Key result
The rare KYNU variant Arg188Gln was significantly more frequent in Chinese patients with hypertension compared to normotensive controls (allele frequency 0.015 vs 0.006; P=0.0075).
Why the study?
Is the rare KYNU variant Arg188Gln associated with essential hypertension and altered kynureninase activity in the Han Chinese population?
Case-Control (n=4,102)
Is the rare KYNU variant Arg188Gln associated with essential hypertension and altered kynureninase activity in the Han Chinese population?
The rare KYNU variant Arg188Gln is associated with reduced kynureninase activity and an increased risk of essential hypertension in the Han Chinese population.
Answers are grounded in this paper and cite their sources.
KYNU Arg188Gln may confer hypertension susceptibility in Han Chinese; leaves open causal validation and therapeutic targeting.
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.
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Zhang et al. (2011) conducted a case-control in Essential hypertension (n=4,102). KYNU rare variant Arg188Gln vs. Wild-type KYNU (Arg188 homozygous) / Normotensive controls was evaluated on 188Gln allele frequency (p=0.0075). The rare KYNU variant Arg188Gln was significantly more frequent in Chinese patients with hypertension compared to normotensive controls (allele frequency 0.015 vs 0.006; P=0.0075).
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