Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival.
Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival.
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DOI：
10.1172/jci170420
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发表时间：
2023-11-01
影响因子：
15.9
通讯作者：
Menon, Madhav C.
中科院分区：
文献类型：
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作者：
Sun, Zeguo;Zhang, Zhongyang;Banu, Khadija;Gibson, Ian W.;Colvin, Robert B.;Yi, Zhengzi;Zhang, Weijia;De Kumar, Bony;Reghuvaran, Anand;Pell, John;Manes, Thomas D.;Djamali, Arjang;Gallon, Lorenzo;O'Connell, Philip J.;He, John Cijiang;Pober, Jordan S.;Heeger, Peter S.;Menon, Madhav C.
人类白细胞抗原（HLA）以外的供体-受体（D-R）错配导致肾移植物丢失，但其机制仍不清楚，特别是内含子错配。我们从来自2个表型良好的移植队列的D-R的单核苷酸多态性（SNP）数据在变体、基因和全基因组尺度上定量非HLA错配：慢性同种异体移植排斥基因组学（GoCAR; n = 385）和器官移植临床试验-01/17（CTOT-01/17; n = 146）。在GoCAR中进行的无偏基因水平筛选发现，LIMS 1基因座是排名第一的基因，其中D-R错配与死亡删失移植物丢失（DCGL）相关。一个以前未报道的内含子，LIMS 1单倍型的30个SNPs独立相关的DCGL在两个队列。单倍型错配显示出剂量效应，而将次要等位基因引入携带主要等位基因的受体显示出更大的DCGL风险。LIMS 1单倍型和先前报道的LIMS 1 SNP rs 893403是免疫细胞中GCC 2（而不是LIMS 1）的表达数量性状位点（eQTL），其编码参与甘露糖-6-磷酸酶受体（M6 PR）再循环的蛋白质。外周血和T细胞转录组分析将GCC 2基因和LIMS 1 SNP与TGF-β1/SMAD通路相关联，表明了调节作用。体外GCC 2调节影响T细胞中活性TGF-β1和下游信号传导的M6 PR依赖性调节。总之，我们的数据链接LIMS 1基因座D-R通过GCC 2 eQTL与DCGL错配，GCC 2 eQTL调节TGF-β1对T细胞的依赖性作用。
Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1–dependent effects on T cells.
长期肾脏同种异体移植功能的外显子组测序和预测。
影响因子：
4.3
作者：
Mesnard L;Muthukumar T;Burbach M;Li C;Shang H;Dadhania D;Lee JR;Sharma VK;Xiang J;Suberbielle C;Carmagnat M;Ouali N;Rondeau E;Friedewald JJ;Abecassis MM;Suthanthiran M;Campagne F
通讯作者：
Campagne F
GCC185 在高尔基体结构维持和 AP-1 介导的囊泡束缚中发挥独立作用。
DOI：
10.1083/jcb.201104019
发表时间：
2011-09-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Brown FC;Schindelhaim CH;Pfeffer SR
通讯作者：
Pfeffer SR