A Rare Variant at the KYNU Gene is Associated with Kynureninase Activity and Essential Hypertension in the Han Chinese Population

Background: Genetic studies in mouse and human suggest that kynureninase activity may influence blood pressure and renal function. The gene coding kynureninase (KYNU) is also located on chromosome band 2q14-q23, where a linkage peak for essential hypertension was previously detected in the Chinese Han population.

Methods And Results: After having found no association with common polymorphisms, this study aimed to assess the role of 1 rare variant of KYNU, Arg188Gln, and kynureninase activity in relation to hypertension. Thirty-three of 1124 Chinese patients with hypertension were heterozygous for Arg188Gln, whereas only 14 of 1084 normotensive controls were heterozygous for Arg188Gln (188G1n allele frequency, 0.015 versus 0.006; P=0.0075). A genotype-discordant sibling-pair study was performed in another 924 individuals from 213 families, indicating that 188G1n carriers had higher systolic blood pressure (168.29 ± 24.67 versus 139.00 ± 12.82 mm Hg, P<0.001) and diastolic blood pressure (105.50 ± 14.08 versus 90.75 ± 11.07 mm Hg, P=0.001) than did Arg188 homozygous siblings. The Arg188Gln variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). The kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (P<0.05). The Kinetic Michaelis constants of 188Gln carriers was lower than that of Arg188 homozygous subjects (0.05 ± 0.02 versus 0.10 ± 0.02 mmol/L, P=0.005). Arg188Gln mutation in vitro also showed less catalytic efficiency than the wild-type KYNU enzyme (maximal reaction velocity/Kinetic Michaelis constant ratio, 0.050 ± 0.012 versus 0.11 ± 0.016 mL/min per mg; P=0.029).

Conclusions: The results show that the rare KYNU variant Arg188Gln affects kynureninase activity and are consistent with the hypothesis that this mutation can predispose to essential hypertension.