Aging-related Traits and Disease Risk Factors in a Sardinian Population Cohort

撒丁岛人群中的衰老相关特征和疾病危险因素

• 批准号: 9345253
• 负责人: David Schlessinger
• 金额: $ 61.61万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9345253
• 关键词: Adolescent and Young Adult; Affect; Age; Age-Years; Aging; Alleles; Antibodies; Autoimmune Diseases; B-Cell Activation; Baltimore; Biochemical; Blood; Blood Pressure; Blood Tests; Bone Density; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Cataloging; Catalogs; Cell Maturation; Cells; Cholesterol; Chronic Kidney Failure; Circadian Rhythms; Clinical; Cohort Studies; DNA; DNA Sequence; Dendritic Cells; Disease; Early Diagnosis; Echocardiography; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiological Factors; Epidemiology; Event; Family; Fetal Hemoglobin; Fibrinogen; Gene Expression Regulation; Genes; Genetic; Genome; Genome Scan; Genotype; Goals; Hearing Tests; Height; Hematopoiesis; Hemoglobin; Hemoglobin concentration result; Hour; Human; Immune; Immune system; Incidence; Individual; Inflammation; Inherited; Insulin-Dependent Diabetes Mellitus; Intervention; Iodide Peroxidase; Island; Leukocytes; Life; Lipids; Longitudinal Studies; Lupus; Lymphocyte; Mammals; Measurement; Measures; Metabolic syndrome; Mining; Molecular Target; Multiple Sclerosis; Mutation; Nature; Nucleotides; Obesity; Outcome; Paper; Patients; Pattern; Personality; Personality Traits; Phenotype; Population; Prevalence; Publications; Publishing; Quality Control; Recording of previous events; Regulation; Regulatory T-Lymphocyte; Reporting; Research Personnel; Risk; Risk Factors; Route; Sampling; Sardinia; Sensory; Series; Serum; Severity of illness; Sickle Cell Anemia; Sorting - Cell Movement; Staging; T-Lymphocyte; Testing; Thalassemia; Thyroid Diseases; Time; To specify; Uric Acid; Variant; Visit; Y Chromosome; age related; arterial stiffness; beta Thalassemia; blood lipid; cardiovascular risk factor; cell type; cellular targeting; cohort; design; disorder risk; endophenotype; exome; frailty; genetic analysis; genetic variant; genome wide association study; heart disease risk; inflammatory marker; interest; loss of function; malignant breast neoplasm; masked hypertension; monocyte; news; novel; phenome; rare variant; study population; trait; trend; whole genome

The SardiNIA study population cohort comprises over 7,000 subjects, starting at ages from 14-102, from a cluster of four towns in Sardinia. The study has been measuring >600 quantitative traits (endophenotypes or quantitative risk-related genetic or environmental factors) that can be scored on a continuous scale, and is designed as a longitudinal studies, with 4 visits over the first 15 years of its tenure. Traits of special interest include a range of cardiovascular risk factors, anthropometric measurements, blood test values, and facets of personality. Fourth visits have been completed for the study cohort to permit more incisive assessment of longitudinal trends and outcomes, as well as the assessment of additional phenotypes related to bone density and frailty as a function of age. For example, 24 hour blood pressure measurements and ECHOcardiography are extending the analysis of cardiovascular traits; hearing tests and retinograms are extending studies to sensory deficits in aging; and the cohort has been specifically extended to over 250 individuals over 92 years of age to analyze effects of extreme age. With this cohort, a variety of epidemiological and genetic factors have been identified, including recent epidemiological studies have been done of personality traits associated with white coat or masked hypertension, with circadian blood pressure patterns, or with uric acid levels; of the prevalence of chronic kidney disease and unknown thyroid disorders; and of arterial stiffness and influences of the metabolic syndrome. Full-genome scans with batteries of single-nucleotide markers were conducted, and were supplemented in the last year with full genome DNA sequencing and genotyping with specialized chips (metabochip, immunochip, and exome chip, and a chip designed to give equal coverage across the entire genome). These have provided a catalogue of over 17,000,000 variants, including a range of relatively rare variants, which are being tested for association with traits and diseases in Genome-wide association scans (GWAS). In addition, 3,500 individuals have provided lymphocyte samples