Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant.
Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant.
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DOI：
10.1093/hmg/ddt619
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发表时间：
2014-05-01
影响因子：
3.5
通讯作者：
Wijmenga C
中科院分区：
文献类型：
--
作者：
Almeida R;Ricaño-Ponce I;Kumar V;Deelen P;Szperl A;Trynka G;Gutierrez-Achury J;Kanterakis A;Westra HJ;Franke L;Swertz MA;Platteel M;Bilbao JR;Barisani D;Greco L;Mearin L;Wolters VM;Mulder C;Mazzilli MC;Sood A;Cukrowska B;Núñez C;Pratesi R;Withoff S;Wijmenga C
使用免疫芯片进行基因分型，我们确定了39个与乳糜泻（CeD）相关的非人类白细胞抗原（非HLA）基因座，CeD是一种免疫介导的疾病，全球发病率为10.1%。最显著的非HLA信号定位于LPP基因中70 kb的内含子区域。我们的目的是精细定位和鉴定LPP基因座中可能的功能变体。我们对来自6个不同人群的25169名个体进行了荟萃分析，这些个体先前使用免疫芯片进行了基因分型。使用来自荷兰基因组和1000个基因组项目的数据进行插补，然后进行荟萃分析，证实了LPP基因座（rs2030519，P = 1.79 × 10−49）上的强关联信号，没有任何新的关联。对该顶部SNP的条件分析表明与单个共同单倍型的关联。通过分别对每个群体以及校正后达到显著性阈值（P < 0.008）的四个群体的组合进行单倍型分析，我们将CeD相关区域从70 kb缩小到2.8 kb（P = 1.35 × 10−44）。通过交叉来自ENCODE项目的调控数据，我们发现了一个功能性SNP，rs4686484（P = 3.12 × 10−49），它映射到几个B细胞增强子元件和一个高度保守的区域。该SNP还被预测改变转录因子IRF4、IRF11、Nkx2.7和Nkx2.9的结合基序，表明其在转录调控中的作用。我们后来发现，与对照组相比，CeD活检组织中LPP mRNA水平显着降低，因此我们的结果表明，rs4686484是该位点的功能变体，而LPP表达在CeD中降低。
Using the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of ∼1%. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was to fine map and identify possible functional variants in the LPP locus. We performed a meta-analysis in a cohort of 25 169 individuals from six different populations previously genotyped using Immunochip. Imputation using data from the Genome of the Netherlands and 1000 Genomes projects, followed by meta-analysis, confirmed the strong association signal on the LPP locus (rs2030519, P = 1.79 × 10−49), without any novel associations. The conditional analysis on this top SNP-indicated association to a single common haplotype. By performing haplotype analyses in each population separately, as well as in a combined group of the four populations that reach the significant threshold after correction (P < 0.008), we narrowed down the CeD-associated region from 70 to 2.8 kb (P = 1.35 × 10−44). By intersecting regulatory data from the ENCODE project, we found a functional SNP, rs4686484 (P = 3.12 × 10−49), that maps to several B-cell enhancer elements and a highly conserved region. This SNP was also predicted to change the binding motif of the transcription factors IRF4, IRF11, Nkx2.7 and Nkx2.9, suggesting its role in transcriptional regulation. We later found significantly low levels of LPP mRNA in CeD biopsies compared with controls, thus our results suggest that rs4686484 is the functional variant in this locus, while LPP expression is decreased in CeD.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
DOI：
10.1097/mpg.0b013e31821a23d0
发表时间：
2012-01-01
影响因子：
2.9
作者：
Husby, S.;Koletzko, S.;Zimmer, K. P.
通讯作者：
Zimmer, K. P.
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
2.1
作者：
Li, Yun;Willer, Cristen J.;Ding, Jun;Scheet, Paul;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
DOI：
10.1056/nejmoa0908547
发表时间：
2010-05-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jin Y;Birlea SA;Fain PR;Gowan K;Riccardi SL;Holland PJ;Mailloux CM;Sufit AJ;Hutton SM;Amadi-Myers A;Bennett DC;Wallace MR;McCormack WT;Kemp EH;Gawkrodger DJ;Weetman AP;Picardo M;Leone G;Taïeb A;Jouary T;Ezzedine K;van Geel N;Lambert J;Overbeck A;Spritz RA
通讯作者：
Spritz RA