Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: A comparison of Asian-Indian and European American populations
Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: A comparison of Asian-Indian and European American populations
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DOI：
10.1016/j.molimm.2008.11.018
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发表时间：
2009-04-01
影响因子：
3.6
通讯作者：
Yu, C. Yung
中科院分区：
文献类型：
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作者：
Saxena, Kapil;Kitzmiller, Kathryn J.;Yu, C. Yung
个体间基因拷贝数变异（CNVs）可能为人类群体提供了应对各种环境挑战的灵活性，但也导致了不同的疾病易感性。我们研究了来自RP-C4-CYP 21-TNX（RCCX）模块的补体成分C4和类固醇21-羟化酶的基因CNV，这些模块位于健康的亚洲-印度裔美国人（AIA）的主要组织相容性复合体中，并将其与欧洲裔美国人进行了比较。使用了产生交叉验证结果的确定性技术组合。C_4及其亚型酸性C_4A和碱性C_4B的中位基因拷贝数分别为4、2和2，但其频率仅为53- 56%。总C4和C4 A的分布模式偏向高拷贝数侧。例如，具有三个C4 A拷贝的AIA受试者的频率（30.7%）是具有单个拷贝的AIA受试者的频率（7.83%）的3.92倍。具有单个C4 B基因和C4 A缺失的单模块短单倍型，在欧洲人中与HLA DPB 1 *0301连锁不平衡，是自身免疫性疾病的强危险因素，在AIA中的频率为0.012，但在健康的欧洲美国人中为0.106（p=6.6 x 10（-8））。C4基因的拷贝数和大小强烈地决定血浆C4蛋白浓度。CYP 21 A（CYP 21 A1 P）和TNXA的拷贝数与总C4也观察到平行变化。值得注意的是，13.1%的AIA受试者有三个功能性CYP 21 B拷贝，这可能是由单模块和双模块RCCX单倍型之间的重组产生的。C4基因的高拷贝数和RCCX基因重组的高频率为自身免疫性疾病和遗传性疾病的流行提供了重要的信息。(C)2008爱思唯尔有限公司保留所有权利。
Inter-individual gene copy-number variations (CNVs) probably afford human populations the flexibility to respond to a variety of environmental challenges, but also lead to differential disease predispositions. We investigated gene CNVs for complement component C4 and steroid 21-hydroxylase from the RP-C4-CYP21-TNX (RCCX) modules located in the major histocompatibility complex among healthy Asian-Indian Americans (AIA) and compared them to European Americans. A combination of definitive techniques that yielded cross-confirmatory results was used. The medium gene copy-numbers for C4 and its isotypes, acidic C4A and basic C4B, were 4, 2 and 2, respectively, but their frequencies were only 53-56%. The distribution patterns for total C4 and C4A are skewed towards the high copy-number side. For example, the frequency of AIA-subjects with three copies of C4A (30.7%) was 3.92-fold of those with a single copy (7.83%). The monomodular-short haplotype with a single C4B gene and the absence of C4A, which is in linkage-disequilibrium with HLA DPB1*0301 in Europeans and a strong risk factor for autoimmune diseases, has a frequency of 0.012 in AIA but 0.106 among healthy European Americans (p=6.6 x 10(-8)). The copy-number and the size of C4 genes strongly determine the plasma C4 protein concentrations. Parallel variations in copy-numbers of CYP21A (CYP21A1P) and TNXA with total C4 were also observed. Notably, 13.1% of AIA-subjects had three copies of the functional CYP21B, which were likely generated by recombinations between monomodular and bimodular RCCX haplotypes. The high copy-numbers of C4 and the high frequency of RCCX recombinants offer important insights to the prevalence of autoimmune and genetic diseases. (C) 2008 Elsevier Ltd. All rights reserved.