Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
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DOI：
10.1002/art.39504
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Jacob CO
中科院分区：
文献类型：
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作者：
Alarcón-Riquelme ME;Ziegler JT;Molineros J;Howard TD;Moreno-Estrada A;Sánchez-Rodríguez E;Ainsworth HC;Ortiz-Tello P;Comeau ME;Rasmussen A;Kelly JA;Adler A;Acevedo-Vázquez EM;Cucho-Venegas JM;García-De la Torre I;Cardiel MH;Miranda P;Catoggio LJ;Maradiaga-Ceceña M;Gaffney PM;Vyse TJ;Criswell LA;Tsao BP;Sivils KL;Bae SC;James JA;Kimberly RP;Kaufman KM;Harley JB;Esquivel-Valerio JA;Moctezuma JF;García MA;Berbotto GA;Babini AM;Scherbarth H;Toloza S;Baca V;Nath SK;Aguilar Salinas C;Orozco L;Tusié-Luna T;Zidovetzki R;Pons-Estel BA;Langefeld CD;Jacob CO
系统性红斑狼疮（SLE）是一种具有强烈遗传成分的慢性自身免疫性疾病。我们的目标是对来自美洲的富含美洲原住民遗产的个体进行第一次全基因组关联研究。我们分析了来自拉丁美洲四个国家和美国的3，710名被诊断患有SLE和健康对照的个体。使用HumanOmni 1 BeadChip对样本进行基因分型。获得HumanOmni2.5的研究外对照数据。使用SNPTEST和SNPGWA进行统计分析。针对基因组对照和FDR调整数据。使用IMPUTE 2和HiBAG对经典HLA等位基因进行插补。IRF 5-TNPO 3区域显示出最强的关联和最大的比值比（OR）（rs 10488631，Pgcadj = 2.61×10−29，OR = 2.12，95%CI：1.88-2.39），其次是DQA 2-DQB 1基因座上的HLA II类（rs9275572，Pgcadj = 1.11 × 10−16，OR = 1.62，95%CI：1.46-1.80; rs9271366，Pgcadj=6.46 × 10−12，OR = 2.06，95%CI：1.71-2.50）。其他已知的SLE相关基因座为ITGAM、STAT 4、TNIP 1、NCF 2和IRAK 1。我们在10q24.33（rs 4917385，Pgcadj =1.4×10−8）上发现了一个具有eQTL效应（在USMG 5/miR 1307上Peqtl=8.0 × 10−37）的新位点，并描述了新位点。我们证实了SLE的风险基因座先前确定的欧洲和亚洲人。当地血统估计表明，HLA等位基因的风险贡献是欧洲祖先的起源。HLA等位基因的插补表明，本土美洲原住民单倍型提供保护。我们的研究结果显示了通过研究混合人群来描绘自身免疫性疾病和复杂疾病的遗传结构所获得的洞察力。
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage. We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles. The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, Pgcadj = 2.61×10−29, OR = 2.12, 95% CI: 1.88–2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, Pgcadj = 1.11 × 10−16, OR = 1.62, 95% CI: 1.46–1.80; rs9271366, Pgcadj=6.46 × 10−12, OR = 2.06, 95% CI: 1.71–2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, Pgcadj =1.4×10−8) with a eQTL effect (Peqtl=8.0 × 10−37 at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection. Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases.