Fingerlin Tasha E, Zhang Weiming, Yang Ivana V, Ainsworth Hannah C, Russell Pamela H, Blumhagen Rachel Z, Schwarz Marvin I, Brown Kevin K, Steele Mark P, Loyd James E, Cosgrove Gregory P, Lynch David A, Groshong Steve, Collard Harold R, Wolters Paul J, Bradford Williamson Z, Kossen Karl, Seiwert Scott D, du Bois Roland M, Garcia Christine Kim, Devine Megan S, Gudmundsson Gunnar, Isaksson Helgi J, Kaminski Naftali, Zhang Yingze, Gibson Kevin F, Lancaster Lisa H, Maher Toby M, Molyneaux Philip L, Wells Athol U, Moffatt Miriam F, Selman Moises, Pardo Annie, Kim Dong Soon, Crapo James D, Make Barry J, Regan Elizabeth A, Walek Dinesha S, Daniel Jerry J, Kamatani Yoichiro, Zelenika Diana, Murphy Elissa, Smith Keith, McKean David, Pedersen Brent S, Talbert Janet, Powers Julia, Markin Cheryl R, Beckman Kenneth B, Lathrop Mark, Freed Brian, Langefeld Carl D, Schwartz David A
Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA.
Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, CO, USA.
BMC Genet. 2016 Jun 7;17(1):74. doi: 10.1186/s12863-016-0377-2.
Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.
We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB115:01 P = 1.3 × 10(-7) and DQB106:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB115:01 and DQB106:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)).
We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
纤维化性特发性间质性肺炎（fIIP）是一组致命的肺部疾病，其病因大多不明，除了肺移植以延长生命外，没有确切的治疗方法。有充分证据表明，罕见和常见的遗传风险等位基因在家族性和散发性疾病中都很重要。我们之前利用全基因组单核苷酸多态性数据确定了fIIP的10个风险位点。在此，我们将这项工作扩展到推断的全基因组基因型，并对肺组织进行新的RNA测序研究，以识别和表征新的fIIP风险位点。
我们对1616名非西班牙裔白人（NHW）患者和4683名NHW对照进行了全基因组基因型推断关联分析，随后进行了验证和复制（878例患者，2017例对照）基因分型以及肺组织中的靶向基因表达分析。在对发现和复制人群进行荟萃分析后，我们在6号染色体的HLA区域确定了一个新的fIIP位点（rs7887 P荟萃分析=3.7×10^(-09)）。经典HLA等位基因的推断确定了两个处于高度连锁不平衡状态且与fIIP相关的等位基因（DRB115:01 P=1.3×10^(-7)和DQB106:02 P=6.1×10^(-8)）。对HLA位点的靶向RNA测序确定了纤维化肺组织和对照肺组织之间21个差异表达的基因（Q<0.001），其中许多基因参与免疫和炎症反应调节。此外，推定的风险等位基因DRB115:01和DQB106:02与fIIP病例中DQB1基因的表达相关（Q<1×10^(-16)）。
我们确定了HLA区域与fIIP之间存在全基因组显著关联。两个HLA等位基因与fIIP相关，并影响肺组织中HLA基因的表达，这表明HLA等位基因导致的潜在遗传风险可能除了改变蛋白质结构外还涉及基因调控。这些研究揭示了HLA区域对fIIP风险的重要性以及自身免疫在fIIP中潜在病因作用的基础。
