Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration:: Characterization, ethnic distribution and evolutionary implications
Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration:: Characterization, ethnic distribution and evolutionary implications
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DOI：
10.1080/07853890601097030
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Dean, Michael
中科院分区：
文献类型：
--
作者：
Hageman, Gregory S.;Hancox, Lisa S.;Dean, Michael
背景补体因子H基因（CFH）的变异与年龄相关性黄斑变性（AMD）有关。CFH和CFH相关基因（CFHR 1 -5）位于染色体1 q32上的补体激活调节子（RCA）位点。在这项研究中，这些基因和AMD之间的结构和进化的关系进行了细化，使用联合遗传学，分子和免疫组化的方法。我们发现并描述了一种包含CFHR 1和CFHR 3基因的大型常见缺失。CFHR 1是一种丰富的血清蛋白，在缺失的纯合子受试者中不存在。两个队列的AMD病例和对照的基因分型分析表明，缺失纯合子占病例的1.1%和对照的5.7%（卡方= 32.8; P = 1.6 E-09）。CFHR 1和CFHR 3转录本在肝脏中丰富，但在眼视网膜色素上皮/脉络膜复合体中检测不到。AMD相关的CFH/CFHR 1/CFHR 3单倍型在人群中广泛存在。CFHR 1和/或CFHR 3的缺失可能是某些CFH单倍型所赋予的保护作用的原因。此外，402 H等位基因和delCFHR 1/CFHR 3等位基因在非洲人群中的高频率表明这些等位基因的古老起源。在该位点积累的相当大的多样性可能是由于选择，这与CFHR基因在先天免疫中的重要作用一致。
Background. Variants in the complement factor H gene (CFH) are associated with age-related macular degeneration (AMD). CFH and five CFH-related genes (CFHR1-5) lie within the regulators of complement activation (RCA) locus on chromosome 1q32.Aims and Methods. In this study, the structural and evolutionary relationships between these genes and AMD was refined using a combined genetic, molecular and immunohistochemical approach.Results. We identify and characterize a large, common deletion that encompasses both the CFHR1 and CFHR3 genes. CFHR1, an abundant serum protein, is absent in subjects homozygous for the deletion. Genotyping analyses of AMD cases and controls from two cohorts demonstrates that deletion homozygotes comprise 1.1% of cases and 5.7% of the controls (chi-square = 32.8; P = 1.6 E-09). CFHR1 and CFHR3 transcripts are abundant in liver, but undetectable in the ocular retinal pigmented epithelium/choroid complex. AMD-associated CFH/CFHR1/CFHR3 haplotypes are widespread in human populations.Conclusion. The absence of CFHR1 and/or CFHR3 may account for the protective effects conferred by some CFH haplotypes. Moreover, the high frequencies of the 402H allele and the delCFHR1/CFHR3 alleles in African populations suggest an ancient origin for these alleles. The considerable diversity accumulated at this locus may be due to selection, which is consistent with an important role for the CFHR genes in innate immunity.