MHC and KIR Region Genomics in Psoriasis

银屑病的 MHC 和 KIR 区域基因组学

• 批准号: 9308668
• 负责人: Wilson Liao
• 金额: $ 70.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-24 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308668
• 关键词: Accounting; Address; Affect; Alleles; American; Arthritis; Asians; Autoimmune Diseases; Bioinformatics; Cells; Cohort Studies; Comorbidity; Conflict (Psychology); DNA sequencing; Data; Data Set; Development; Digit structure; Disease; Disease Progression; Disease susceptibility; Ethnic group; European; Exhibits; Flow Cytometry; Genes; Genetic; Genetic Models; Genetic Variation; Genetic study; Genomic Segment; HLA-C Antigens; Immune; Immunogenetics; Immunoglobulins; Immunologist; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-12; International; Killer Cells; Lead; Ligands; Light; Linkage Disequilibrium; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Mediating; Methods; Mica; Modeling; Myocardial Infarction; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Patients; Population; Predisposition; Problem Solving; Protocols documentation; Psoriasis; Psoriatic Arthritis; Receptor Gene; Refractory; Reporting; Research Design; Residual state; Resolution; Role; SNP array; SNP genotyping; Sample Size; Severities; Signal Transduction; Skin; Stroke; Susceptibility Gene; Systemic disease; Systems Biology; TNF gene; Techniques; Technology; Time; United States; Variant; Work; cohort; cost; deep sequencing; genetic association; genetic variant; genome wide association study; improved; innovation; insertion/deletion mutation; multidisciplinary; next generation sequencing; novel; novel therapeutics; population health; public health relevance; receptor; response; skin disorder; tool; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): Psoriasis is a common, immune-mediated, inflammatory skin disease associated with arthritis and systemic inflammation. Genome-wide association studies of psoriasis have identified over 40 susceptibility loci implicating both innat and adaptive immune pathways. The genetic locus exhibiting the greatest association with psoriasis is the MHC, with HLAC:06:02 showing very strong association in multiple ethnic groups. However, significant residual genetic signal remains in the MHC after accounting for the effects of HLAC:06:02 and it is not clear whether the residual signal resides in other HLA alleles, additional nearby genes, or regulatory variants. There is also evidence to suggest psoriasis susceptibility may be influenced by the interaction of killer cell immunoglobulin-like receptors (KIR) with HLA class I ligands; however, studies to date of HLA-KIR in psoriasis have generally been hampered by the time-consuming nature and high cost of HLA and KIR typing. Finally, although HLAC:06:02 is known to associate significantly with psoriasis and HLAC:06:02-positive psoriasis patients show differences in disease onset, severity, and response to therapy compared to HLAC:06:02-negative psoriasis patients, the mechanism by which HLAC:06:02 contributes to psoriasis has not been well studied. In this application, we utilize a variety of innovative approaches to address these questions. First, we perform high fidelity next-generation sequencing of the extended MHC in a psoriasis reference cohort and impute identified variants into European and Asian GWAS cohorts totaling over 8,500 cases and 17,000 controls. We construct a comprehensive genetic model to best explain the genetic association within the MHC using multiple model inputs including 4-digit resolution calls for 26 HLA/MICA/MICB/TAP genes, SNPs, indels, and functional variables. Second, we optimize a novel KIR imputation method that uses SNP array data to accurately call KIR copy number and apply this method to examine HLA-KIR associations in psoriasis using a large cohort. Finally, we utilize a novel flow cytometry protocol to sort psoriasis-relevant cell populations from the ski of HLAC:06:02-positive and HLAC:06:02- negative psoriasis patients, perform whole transcriptome RNA-sequencing on individual cell populations, and use systems biology analytical approaches to better understand the contribution of HLAC:06:02 to psoriasis pathogenesis. Together, the proposed work will identify causal variants in psoriasis, shed light on functional mechanisms, and potentially identify novel therapeutic pathways. The approaches and tools developed here will greatly facilitate the study of other immune-mediated diseases.

 描述（由应用提供）：牛皮癣是一种常见的，免疫介导的，炎症性皮肤疾病，与关节炎和全身性炎症有关。牛皮癣的全基因组关联研究已经确定了40多个敏感性基因座隐含了innat和适应性免疫病。 MHC是与牛皮癣最大关联的遗传基因座，HLAC：06：02在多个族裔中显示出非常牢固的关联。然而，在考虑到HLAC的影响：06：02之后，MHC的显着残留遗传信号仍保留在MHC中，尚不清楚残留信号是否存在于其他HLA等位基因中， 附近的其他基因或调节变体。还有证据表明，牛皮癣的易感性可能受到杀伤细胞免疫球蛋白样受体（KIR）与HLA I类配体的相互作用的影响。但是，牛皮癣中HLA-KIR迄今的研究通常受到耗时的性质和高成本的HLA和KIR键入的阻碍。 Finally, although HLAC:06:02 is known to associate significantly with psoriasis and HLAC:06:02-positive psoriasis patients show differences in disease onset, severity, and response to therapy compared to HLAC:06:02-negative psoriasis patients, the mechanism by which HLAC:06:02 contributes to psoriasis has not been well studiod.在此应用程序中，我们利用各种创新方法来解决这些问题。首先，我们在牛皮癣参考队列中对扩展的MHC进行了高保真度的下一代测序，并将估计的变体定为欧洲和亚洲GWAS队列，总计超过8,500例和17,000例对照。我们使用多个模型输入（包括4位分辨率呼叫的26 HLA/MICA/MICB/TAP/TAP基因，SNP，INDELS和功能变量）构建了一个综合遗传模型，以最好地解释MHC中MHC中的遗传关联。其次，我们优化了一种新颖的KIR归合方法，该方法使用SNP阵列数据准确调用KIR拷贝号，并应用此方法使用大型同类群检查牛皮癣中的HLA-KIR关联。 Finally, we utilize a novel flow cytometry protocol to sort psoriasis-relevant cell populations from the ski of HLAC:06:02-positive and HLAC:06:02- negative psoriasis patients, perform whole transcriptome RNA-sequencing on individual cell populations, and use systems biology analytical approaches to better understand the contribution of HLAC:06:02 to psoriasis pathogenesis.拟议的工作一起将确定牛皮癣中的因果变异，阐明了功能机制，并有可能识别新的治疗途径。这里开发的方法和工具将极大地支持对其他免疫介导的疾病的研究。