Coding and Noncoding Variants in CFH Act Synergistically for Complement Activation in Immunoglobulin A Nephropathy
Coding and Noncoding Variants in CFH Act Synergistically for Complement Activation in Immunoglobulin A Nephropathy
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CFH 中的编码和非编码变体在免疫球蛋白 A 肾病中协同激活补体。
DOI：
10.1016/j.amjms.2018.04.006
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发表时间：
2018-08-01
影响因子：
3.1
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
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作者：
Guo, Wei-yi;Liu, Qing-zhen;Zhang, Hong
背景：在免疫球蛋白A肾病（IgAN）中，补体激活发生在体循环和原位（肾小球）。最近的IgAN全基因组关联研究（GWAS）确定1 q32为IgAN易感基因座，包含补体调节蛋白编码基因补体因子H（CFH）。在此，我们探讨了CFH基因编码和非编码区rs6677604和rs 800292对IgAN.Methods补体激活的联合遗传效应：共招募了1,194例IgAN患者和900名健康对照者，均为近期IgAN-GWAS北京发现队列的研究对象。从GWAS数据中提取rs 800292和rs6677604的基因分型信息，而关于血浆C3水平和系膜C3沉积的信息从病历中收集。我们发现rs 800292-GG和rs6677604-GG都是IgAN患者补体激活的危险基因型，分别由rs 800292-GG IgAN患者较低的血浆C3水平和rs6677604-GG IgAN患者较高的肾小球C3沉积强度所代表。此外，与无风险基因型（rs 800292-AA/AG和rs6677604-AA/AG）的IgAN患者相比，具有2种风险基因型（rs 800292-GG和rs6677604-GG）的IgAN患者显示出更高程度的补体激活，表现为较低的血浆C3水平和较高强度的肾小球C3沉积。此外，当rs 800292或rs6677604单独相比，rs 800292和rs6677604的组合遗传效应表现出更强的关联与IgAN susceptibility.Conclusions：我们的研究结果表明，编码和非编码的CFH的变体协同作用，以调节补体激活的程度，从而有助于IgAN的易感性。
Background: In immunoglobulin A nephropathy (IgAN), complement activation occurs in both the systemic circulation and in situ (glomerular). A recent IgAN-genome-wide association study (GWAS) identified 1q32 as an IgAN susceptible locus that contained the complement regulatory protein coding gene complement factor H (CFH). Here, we explored the combined genetic effects of coding and noncoding variants in CFH, rs6677604 and rs800292 on complement activation in IgAN.Methods: In total, 1,194 IgAN patients and 900 healthy controls who were the same as the Beijing Discovery Cohort in our recent IgAN-GWAS were recruited. The genotyping information of rs800292 and rs6677604 were extracted from GWAS data, while the information regarding plasma C3 levels and mesangial C3 deposits were collected from medical records.Results: We found both rs800292-GG and rs6677604-GG were risk genotypes for complement activation in IgAN patients, as represented by lower plasma C3 levels in IgAN patients with rs800292-GG and a higher intensity of glomerular C3 deposits in those with rs6677604-GG, respectively. Additionally, IgAN patients with 2 risk genotypes (rs800292-GG and rs6677604-GG) showed a higher degree of complement activation compared to those with no risk genotypes (rs800292-AA/AG and rs6677604-AA/AG), as represented by both lower plasma C3 levels and a higher intensity of glomerular C3 deposits. Moreover, when compared to rs800292 or rs6677604 alone, the combined genetic effects of rs800292 and rs6677604 showed a stronger association with IgAN susceptibility.Conclusions: Our findings suggested that both coding and noncoding variants in CFH acted synergistically to regulate the degree of complement activation and thereby contributed to IgAN susceptibility.