Identifying Susceptibility Genes for Endometriosis

鉴定子宫内膜异位症的易感基因

• 批准号: 7096821
• 负责人: GRANT W MONTGOMERY
• 金额: $ 39.97万
• 依托单位: QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-21 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096821
• 关键词: clinical research; endometriosis; family genetics; genetic susceptibility; human genetic material tag; human population genetics; human tissue; linkage disequilibriums; linkage mapping; mass spectrometry; matrix assisted laser desorption ionization; molecular dynamics; single nucleotide polymorphism

DESCRIPTION (provided by applicant): This RO1 application seeks to conduct fine mapping and association studies under a region of significant linkage to endometriosis identified in a large collaborative study. Endometriosis is a complex gynecologic disorder affecting up to 10% of women, an estimated 5.5 million women in the US alone. In endometriosis, endometrial tissue is found outside the uterus, growing, bleeding cyclically arid causing adhesions. Common symptoms are severe pelvic pain, painful menstrual periods and infertility. The disorder often recurs and has a major impact on women's health, relationships, productivity and life choices. Genetic factors contribute to endometriosis, and this study's long-term objective is to identify genetic variants predisposing women to the disorder. DNA samples were obtained from 1,221 affected sister pair (ASP) and 1,616 triad (case plus both parent) families. DNA is also available from 950 unrelated cases and 950 controls. All affected women were diagnosed during pelvic surgery. A 10-cM genome scan, completed in 1,176 ASP families, has identified significant linkage to chromosome 10, with evidence for two distinct susceptibility loci. The project aims to identify susceptibility genes by genotyping single nucleotide polymorphisms (SNPs) in 286 genes within our region of significant linkage and tagging SNPs at a density of approximately 10 Kb across the region. We will initially test for association using a case control design, with cases drawn from the ASP families in which the initial linkage was identified and unrelated controls, using Illumina SNP genotyping technology. SNPs showing association with endometriosis will be further tested by conducting replication studies in independent cases and controls using Sequenom MALDI-TOF mass spectrometry. Variants showing significant association in the replication sample, together with adjacent SNPs, will be genotyped in ASP and triad families to control for population stratification and conduct joint linkage: linkage disequilibrium analysis to identify SNP associations accounting for the linkage signal. Knowledge of the susceptibility genes in endometriosis will lead to better diagnosis and more targeted treatments based upon a clearer understanding of the aberrant cellular and molecular mechanisms.

描述（由申请人提供）：此RO1申请旨在在与大型协作研究中确定的子宫内膜异位症的区域中进行精细的映射和关联研究。子宫内膜异位症是一种复杂的妇科疾病，影响多达10％的妇女，仅在美国估计有550万妇女。在子宫内膜异位症中，子宫内膜组织在子宫外发现，生长，循环干燥，引起粘附。常见症状是严重的骨盆疼痛，月经期和不育症。该疾病通常会复发，并对妇女的健康，人际关系，生产力和生活选择产生重大影响。遗传因素有助于子宫内膜异位症，这项研究的长期目标是确定使女性患疾病的遗传变异。 DNA样品是从1,221个受影响的姊妹对（ASP）和1,616个三合会（案例加两个父母）家庭中获得的。 DNA也可从950例无关病例和950个对照中获得。在骨盆手术期间，所有受影响的妇女均被诊断出。在1,176个ASP家族中完成的10厘米基因组扫描已确定与10号染色体的显着连接，并有两个不同的敏感位点的证据。 该项目旨在通过在我们区域内的286个基因中的单核苷酸多态性（SNP）进行基因分型来鉴定敏感性基因，并在整个区域以大约10 kb的密度标记SNP。我们最初将使用案例控制设计测试关联，并使用Illumina SNP基因分型技术从ASP家族中得出的案例，并从ASP家族中汲取了初始链接和无关的控制。通过在独立病例中进行复制研究和使用Secenom Maldi-TOF质谱法进行复制研究，将进一步测试显示与子宫内膜异位症相关的SNP。在复制样本中显示出显着关联的变体以及相邻的SNP将在ASP和Triad家族中进行基因分型，以控制人口分层和进行关节链接：链接不平衡分析，以识别SNP关联，以考虑链接信号的核算。基于对异常细胞和分子机制的更清晰的了解，对子宫内膜异位症中易感性基因的了解将导致更好的诊断和更具针对性的治疗方法。