Background/Purpose:

Uric acid (UA) has been associated with blood pressure (BP) and hypertension. During the final stage of purine metabolism, xanthine oxidoreductase (XOR) breaks down hypoxanthine to xanthine, and xanthine to UA, while reactive oxygen species (ROS) are formed. These ROS inactivate the vasodilator nitric oxide. We hypothesize that variants in the XOR gene, responsible for the production of UA, are associated with elevated BP and hypertension. The aim of the present study is to investigate the association of variants in the XOR gene with BP and the development of hypertension.

Methods:

Analyses were conducted in the prospective Flemish FLEMENGHO and European EPOGH study (n=2769). 28 tagging SNPs that are in disequilibrium (r²>0.80) with 387 SNPs covering the entire gene were selected. 24 SNPs remained after exclusion of 4 SNPs not meeting the Hardy-Weinberg equilibrium. Minor allele carriers were determined by using the European HAPMAP population as reference. The minor allele homozygotes and heterozygotes were compared with the major allele homozygotes. BP was measured by trained observers at baseline (1985-2004) and repeatedly during follow-up (1991-2013). The relation between variants of the XOR gene and changes in pulse pressure (PP) and mean arterial pressure (MAP) over time; and incidence of hypertension, were analysed using multivariable mixed models and cox-regression, respectively. Family clusters were modelled as random effect. Analyses were corrected for multiple testing by the Benjamini Hochberg correction, the false discovery rate was set at 0.25.

Results:

Follow-up data for BP were available at 1, 2, or ≥3 occasions in 2769, 1450, and 1035 participants, respectively (median follow-up: 8.79 yrs (IQR: 6.54)). The rise in PP from baseline to the last available measurement was significantly associated with SNP rs11904439, in the crude and confounder adjusted model (adjusted P=<0.01), averaging 8.55 mm Hg (SD 13.6) in minor G allele carriers and 6.33 mm Hg(SD 13.6) in AA homozygotes. The association remained significant after correction for multiple testing. No association with change in MAP was found. Among 2050 participants normotensive at baseline, 753 (36.7%) developed hypertension during follow-up (median follow-up: 10.7 yrs (IQR: 7.3)). Multivariably, two SNPs, rs148756340 and rs11904439, were associated with onset of hypertension. For SNP rs148756340 the minor G allele carriers had a higher risk of hypertension compared to AA homozygotes (adjusted HR: 1.69; 95% CI 1.11 to 2.57, p=0.01). For SNP rs11904439 minor G allele carriers had a higher risk of hypertension compared to AA homozygotes (adjusted HR: 1.33; 95% CI 1.04 to 1.70, p=0.02). For both SNPs the association remained significant after correction for multiple testing.

Conclusion:

Two SNPs, rs11904439 and rs148756340, of the XOR gene were associated with change in PP over time and/or the development of hypertension. This suggests that UA production may be associated with BP and the development of hypertension. Because of the exploratory nature of this study and because it is unknown if the SNP has an effect on the enzyme activity, further investigation is required.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/xanthine-oxidase-gene-variants-and-their-association-with-blood-pressure-and-incident-hypertension-a-population-based-study/