Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations.
Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations.
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DOI：
10.1002/art.39589
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发表时间：
2016-06
影响因子：
13.3
通讯作者：
Yu, C. Yung
中科院分区：
文献类型：
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作者：
Chen, Ji Yih;Wu, Yee Ling;Mok, Mo Yin;Wu, Yeong-Jian Jan;Lintner, Katherine E.;Wang, Chin-Man;Chung, Erwin K.;Yang, Yan;Zhou, Bi;Wang, Huanyu;Yu, Denise J. H. C.;Alhomosh, Alaaedin;Jones, Karla;Spencer, Charles H.;Nagaraja, Haikady N.;Lau, Yu Lung;Lau, Chak-Sing;Yu, C. Yung
人补体C4是非常复杂的，具有多层多样性。本研究旨在阐明C4 A和C4 B基因在SLE发病风险中的CNV，并比较东亚人和欧洲人C4 A缺乏的种族特异性基础。我们的EA研究人群包括999名SLE患者和1，347名健康受试者。通过独立的基因分型技术，确定并严格验证了总C4、C4 A、C4 B、长和短基因的基因拷贝数（GCN）变异。研究了具有C4 B 96的基因组区域，以确定与C4 A缺陷同时存在的最基本C4 B蛋白的基础。在EA中，高C4和C4 A GCN对SLE的强保护作用是显著的，低和中等C4和C4 A GCN以及短基因的缺失是SLE的危险因素。纯合子C4 A缺陷是罕见的，但有一个比值比（OR）为12.4（p=0.0015）。血清补体极低的患者与总C4（OR=3.27，p=7.0×10−7）和C4 B（OR=2.55，p=2.5×10−5）的低GCN相关。低补体患者抗dsDNA抗体（OR=4.96，p=9.7×10−17）、溶血性贫血（OR=3.89，p=3.6×10−10）和肾脏疾病（OR=2.18，p=8.5×10−6）的发生率较高。与欧洲流行的HLA-DRB 1 *0301连锁不平衡的C4 A缺乏的单模块短单倍型在EA中罕见。相反，大多数患有C4 A缺陷的EA受试者共享编码C4 B1和C4 B 96的双模块LS的重组单倍型，其与HLA-DRB 1 *1501相关联。DNA测序显示C4 B 96的E920 K多态性。C4 CNVs和C4 A缺乏在东亚和欧洲SLE的风险和表现中是重要的。
Human complement C4 is sophisticatedly complex with multiple layers of diversity. This study aims to elucidate the CNVs of C4A and C4B in disease risk of SLE, and compare the basis of race-specific C4A-deficiency in East-Asians (EA) and Europeans. Our EA study-population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy-numbers (GCNs) for total C4, C4A, C4B, long and short genes were determined and validated rigorously by independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein that is concurrent with C4A-deficiency. In EA, strong protective effects of high GCNs for total C4 and C4A against SLE were notable; low and medium GCNs for total C4 and C4A, and the absence of short genes were risk factors of SLE. Homozygous C4A-deficiency was infrequent but had an odds-ratio (OR) of 12.4 (p=0.0015). Patients who experienced very-low serum complement were associated with low GCNs of total C4 (OR=3.27, p=7.0×10−7) and C4B (OR=2.55, p=2.5×10−5). Patients with low complement had high frequencies of anti-dsDNA (OR=4.96, p=9.7×10−17), hemolytic anemia (OR=3.89, p=3.6×10−10) and renal disease (OR=2.18, p=8.5×10−6). The monomodular-short haplotype with C4A-deficiency and in linkage-disequilibrium with HLA-DRB1*0301 prevalent in European was scarce in EA. Instead, most EA-subjects with C4A-deficiency shared a recombinant haplotype with bimodular-LS encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA sequencing revealed the E920K polymorphism for C4B96. C4 CNVs and C4A-deficiency are important in the risk and manifestations of East-Asian and European SLE.
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影响因子：
--
作者：
Petri, Michelle;Orbai, Ana-Maria;Alarcon, Graciela S.;Gordon, Caroline;Merrill, Joan T.;Fortin, Paul R.;Bruce, Ian N.;Isenberg, David;Wallace, Daniel J.;Nived, Ola;Sturfelt, Gunnar;Ramsey-Goldman, Rosalind;Bae, Sang-Cheol;Hanly, John G.;Sanchez-Guerrero, Jorge;Clarke, Ann;Aranow, Cynthia;Manzi, Susan;Urowitz, Murray;Gladman, Dafna;Kalunian, Kenneth;Costner, Melissa;Werth, Victoria P.;Zoma, Asad;Bernatsky, Sasha;Ruiz-Irastorza, Guillermo;Khamashta, Munther A.;Jacobsen, Soren;Buyon, Jill P.;Maddison, Peter;Dooley, Mary Anne;van vollenhoven, Ronald F.;Ginzler, Ellen;Stoll, Thomas;Peschken, Christine;Jorizzo, Joseph L.;Callen, Jeffrey P.;Lim, S. Sam;Fessler, Barri J.;Inanc, Murat;Kamen, Diane L.;Rahman, Anisur;Steinsson, Kristjan;Franks, Andrew G., Jr.;Sigler, Lisa;Hameed, Suhail;Fang, Hong;Ngoc Pham;Brey, Robin;Weisman, Michael H.;McGwin, Gerald, Jr.;Magder, Laurence S.
通讯作者：
Magder, Laurence S.
影响因子：
9.8
作者：
Chung, EK;Yang, Y;Yu, CY
通讯作者：
Yu, CY
影响因子：
2.6
作者：
Orbai AM;Truedsson L;Sturfelt G;Nived O;Fang H;Alarcón GS;Gordon C;Merrill J;Fortin PR;Bruce IN;Isenberg DA;Wallace DJ;Ramsey-Goldman R;Bae SC;Hanly JG;Sanchez-Guerrero J;Clarke AE;Aranow CB;Manzi S;Urowitz MB;Gladman DD;Kalunian KC;Costner MI;Werth VP;Zoma A;Bernatsky S;Ruiz-Irastorza G;Khamashta MA;Jacobsen S;Buyon JP;Maddison P;Dooley MA;Van Vollenhoven RF;Ginzler E;Stoll T;Peschken C;Jorizzo JL;Callen JP;Lim SS;Fessler BJ;Inanc M;Kamen DL;Rahman A;Steinsson K;Franks AG Jr;Sigler L;Hameed S;Pham N;Brey R;Weisman MH;McGwin G Jr;Magder LS;Petri M
通讯作者：
Petri M
影响因子：
9.8
作者：
Boteva, Lora;Morris, David L.;Fernando, Michelle M. A.
通讯作者：
Fernando, Michelle M. A.
影响因子：
--
作者：
Manzi, S;Navratil, JS;Ahearn, JM
通讯作者：
Ahearn, JM