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Abstract：
Although the genetic susceptibility to diseases has been extensively studied, the genetic loci and the primary molecular and cellular mechanisms that control disease tolerance are still largely unknown. Bovine paratuberculosis (PTB) is an enteritis caused by Mycobacterium avium subsp. paratuberculosis (MAP). PTB affects cattle worldwide and represents a major issue on animal health. In this study, the associations between host genetic and PTB tolerance were investigated using the genotypes from 277 Spanish Holstein cows with two distinct phenotypes: cases) infected animals with positive PCR and bacteriological culture results but without lesions in gut tissues (N= 24), and controls) animals with negative PCR and culture results but with PTB-associated lesions (N= 253). DNA from peripheral blood of the study population was genotyped with the Bovine EuroG MD Bead Chip, and the corresponding genotypes were imputed to whole-genome sequencing (WGS) data. A genome-wide association study was performed using the WGS data and the defined phenotypes in a case-control approach. A total of 142 single nucleotide polymorphisms (SNPs) were associated (false discovery rate ≤ 0.05, P values between 1.5 × 10-7 and 5.7 × 10-7) with tolerance (heritability= 0.55). The 40 SNPs with P-values < 5 × 10-7 defined 9 QTLs and 98 candidate genes located on BTA4, BTA9, BTA16, BTA25, and BTA26. Some of the QTLs identified in this study overlap with QTLs previously associated with PTB, bovine tuberculosis, mastitis, somatic cell score, bovine diarrhea virus persistent infection, tick resistance, and length of productive life. Two candidate genes with important roles in DNA damage response (ERCC4 and RMI2) were identified on BTA25. Functional analysis using the 98 candidate genes revealed a significant enrichment of the DNA packaging process (TNP2/PRMI1/PRM2/PRM3). In addition, the TNF-signaling (bta04668; TRAF5/CREB5/CASP7/CHUK) and the toxoplasmosis (bta05145; TGFβ2/CHUK/CIITA/SOCS1) pathways were significantly enriched. Interestingly, the nuclear Factor NF-κβ Inhibitor Kinase Alpha (CHUK), a key molecule in the regulation of the NF-κB pathway, was enriched in both pathways. Taken together, our results define a distinct immunogenetic profile in the PTB-tolerant animals designed to control bacterial growth, modulate inflammation, limit tissue damage and increase repair, thus reducing the severity of the disease.
摘要：
尽管对疾病的遗传易感性已被广泛研究,控制疾病耐受性的遗传基因座和主要的分子和细胞机制在很大程度上仍然未知。牛副结核（PTB）是由鸟分枝杆菌亚种引起的肠炎。副结核病（MAP）。PTB影响全世界的牛并且代表动物健康的主要问题。在这项研究中,使用277只西班牙荷斯坦奶牛的基因型研究了宿主遗传和PTB耐受性之间的关联，这些奶牛具有两种不同的表型：病例）感染的动物，PCR和细菌学培养结果阳性，但肠道组织中没有病变（N=24），和对照）具有阴性PCR和培养结果但具有PTB相关病变的动物（N=253）。用牛EuroGMD珠芯片对研究人群外周血的DNA进行基因分型，并将相应的基因型归入全基因组测序（WGS）数据。在病例对照方法中，使用WGS数据和定义的表型进行了全基因组关联研究。共有142个单核苷酸多态性（SNP）与耐受性（遗传率=0.55）相关（错误发现率≤0.05，P值在1.5×10-7和5.7×10-7之间）。P值<5×10-7的40个SNP定义了位于BTA4，BTA9，BTA16，BTA25和BTA26上的9个QTL和98个候选基因。本研究中确定的一些QTL与先前与PTB相关的QTL重叠，牛结核病,乳腺炎,体细胞评分,牛腹泻病毒持续感染，tick电阻，和生产寿命的长短。在BTA25上鉴定了两个在DNA损伤应答中具有重要作用的候选基因(ERCC4和RMI2)。使用98个候选基因的功能分析揭示了DNA包装过程的显著富集(TNP2/PRMI1/PRM2/PRM3)。此外,TNF-信号(bta04668;TRAF5/CREB5/CASP7/CHUK)和弓形虫病(bta05145;TGFβ2/CHUK/CIITA/SOCS1)途径显著富集.有趣的是,核因子NF-κβ抑制激酶α（CHUK），调节NF-κB途径的关键分子，在这两种途径中都得到了丰富。一起来看,我们的结果在PTB耐受动物中定义了独特的免疫遗传学特征，旨在控制细菌生长，调节炎症，限制组织损伤并增加修复，从而降低疾病的严重程度。
