Zhang Yi, Shen Jie, He Xin, Zhang Kuixing, Wu Shengnan, Xiao Bing, Zhou Xueya, Phillips Robert S, Gao Pingjin, Jeunemaitre Xavier, Zhu Dingliang
State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology and Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Circ Cardiovasc Genet. 2011 Dec;4(6):687-94. doi: 10.1161/CIRCGENETICS.110.959064. Epub 2011 Oct 19.
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.
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).
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.
对小鼠和人类的基因研究表明，犬尿氨酸酶活性可能会影响血压和肾功能。编码犬尿氨酸酶（KYNU）的基因也位于2号染色体2q14 - q23区域，此前在中国汉族人群中检测到该区域存在原发性高血压的连锁峰值。
在发现与常见多态性无关联后，本研究旨在评估KYNU的一种罕见变体Arg188Gln以及犬尿氨酸酶活性与高血压的关系。1124例中国高血压患者中有33例为Arg188Gln杂合子，而1084例血压正常的对照者中只有14例为Arg188Gln杂合子（188Gln等位基因频率分别为0.015和0.006；P = 0.0075）。对来自213个家庭的另外924名个体进行了基因型不一致的同胞对研究，结果表明，与Arg188纯合子同胞相比，188Gln携带者的收缩压（168.29±24.67对139.00±12.82 mmHg，P < 0.001）和舒张压（105.50±14.08对90.75±11.07 mmHg，P = 0.001）更高。在另外两个种族群体中，Arg188Gln变体更为罕见（880例法国高血压白人中有3例杂合子，90例非洲裔高血压患者中无杂合子）。高血压家族受试者血浆中的犬尿氨酸酶活性与血压相关（P < 0.05）。188Gln携带者的动力学米氏常数低于Arg188纯合子受试者（0.05±0.02对0.10±0.02 mmol/L，P = 0.005）。体外实验中，Arg188Gln突变体的催化效率也低于野生型KYNU酶（最大反应速度/动力学米氏常数比值为0.050±0.012对0.11±0.016 mL/min per mg；P = 0.029）。
结果表明，罕见的KYNU变体Arg188Gln会影响犬尿氨酸酶活性，这与该突变可能导致原发性高血压的假说一致。
