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: 8736589
• 负责人: David Schlessinger
• 金额: $ 55.08万
• 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/8736589
• 关键词: Affect; Age; Age-Years; Aging; Alleles; Autoimmune Diseases; Baltimore; Bibliography; Biochemical; Blood Pressure; Blood Tests; Bone Density; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cataloging; Catalogs; Cell Maturation; Cells; Cholesterol; Clinical; Cohort Studies; DNA; DNA Sequence; Dendritic Cells; Disease; Early Diagnosis; Echocardiography; Environment; Environmental Risk Factor; Epidemiological Factors; Event; Family; Genes; Genetic; Genetic Variation; Genome; Genome Scan; Genotype; Goals; Hematopoiesis; Hour; Human; Immune; Immune system; Incidence; Individual; Inherited; Insulin-Dependent Diabetes Mellitus; Intervention; Leukocytes; Life; Longitudinal Studies; Lymphocyte; Measurement; Measures; Molecular Target; Multiple Sclerosis; Nucleotides; Obesity; Outcome; Overweight; Patients; Personality; Phenotype; Population; Population Study; Publications; Recording of previous events; Regulation; Regulatory T-Lymphocyte; Risk; Risk Factors; Route; Sampling; Sardinia; Series; Severity of illness; Sickle Cell Anemia; Sorting - Cell Movement; Staging; T-Lymphocyte; Testing; Thalassemia; Time; To specify; Variant; Visit; Weight; Y Chromosome; age related; blood lipid; cardiovascular risk factor; cell type; cellular targeting; cohort; design; disorder risk; endophenotype; exome; frailty; genetic analysis; genome wide association study; interest; loss of function; malignant breast neoplasm; monocyte; trait; trend

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 >300 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 13 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 are now in progress for the study cohort to permit the 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; and the cohort is being specifically extended to over 250 individuals over 92 years of age to analyze effects of extreme age. With this cohort, 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, 1,000 individuals have provided lymphocyte samples for analysis (see below). In studies thus far, GWAS have pointed to genes/variants that determine a significant portion of the genetic contribution to variance for each trait and disease studied. 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 particular, genes associated with HbF levels as a modulator of thalassemia/sickle cell disease severity have been identified, as well as findings of genetic factors determining loci for blood pressure, many affecting adiposity; and personality facets affecting under- and over-weight (see bibliography for a complete list). Supporting the range and depth of results are 3 of the most recent publications: in one, human demographic history was reconstructed from DNA sequences of 1,204 Y chromosomes in the cohort; a second inferred DNA variants that control up to 80% of the variability of at least one of 95 separated immune cell types; and a third identified a genetic locus that is associated with part of hereditary capacity for educational attainment. In an additional new initiative in the past year, 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 the 12,500,000 SNP set 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 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. GWAS with approximately 6.6 million SNPs in over 3,000 patients and 3,500 controls identified CBLB as associated with MS. CBLB involvement in MS was technically easier to find in Sardinia, but has now been widely replicated in other patient cohorts. Our analyses 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研究人群队列包括来自撒丁岛四个城镇的7，000多名受试者，年龄从14-102岁开始。该研究已经测量了超过300个数量性状（内表型或定量风险相关的遗传或环境因素），可以在连续量表上进行评分，并被设计为纵向研究，在其任期的前13年内进行了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，血液测试值和个性方面。研究队列的第四次访视正在进行中，以评估纵向趋势和结局，以及评估与骨密度和脆弱性相关的其他表型作为年龄的函数。例如，24小时血压测量和超声心动图正在扩展对心血管特征的分析;该队列正在特别扩展到超过250名92岁以上的人，以分析极端年龄的影响。 在这个队列中，使用单核苷酸标记电池进行了全基因组扫描，并在去年补充了全基因组DNA测序和专用芯片的基因分型（代谢芯片，免疫芯片和外显子组芯片，以及设计用于在整个基因组中提供相等覆盖的芯片）。这些研究提供了超过17，000，000种变异的目录，包括一系列相对罕见的变异，这些变异正在全基因组关联扫描（GWAS）中进行与性状和疾病的关联测试。 此外，1 000人提供了淋巴细胞样本供分析（见下文）。 在迄今为止的研究中，GWAS已经指出了决定所研究的每个性状和疾病的遗传方差的重要部分的基因/变异。与其他人群队列的联盟努力相结合，包括巴尔的摩老龄化纵向研究和由NIA支持的InCHIANTI研究，越来越多的出版物鉴定了与肥胖、心血管特征、血脂和血液成分水平相关的基因。特别是，已经确定了与HbF水平相关的基因作为地中海贫血/镰状细胞病严重程度的调节剂，以及确定血压基因座的遗传因素的发现，许多影响肥胖;以及影响体重不足和超重的个性方面（完整列表见参考书目）。支持结果的范围和深度的是3个最近的出版物：在一个，人类人口统计学史是从队列中1,204个Y染色体的DNA序列重建的;第二个推断的DNA变异控制了95个分离的免疫细胞类型中至少一个的变异性高达80%;第三个人发现了一个与教育程度的遗传能力有关的遗传位点。 在过去一年的另一项新举措中，通过流式分选对3 400人的95种免疫系统细胞进行了分离，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、树突状细胞和T细胞成熟阶段的亚类;许多细胞类型尤其是T细胞的水平变化高达87%是由遗传决定的;对具有12，500，000个SNP集的1，200个个体的GWAS分析随后揭示了23个对至少一种细胞类型具有较大影响。例如，已经与几种自身免疫性疾病和造血负调控相关的R262 W SH 2B 3变体被证明特别影响CD 4 + T细胞的数量，可能导致功能丧失。 在一种互补的方法中，撒丁岛患者和对照组的队列被组装并对几种疾病中的每一种进行GWAS基因分型，1型糖尿病，多发性硬化症（MS）和乳腺癌。GWAS在超过3，000名患者和3，500名对照中发现了约660万个SNP，将CBLB确定为与MS相关。在撒丁岛，CBLB参与MS在技术上更容易找到，但现在已在其他患者队列中广泛复制。 我们的分析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。 这为可能的最终干预提供了进一步的标志物和潜在的分子和细胞靶点。