Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India.
Department of Gastroenterology, Dayanand Medical College & Hospital, Ludhiana, Punjab, India.
Sci Rep. 2019 Sep 25;9(1):13811. doi: 10.1038/s41598-019-50120-4.
Receptors are essential mediators of cellular physiology, which facilitate molecular and cellular cross-talk with the environment. Nearly 20% of the all known celiac disease (CD) genes are receptors by function. We hypothesized that novel biologically relevant susceptibility receptor genes act in synergy in CD pathogenesis. We attempted to identify novel receptor genes in CD by re-analyzing published Illumina Immunochip dense genotype data for a north Indian and a European (Dutch) cohort. North Indian dataset was screened for 269 known receptor genes. Association statistics for SNPs were considered with minor allele frequency >15% and association P ≤ 0.005 to attend desired study power. Identified markers were tested for cross-ethnic replication in a European CD dataset. Markers were analyzed in-silico to explain their functional significance in CD. Six novel SNPs from MOG (rs29231, p = 1.21e-11), GABBR1 (rs3025643, p = 1.60e-7), OR2H2 (rs1233388, p = 0.0002), ABCF1 (rs9262119, p = 0.0005), ADRA1A (rs10102024, p = 0.003), and ACVR2A (rs7560426, p = 0.004) were identified in north Indians, of which three genes namely, GABBR1 (rs3025643, p = 5.38e-8), OR2H2 (rs1233388, p = 3.29e-5) and ABCF1 (rs9262119, p = 0.0002) were replicated in Dutch. Tissue specific functional annotation, potential epigenetic regulation, co-expression, protein-protein interaction and pathway enrichment analyses indicated differential expression and synergistic function of key genes that could alter cellular homeostasis, ubiquitination mediated phagosome pathway and cellular protein processing to contribute for CD. At present multiple therapeutic compounds/drugs are available targeting GABBR1 and ADRA1A, which could be tested for their effectiveness against CD in controlled drug trials.
受体是细胞生理学的重要介质，促进了分子和细胞与环境的交流。近 20%的已知乳糜泻（CD）基因是通过功能来确定的受体。我们假设新的具有生物学意义的易感受体基因在 CD 发病机制中协同作用。我们通过重新分析已发表的北印度和欧洲（荷兰）队列的 Illumina Immunochip 密集基因型数据来尝试鉴定 CD 中的新受体基因。北印度数据集筛选了 269 个已知的受体基因。对 SNP 的关联统计数据进行了考虑，其次要等位基因频率（MAF）>15%，关联 P 值（P）≤0.005，以满足预期的研究效能。在欧洲 CD 数据集中对鉴定出的标记进行了跨种族复制检验。对标记进行了分析，以解释它们在 CD 中的功能意义。在 MOG（rs29231，p=1.21e-11）、GABBR1（rs3025643，p=1.60e-7）、OR2H2（rs1233388，p=0.0002）、ABCF1（rs9262119，p=0.0005）、ADRA1A（rs10102024，p=0.003）和 ACVR2A（rs7560426，p=0.004）中从北印度人鉴定出了六个新的 SNP，其中三个基因，即 GABBR1（rs3025643，p=5.38e-8）、OR2H2（rs1233388，p=3.29e-5）和 ABCF1（rs9262119，p=0.0002）在荷兰得到了复制。组织特异性功能注释、潜在的表观遗传调控、共表达、蛋白质-蛋白质相互作用和途径富集分析表明，关键基因的差异表达和协同作用可能会改变细胞内稳态、泛素化介导的吞噬体途径和细胞蛋白加工，从而导致 CD。目前有多种针对 GABBR1 和 ADRA1A 的治疗性化合物/药物，可在对照药物试验中测试其对 CD 的有效性。