for analysis (see below). GWAS pointed to genes/variants that determine a significant portion of the genetic contribution to variance for each trait and disease. In conjunction with consortium efforts on other population cohorts, including the Baltimore Longitudinal Study of Aging and the InCHIANTI study supported by the NIA, an increasing number of publications have resulted that identify genes associated with obesity, cardiovascular traits, and levels of lipids and blood components. In previous years, GWAS consortium studies have also advanced technical approaches, including the usefulness of averaging of quantitative blood pressure traits; quality control; integrative annotation of variants; and mining the human phenome using allelic scores. As for GWAS of genetic factors involved in traits and diseases, Consortium efforts in the last year have discovered variants associated with the QT interval; thyroid peroxidase antibodies and clinical thyroid disease; fibrinogen levels; and BMI in adolescents and young adults. Supporting the range and depth of results are, for example, a publication in which human demographic history was reconstructed from DNA sequences of 1,204 Y chromosomes in the cohort; a second that inferred DNA variants that control up to 80% of the variability of at least one of 95 separated immune cell types; and a third that identified a genetic locus that is associated with part of hereditary capacity for educational attainment. In a new initiative in the past two years, separation of 95 types of immune system cells was done for 3,400 individuals by flow-sorting to determine levels of general leukocyte sub-populations (B and T, natural killer, monocytes, etc.) and subclasses of T-regulatory cells, dendritic cells, and T cell maturation stages; the variation of levels of many cell types especially Tregs is up to 87% genetically determined; and GWAS analysis on 1,200 individuals with then revealed 23 with a large effect on at least one cell type. For example, the R262W SH2B3 variant, already associated with several autoimmune diseases and negative regulation of hematopoiesis, was shown to particularly affect the numbers of CD4+ T cells, likely resulting in a loss of function. In the last two years, GWAS findings with the 17.5 million SNP set have been reported for seveal traits in three Nature Genetics papers, published along with a cover and News and Views: Height -- Two new gene variants were found to have a significant effect on stature in Sardinians. Together, they appear to reduce height by 6 centimeters. Researchers found additional height-decreasing gene variants consistently across the Sardinian population that reflect an observed island effect in which large, island-dwelling mammals decrease in size over time. Lipids and Inflammation -- We identified 14 novel genetic variants associated with serum lipid levels, as well as 19 associated with inflammatory markers in the blood. Both lipid levels and inflammatory markers influence risk of heart disease. Hemoglobin -- For the first time, researchers concurrently analyzed gene regulation of A1, A2 and fetal hemoglobin levels, to see if there was any coordination in their regulation. Twenty-three associations were seen at 10 loci, including five new gene candidates. Half the variants showed associations with more than one type of hemoglobin. Hemoglobin deficiency can cause life-threatening diseases like beta-thalassemia and sickle cell anemia. In particular, genes associated with HbF levels as a modulator of thalassemia/sickle cell disease severity have been identified. In a complementary approach, cohorts of Sardinian patients and controls were assembled and genotyped for GWAS for each of several diseases, Type 1 diabetes, multiple sclerosis (MS), and breast cancer. In the past year, this has permitted the discovery of a genetic change in the gene that encodes B-cell activation factor, conferring significant risk of MS and lupus in Sardinia and elsewhere, but technically easier to find in Sardinia. In general, Sardinia provides novel alleles, often of large effect, for traits and diseases, and analyses in the immune system in particular extend associations of variants with a disease to specify the cell types in which the alleles have their effects. This provides a further step in supplying markers and potential molecular and cellular targets for possible eventual intervention.

