Examination of the role of LPIN2 variations in skin and bone inflammation

检查 LPIN2 变异在皮肤和骨骼炎症中的作用

• 批准号: 7268147
• 负责人: HATEM I EL-SHANTI
• 金额: $ 12.68万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268147
• 关键词: Affect; Candidate Disease Gene; Characteristics; Chemicals; Childhood; Chronic; Complex; Congenital dyserythropoietic anemia; Detection; Development; Disease; Environmental Exposure; Etiology; Family; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Hereditary Disease; Individual; Inflammation; Inflammatory; Minor; Mutation; Numbers; Osteitis; Osteomyelitis; Parents; Pathogenesis; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Play; Predisposing Factor; Predisposition; Process; Psoriasis; Recurrence; Role; SNP genotyping; Skin; Structure; Susceptibility Gene; Sweet' s Syndrome; Syndrome; Techniques; Triad Acrylic Resin; Variant; bone; cohort; design; falls; skin disorder

DESCRIPTION (provided by applicant): Multifactorial diseases result from complex interactions between a number of predisposing factors, including genotypes at one or more loci and a variety of environmental exposures that trigger, accelerate or exacerbate the disease process. One approach to the identification of the gene loci involved in a complex disorder is to examine the involvement of a candidate gene - identified due to its physiologic role or its causal role in a monogenic disorder of a similar phenotype - by genotyping for polymorphisms within the gene and performing association studies. Chronic recurrent multifocal osteomyelitis (CRMO) associated with congenital dyserythropoietic anemia (CDA) and an inflammatory dermatosis is a complex childhood syndrome with autosomal recessive inheritance (Majeed syndrome). The inflammatory dermatoses in Majeed syndrome are Sweet syndrome in affected individuals and psoriasis in some carriers. More frequently, CRMO, CDA, Sweet syndrome and psoriasis occur independent of each other as isolated entities posing as multifactorial "complex" disorders. We have shown that homozygous mutations in LPIN2 are responsible for Majeed syndrome in two unrelated families. Furthermore, LPIN2 is located within a psoriasis susceptibility locus. We hypothesize that LPIN2 is the gene that predisposes to psoriasis in this locus. We also hypothesize that LPIN2 variations play a role in the genetic etiology of the non-syndromic CRMO. We are proposing to examine these hypotheses by performing association studies with markers within the LPIN2 gene on two cohorts of patients with psoriasis and a cohort of patients with CRMO and their parents. The association studies will be followed by sequencing to identify LPIN2 variantions and by techniques to detect large deletions or duplications within the genomic structure of LPIN2. The long term objective is to identify the mechanism and biologic pathway of bone and skin inflammation to lay the background for the development of pathogenesis oriented and targeted biologic or chemical therapy. The goal of this project is to determine whether the gene, LPIN2, which is responsible for a rare genetic disorder of bone and skin inflammation is one of the genes that predispose to psoriasis. It also examines whether LPIN2 can be a cause of chronic recurrent multifocal osteomyelitis (CRMO). Understanding the mechanisms behind psoriasis and CRMO is very important for the development of appropriate therapy.

描述（由申请人提供）：多因素疾病是由许多诱发因素之间的复杂相互作用引起的，包括一个或多个基因座的基因型和触发、加速或加剧疾病过程的各种环境暴露。鉴定复杂疾病中涉及的基因位点的一种方法是通过基因内多态性的基因分型和进行关联研究来检查候选基因的参与-由于其生理作用或其在类似表型的单基因疾病中的因果作用而鉴定。慢性复发性多灶性骨髓炎（CRMO）与先天性红细胞生成不良性贫血（CDA）和炎性皮肤病相关，是一种复杂的常染色体隐性遗传儿童综合征（Majeed综合征）。Majeed综合征中的炎性皮肤病在受影响的个体中是Sweet综合征，在一些携带者中是银屑病。更常见的是，CRMO、CDA、Sweet综合征和银屑病作为多因素“复杂”疾病的孤立实体彼此独立地发生。我们已经证明，LPIN 2的纯合突变是两个无关家族中Majeed综合征的原因。此外，LPIN 2位于银屑病易感性基因座内。我们假设LPIN 2是该基因座中易患银屑病的基因。我们还假设LPIN 2变异在非综合征型CRMO的遗传病因学中起作用。我们建议通过对两组银屑病患者和一组CRMO患者及其父母进行LPIN 2基因标记物的关联研究来检验这些假设。相关性研究之后将进行测序以鉴定LPIN 2变异，并通过技术检测LPIN 2基因组结构内的大缺失或重复。长期目标是确定骨和皮肤炎症的机制和生物学途径，为发展以发病机制为导向的靶向生物或化学治疗奠定基础。该项目的目标是确定导致骨骼和皮肤炎症的罕见遗传性疾病的基因LPIN 2是否是易患银屑病的基因之一。它还检查了LPIN 2是否可以是慢性复发性多灶性骨髓炎（CRMO）的原因。了解银屑病和CRMO背后的机制对于开发适当的治疗非常重要。