A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors
A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors
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DOI：
10.1086/496899
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发表时间：
2005-10-01
影响因子：
9.8
通讯作者：
Rouleau, GA
中科院分区：
文献类型：
--
作者：
Duan, QL;Nikpoor, B;Rouleau, GA
血管紧张素i转换酶抑制剂（ACEi）用于治疗常见的心血管疾病，与潜在的危及生命的不良反应血管水肿（AE-ACEi）有关。我们之前已经记录了AE-ACEi与低血浆氨基肽酶P （APP）活性之间的显著关联。通过8个大家系，我们证明了这一数量性状部分受到遗传因素的调控。我们使用方差成分QTL分析了10厘米全基因组微卫星扫描，在两个候选区域富集了7个标记。我们发现了与一个包含编码膜结合APP的YPNPEP2候选基因的位点的显著连锁（LOD = 3.75）。该QTL的突变筛选在一个家系中发现了一个大的编码缺失分离，在其余七个家系中发现了上游单核苷酸多态性（C2399A SNP）分离。测量的基因型分析强烈表明，该位点的APP活性连锁信号主要由SNP关联决定。在另一项单独的病例对照研究（20例和60例对照）中，我们发现该SNP与acei诱导的AE有显著关联（P =.0364）。总之，我们的研究结果提供了支持证据，表明YPNPEP2中的C-2399A变体与APP活性降低和AE-ACEi发生率升高有关。
Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the YPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P =.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in YPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.