SardiNIA 研究人口队列由来自撒丁岛四个城镇的 7,000 多名受试者组成，年龄从 14 岁到 102 岁不等。该研究测量了超过 600 个数量性状（内表型或定量风险相关遗传或环境因素），这些性状可以连续评分，并被设计为纵向研究，在其研究的前 15 年中进行了 4 次访问。特别感兴趣的特征包括一系列心血管危险因素、人体测量、血液测试值和性格的各个方面。该研究队列已完成第四次访视，以便对纵向趋势和结果进行更深入的评估，并评估与骨密度和脆弱性随年龄变化相关的其他表型。例如，24小时血压测量和超声心动图正在扩展心血管特征的分析；听力测试和视网膜图正在将研究扩展到衰老过程中的感觉缺陷；该队列已专门扩展到超过 250 名 92 岁以上的个体，以分析极端年龄的影响。 通过这个队列，已经确定了多种流行病学和遗传因素，包括最近对与白大衣或隐匿性高血压、昼夜血压模式或尿酸水平相关的人格特征进行的流行病学研究；慢性肾病和未知甲状腺疾病的患病率；以及动脉硬化和代谢综合征的影响。使用单核苷酸标记组进行了全基因组扫描，并在去年补充了全基因组 DNA 测序和专用芯片（元芯片、免疫芯片和外显子组芯片，以及旨在提供平等覆盖范围的芯片）的基因分型。整个基因组）。这些提供了超过 17,000,000 个变异的目录，包括一系列相对罕见的变异，正在全基因组关联扫描 (GWAS) 中测试这些变异与性状和疾病的关联。 此外，还有 3,500 人提供了淋巴细胞样本进行分析（见下文）。 GWAS 指出，基因/变异决定了每个性状和疾病变异的遗传贡献的很大一部分。与 NIA 支持的巴尔的摩纵向衰老研究和 InCHIANTI 研究等其他人口队列的联盟合作，越来越多的出版物已确定与肥胖、心血管特征以及脂质和血液成分水平相关的基因。 前几年，GWAS 联盟研究还提出了先进的技术方法，包括对血压定量特征进行平均的有用性；质量控制；变异的综合注释；并使用等位基因分数挖掘人类表型。 至于与性状和疾病相关的遗传因素的GWAS，联盟去年的努力发现了与QT间期相关的变异；甲状腺过氧化物酶抗体与临床甲状腺疾病；纤维蛋白原水平；以及青少年和年轻人的体重指数。例如，一份出版物支持了结果的范围和深度，其中根据队列中 1,204 条 Y 染色体的 DNA 序列重建了人类人口统计历史；第二个推断 DNA 变异控制着 95 种独立免疫细胞类型中至少一种的高达 80% 的变异性；第三个确定了与部分教育程度遗传能力相关的遗传位点。 在过去两年的一项新举措中，通过流式分选对 3,400 名个体进行了 95 种类型的免疫系统细胞的分离，以确定一般白细胞亚群（B 和 T、自然杀伤细胞、单核细胞等）的水平，以及T 调节细胞亚类、树突状细胞和 T 细胞成熟阶段；许多细胞类型尤其是 Tregs 水平的变异高达 87% 是由基因决定的；对 1,200 名个体进行 GWAS 分析，然后发现 23 名个体对至少一种细胞类型有很大影响。例如，R262W SH2B3 变体已经与多种自身免疫性疾病和造血负调节相关，并且被证明特别影响 CD4+ T 细胞的数量，可能导致功能丧失。 在过去的两年里，三篇《自然遗传学》论文中报道了 1750 万个 SNP 集的 GWAS 发现，其中涉及几个性状，并与封面和新闻与观点一起发表： 身高——发现两种新的基因变异对撒丁岛人的身高有显着影响。两者加起来似乎使身高降低了 6 厘米。研究人员发现，撒丁岛人群中始终存在额外的身高减小基因变异，这反映了观察到的岛屿效应，即居住在岛屿上的大型哺乳动物的体型随着时间的推移而减小。 脂质和炎症——我们鉴定了 14 种与血清脂质水平相关的新遗传变异，以及 19 种与血液中炎症标记物相关的遗传变异。脂质水平和炎症标志物都会影响心脏病的风险。 血红蛋白——研究人员首次同时分析了 A1、A2 和胎儿血红蛋白水平的基因调控，看看它们的调控是否存在协调。在 10 个位点上发现了 23 个关联，其中包括 5 个新候选基因。一半的变异显示与不止一种类型的血红蛋白相关。血红蛋白缺乏会导致危及生命的疾病，如β地中海贫血和镰状细胞性贫血。特别是，与 HbF 水平相关的基因已被鉴定为地中海贫血/镰状细胞病严重程度的调节剂。 采用补充方法，对撒丁岛患者和对照人群进行了组装，并针对 1 型糖尿病、多发性硬化症 (MS) 和乳腺癌等多种疾病进行了 GWAS 基因分型。去年，我们发现了编码 B 细胞激活因子的基因发生了遗传变化，从而在撒丁岛和其他地方带来了患多发性硬化症和狼疮的显着风险，但从技术上讲，在撒丁岛更容易发现。 一般来说，撒丁岛提供了新的等位基因，通常对性状和疾病有很大的影响，并且免疫系统中的分析特别扩展了变异与疾病的关联，以指定等位基因发挥作用的细胞类型。 这为提供可能的最终干预的标记物以及潜在的分子和细胞靶标提供了进一步的步骤。