24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes
24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes
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DOI：
10.1038/sj.ki.5001590
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发表时间：
2006-08-01
影响因子：
19.6
通讯作者：
Melander, O.
中科院分区：
文献类型：
--
作者：
Fava, C.;von Wowern, F.;Melander, O.
大量的连锁研究表明，染色体18q21-22是血压调节的重要基因座。该基因座含有神经前体细胞表达的发育下调的4-样蛋白(NEDD4L)基因，该基因对阿米洛利敏感的上皮钠通道(ENaC)具有调节作用。对18号染色体70~104 cM范围内的16个标记(包括位于NEDD4L基因内的两个单核苷酸多态标记)与动态血压的连锁研究中，发现NEDD4L基因座(82.25cM)与24小时动态血压和日间收缩压连锁最明显(P=0.0014)。在大规模人群样本(n=4001)中，我们随后发现NEDD4L基因变异(Rs4149601)与舒张压(DBP)(P=0.03)和DBP随时间的进展相关(P=0.04)。通过选择性剪接，NEDD4L基因变异导致一个功能关键的C2结构域的表达发生变化。Rs4149601和内含子NEDD4L标记(Rs2288774)的基因型组合与收缩压(SBP)(P=0.01)、舒张压(P=0.04)以及随时间推移的SBP(P=0.03)和DBP(P=0.05)的进展有关。在rs4149601的家系材料中的定量传递不平衡测试支持该NEDD4L变体至少部分地导致连锁结果。综上所述，我们的研究结果表明，位于82.25 cM的18号染色体连锁高峰可能是由于NEDD4L与ENaC相互作用的改变而导致的影响横断面和纵向血压的遗传变异。
Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleoticle polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P = 0.0014). In a large population sample (n = 4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P = 0.03) and DBP progression over time (P = 0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P = 0.01), DBP (P = 0.04), and progression of both SBP (P = 0.03) and DBP (P = 0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.