |
P |
RR (95% CI) |
P |
RR (95% CI) |
P |
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rs12498742 |
SLC2A9 |
A |
1.44 (1.26-1.64) |
<0.001 |
1.76 (1.43-2.17) |
<0.001 |
1.57 (1.29-1.90) |
<0.001 |
0.11 |
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rs2231142 |
ABCG2 |
T |
1.71 (1.49-1.96) |
<0.001 |
1.41 (1.15-1.74) |
0.001 |
1.58 (1.32-1.90) |
<0.001 |
0.14 |
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rs1260326 |
GCKR |
T |
1.17 (1.06-1.30) |
0.002 |
1.28 (1.10-1.48) |
0.001 |
1.21 (1.11-1.31) |
<0.001 |
0.35 |
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rs17632159 |
TMEM171 |
C |
0.89 (0.79-0.99) |
0.04 |
0.97 (0.82-1.14) |
0.692 |
0.91 (0.83-1.00) |
0.057 |
0.38 |
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rs1165151 |
SLC17A1 |
T |
0.86 (0.77-0.95) |
0.004 |
0.91 (0.79-1.06) |
0.216 |
0.88 (0.80-0.95) |
0.002 |
0.52 |
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rs729761 |
VEGFA |
T |
0.84 (0.75-0.95) |
0.005 |
1.00 (0.85-1.18) |
0.99 |
0.91 (0.77-1.07) |
0.27 |
0.10 |
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rs3741414 |
INHBC |
T |
0.84 (0.74-0.95) |
0.007 |
1.10 (0.93-1.31) |
0.25 |
0.96 (0.73-1.25) |
0.74 |
0.01 |
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rs1394125 |
UBE2Q2 |
A |
1.16 (1.05-1.29) |
0.006 |
1.07 (0.92-1.25) |
0.39 |
1.13 (1.04-1.24) |
0.006 |
0.38 |
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rs10480300 |
PRKAG2 |
T |
1.05 (0.94-1.17) |
0.42 |
0.83 (0.70-0.99) |
0.04 |
0.94 (0.75-1.18) |
0.60 |
0.03 |
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rs10813960 |
B4GALT1 |
T |
0.99 (0.88-1.11) |
0.84 |
0.73 (0.62-0.88) |
0.001 |
0.86 (0.64-1.15) |
0.31 |
0.01 |
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rs7188445 |
MAF |
A |
0.91 (0.82-1.02) |
0.12 |
0.84 (0.72-0.99) |
0.041 |
0.89 (0.81-0.98) |
0.015 |
0.43 |
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rs7224610 |
HLF |
A |
1.00 (0.90-1.11) |
0.97 |
0.79 (0.68-0.91) |
0.001 |
0.89 (0.71-1.13) |
0.348 |
0.01 |
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Disclosure:
H. K. Choi,
Takeda Pharmaceuticals International, Inc;,
5,
AstraZeneca,
5;
G. Curhan,
None;
Y. Bao,
None;
E. A. Stahl,
None;
P. Kraft,
None;
R. M. Plenge,
None;
Y. Zhang,
None;
T. R. Merriman,
None.
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