Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease.
Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease.
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DOI：
10.1371/journal.pone.0119085
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
van Laar JA
中科院分区：
文献类型：
--
作者：
Kappen JH;Medina-Gomez C;van Hagen PM;Stolk L;Estrada K;Rivadeneira F;Uitterlinden AG;Stanford MR;Ben-Chetrit E;Wallace GR;Soylu M;van Laar JA
白塞病（BD）的病因不明，但广泛认为是遗传易感宿主中过度的T细胞介导的炎症反应。最近的全基因组关联研究（GWAS）显示了有限数量的新位点关联。不同种族背景之间疾病患病率的罕见性和不平等分布阻碍了GWAS在混合种族和足够样本量的队列中的使用。然而，新的统计方法现在已经在混合队列中启用了GWAS。我们对336例BD病例和5，843例对照进行了GWAS。这些病例包括西欧、中东和土耳其人。来自R世代研究（荷兰鹿特丹的一项多种族出生队列研究）的参与者被用作对照。对所有样品进行基因分型并合并数据。使用基因组主成分和线性混合模型校正线性回归模型用于群体分层。对先前发表的选定结果进行荟萃分析。我们鉴定了与6p21.33（HLA）区域在全基因组显著水平映射相关的SNP。除了这个已知的信号，还发现了6号和18号染色体上的两个潜在的新关联，但次要等位基因频率较低。扩展的荟萃分析揭示了GWS与3号染色体上的IL12A变体rs17810546的关联。我们证明，新的统计技术，使GWAS分析在一个规模有限的混合种族的队列。实施后，我们证实了HLA区域在疾病中的核心作用，并确定了新的感兴趣区域。此外，我们通过与先前工作的荟萃分析验证了IL 2A基因中变体的关联。这些发现增强了我们对遗传关联和BD的认识，并为在这种疾病和其他罕见疾病的低患病率下进行遗传研究的集体倡议提供了进一步的理由。
The etiology of Behçet’s disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts. We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published. We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3. We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.
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影响因子：
7.3
作者：
Khaib Dit Naib O;Aribi M;Idder A;Chiali A;Sairi H;Touitou I;Lefranc G;Barat-Houari M
通讯作者：
Barat-Houari M
影响因子：
3.5
作者：
McCarthy, Mark I.;Hirschhorn, Joel N.
通讯作者：
Hirschhorn, Joel N.
影响因子：
13.6
作者：
Jaddoe, Vincent W. V.;van Duijn, Cornelia M.;Hofman, Albert
通讯作者：
Hofman, Albert
影响因子：
--
作者：
Altenburg, A.;Mahr, A.;Zouboulis, C. C.
通讯作者：
Zouboulis, C. C.
影响因子：
64.8
作者：
Gibbs, RA;Belmont, JW;Tanaka, T
通讯作者：
Tanaka, T