Zhu Haidong, Lu Yanhui, Wang Xiaoling, Treiber Frank A, Harshfield Gregory A, Snieder Harold, Dong Yanbin
Georgia Prevention Institute, Department of Pediatrics, Medical College of Georgia, Building HS-1640, Augusta, GA 30912-3715, USA.
Am J Hypertens. 2006 Jan;19(1):61-6. doi: 10.1016/j.amjhyper.2005.07.007.
G protein-coupled receptor kinase 4 (GRK4) is involved in activity of dopamine receptors in renal proximal tubules and thus mediates sodium reabsorption and blood pressure (BP) regulation. The present study evaluated the impact of the GRK4 gene variants on BP levels in normotensive adolescents and young adults.
Three functional polymorphisms of R65L, A142V, and A486V were genotyped in 934 white and African American (44.2%) twin subjects (17.4 +/- 3.4 years of age). A number of association approaches including single-locus analyses, haplotype trend regression analyses, and sib-pair transmission disequilibrium tests were carried out.
Single-locus analyses revealed a significant interaction between R65L and age for SBP (P = .019) with an obvious gene-dose effect. In L65L homozygotes SBP showed the steepest increase with age (beta = 0.85, P = .003), R65L heterozygotes showed the next steepest increase (beta = 0.54, P < .001), and the effect of age on SBP was absent in R65R homozygotes. Stratified analyses showed that the SBP increasing effect of the 65L allele was significant only in the older group of subjects (114.1 +/- 11.1 mm Hg v 110.1 +/- 9.6 mm Hg, P = .024). Sib-pair transmission disequilibrium tests analyses in 72 informative dizygotic twin pairs confirmed the significant effect of the 65L on SBP; carriers of the 65L allele had a higher SBP compared with noncarriers (110.3 +/- 8.2 v 107.3 +/- 7.8 mm Hg, P = .047). Haplotype analyses uncovered an interaction between haplotype 65L-142V-486A and age for SBP (P = .017); individuals who were homozygous for haplotype 65L-142V-A486 showed a 1.05-mm Hg steeper increase in SBP per year increase in age compared with those homozygous for the most common R65-A142-A486 haplotype.
Our data indicate that the R65L polymorphism of the GRK4 gene plays a role in BP regulation in adolescents and young adults.
G蛋白偶联受体激酶4（GRK4）参与肾近端小管中多巴胺受体的活性，从而介导钠重吸收和血压（BP）调节。本研究评估了GRK4基因变异对血压正常的青少年和年轻成年人血压水平的影响。
对934名白人和非裔美国人（44.2%）双胞胎受试者（17.4±3.4岁）的R65L、A142V和A486V这三种功能性多态性进行基因分型。进行了多种关联分析方法，包括单基因座分析、单倍型趋势回归分析和同胞对传递不平衡检验。
单基因座分析显示，R65L与年龄对收缩压（SBP）有显著交互作用（P = 0.019），具有明显的基因剂量效应。在L65L纯合子中，SBP随年龄增长上升最为陡峭（β = 0.85，P = 0.003），R65L杂合子其次（β = 0.54，P < 0.001），而在R65R纯合子中年龄对SBP无影响。分层分析表明，65L等位基因对SBP的升高作用仅在年龄较大的受试者组中显著（114.1±11.1 mmHg对110.1±9.6 mmHg，P = 0.024）。对72对有信息的异卵双胞胎进行的同胞对传递不平衡检验分析证实了65L对SBP有显著影响；65L等位基因携带者的SBP高于非携带者（110.3±8.2对107.3±7.8 mmHg，P = 0.047）。单倍型分析发现单倍型65L - 142V - 486A与年龄对SBP有交互作用（P = 0.017）；与最常见的R65 - A142 - A486单倍型纯合子相比，65L - 142V - A486单倍型纯合子个体的SBP每年随年龄增长上升幅度陡1.05 mmHg。
我们的数据表明，GRK4基因的R65L多态性在青少年和年轻成年人的血压调节中起作用。
