Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.
Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.
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DOI：
10.1016/j.jhep.2012.03.031
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发表时间：
2012-08
影响因子：
25.7
通讯作者：
Karlsen, Tom H.
中科院分区：
文献类型：
--
作者：
Folseraas, Trine;Melum, Espen;Rausch, Philipp;Juran, Brian D.;Ellinghaus, Eva;Shiryaev, Alexey;Laerdahl, Jon K.;Ellinghaus, David;Schramm, Christoph;Weismueller, Tobias J.;Gotthard, Daniel Nils;Hov, Johannes Roksund;Clausen, Ole Petter;Weersma, Rinse K.;Janse, Marcel;Boberg, Kirsten Muri;Bjornsson, Einar;Marschall, Hanns-Ulrich;Cleynen, Isabelle;Rosenstiel, Philip;Holm, Kristian;Teufel, Andreas;Rust, Christian;Gieger, Christian;Wichmann, H-Erich;Bergquist, Annika;Ryu, Euijung;Ponsioen, Cyriel Y.;Runz, Heiko;Sterneck, Martina;Vermeire, Severine;Beuers, Ulrich;Wijmenga, Cisca;Schrumpf, Erik;Manns, Michael P.;Lazaridis, Konstantinos N.;Schreiber, Stefan;Baines, John F.;Franke, Andre;Karlsen, Tom H.
关键词：
原发性硬化性胆管炎（PSC）的遗传危险因素有限。为了进一步发现PSC的遗传易感性因素，我们对来自全基因组关联研究（GWAS）的第二层单核苷酸多态性（SNP）进行了随访。我们分析了1221例PSC病例和3508例对照的45个SNP。将来自复制分析和原始GWAS（715例PSC病例和2962例对照）的关联结果合并到包括1936例PSC病例和6470例对照的荟萃分析中。我们通过16 S rRNA测序对39例PSC患者的胆汁微生物群落组成进行了分析。代表12个不同遗传位点的17个SNPs在复制中达到名义上的显著性（重复率<0.05）。在染色体1 p36（rs3748816; Pcombined=2.1×10−8）检测到最强的新关联，其中MMEL 1和TNFRSF 14基因代表潜在的疾病基因。另外8个新的基因座显示出关联的暗示性证据（Prepl<0.05）。位于染色体19 q13的FUT 2（rs602662; Pcomb=1.9×10−6，rs 281377; Pcomb = 2.1×10−6和rs601338; Pcomb=2.7×10−6）是值得注意的，因为它暗示着对感染性病原体的易感性改变。我们发现FUT 2分泌状态和rs601338定义的基因型显著影响PSC患者的胆汁微生物群落组成。我们通过对PSC GWAS的扩展分析确定了多个新的PSC风险位点。在评估微生物群对PSC中胆道病理学的影响时，需要考虑FUT 2基因型。
A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (Preplication<0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; Pcombined=2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (Prepl<0.05). FUT2 at chromosome 19q13 (rs602662; Pcomb=1.9×10−6, rs281377; Pcomb = 2.1×10−6 and rs601338; Pcomb=2.7×10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influences biliary microbial community composition in PSC patients. We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence from microbiota on biliary pathology in PSC.
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影响因子：
3
作者：
Silva, Lara M.;Carvalho, Ana S.;David, Leonor
通讯作者：
David, Leonor
影响因子：
5.9
作者：
FAITH, DP
通讯作者：
FAITH, DP
影响因子：
4.1
作者：
Serpa, J;Mendes, N;David, L
通讯作者：
David, L
影响因子：
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作者：
Oya, Yoshihiro;Watanabe, Norihiko;Owada, Takayoshi;Oki, Mie;Hirose, Koichi;Suto, Akira;Kagami, Shin-ichiro;Nakajima, Hiroshi;Kishimoto, Takashi;Iwamoto, Itsuo;Murphy, Theresa L.;Murphy, Kenneth M.;Saito, Yasushi
通讯作者：
Saito, Yasushi
影响因子：
29.4
作者：
Karrar, Azza;Broome, Ulrika;Sumitran-Holgersson, Suchitra
通讯作者：
Sumitran-Holgersson, Suchitra