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）：该 RO1 申请旨在对大型合作研究中确定的与子宫内膜异位症有显着关联的区域进行精细绘图和关联研究。子宫内膜异位症是一种复杂的妇科疾病，影响多达 10% 的女性，仅在美国估计就有 550 万女性。在子宫内膜异位症中，子宫内膜组织位于子宫外，生长、周期性出血并导致粘连。常见症状是严重的骨盆疼痛、经期疼痛和不孕。这种疾病经常复发，并对女性的健康、人际关系、生产力和生活选择产生重大影响。遗传因素导致子宫内膜异位症，这项研究的长期目标是确定导致女性易患这种疾病的遗传变异。 DNA 样本取自 1,221 个受影响的姐妹对 (ASP) 家庭和 1,616 个三合会（病例加上父母双方）家庭。还可以从 950 个无关病例和 950 个对照中获得 DNA。所有受影响的女性都是在盆腔手术期间确诊的。在 1,176 个 ASP 家族中完成的 10-cM 基因组扫描已确定与 10 号染色体的显着连锁，并提供了两个不同易感性位点的证据。 该项目旨在通过对我们显着连锁区域内 286 个基因的单核苷酸多态性 (SNP) 进行基因分型，并在整个区域以约 10 Kb 的密度标记 SNP，来识别易感基因。我们将首先使用病例对照设计测试关联性，其中使用 Illumina SNP 基因分型技术，从 ASP 家族中提取病例，其中确定了初始连锁，并使用不相关的对照。显示与子宫内膜异位症相关的 SNP 将通过使用 Sequenom MALDI-TOF 质谱法在独立病例和对照中进行复制研究来进一步测试。在复制样本中表现出显着关联的变体以及相邻的 SNP 将在 ASP 和三联体家族中进行基因分型，以控制群体分层并进行联合连锁：连锁不平衡分析，以识别导致连锁信号的 SNP 关联。了解子宫内膜异位症的易感基因将有助于在更清楚地了解异常细胞和分子机制的基础上进行更好的诊断和更有针对性的治疗。