Governance and current state of the Project
Concerning distribution of effort in ongoing and planned work, data collection continues at the SardiNIA/ProgeNIA clinic in Lanusei, where the genotyping work at different level of resolution is also performed, and island-wide sites for the collection of disease-specific and blood bank control samples. Sequencing work is done in a joint effort at the Sardinian and U. Michigan collaborative sites.
NIA investigators, led by Dr. Schlessinger, are involved in choosing and analyzing traits and test protocols for frailty, cardiovascular, and psychological traits; in the maintenance of the master database and preparation of summaries of heritability and age- and gender-specific distributions for all traits; they also actively collaborate on immunosenescence studies performed in Sardinia; in the development of algorithms for targeted types of analyses, and in the preparation of all manuscripts.The SardiNIA investigators operating in Sardinia, led by Dr. Cucca, are the primary producers and analysts of all genetic data, including the design and coordination of the genotyping and sequencing work (in close collaboration with the University of Michigan team led by Dr. Abecasis) as well as of the phenotypic data, with the supervision of all clinical activities performed in the Center in Lanusei. They are also the primary investigators in traits and test protocols for hematological, inflammatory, immunological (both cellular and humoral), and anthropometric (including those related to internal organs) phenotypes, as well as those related to kidney function. They also participate actively in the design and analysis of cardiovascular traits, with special emphasis in Echocardiographic cardiovascular measures. They also take the lead in writing papers and obtaining grants for the traits of paramount relevance for this component of the project
The Core Project is supported by the ongoing contract from the National Institute on Aging with cost-sharing by the IRGB, aided by cost-sharing from the Italian National Research Council and awards and collaborative grants from other funding sources for specific topics. They include support for 1) extensive study of immune cells and molecules; 2) extensive DNA sequencing, with assessment of DNA methylation patterns; 3) RNA and methylation sequencing for white cells from the cohort; and 4) refined study of immune system cell types in cohort members.
Auxiliary studies that have continued to benefit from the cohort and population structure and repeated visits include analyses of human demographic history, involving the groups of Dr. John Novembre at the University of Chicago and Antonio Torroni at the Universita degli Studi di Pavia, and analyses of genetic and environmental effects on RNA levels with the team of Dr. Stephen Montgomery.
Case-control studies have concentrated on diseases strikingly common in Sardinia such as autoimmune multiple sclerosis and type 1 diabetes as well as thalassemia. They also include diseases of more global high prevalence such as common hypertension, chronic kidney disease and breast cancer.
For these case-control studies, the entire island remains the catchment to recruit enough cases from among well characterized clinical series collected by Sardinian physicians, compared with unaffected Sardinians represented by healthy blood donors collected in the main Transfusion Centers on the island.
The results of the case-control studies and those of related quantitative traits generated in the SardiNIA project are analyzed jointly to reveal coincident associations, indicative of molecules, cells and pathways primarily involved in the disease process. The results of these studies as well as those focusing on aging have the potential to translate into substantial improvement in clinical diagnosis and identification of new targets for treatment.
A complete list of the publications in whole or in part from the Project (as of January 1, 2016) is given under the PUBLICATIONS rubric at this WEB site, and is updated continuously there. The publications include epidemiological studies, mainly on cardiovascular and personality topics, and genetic studies, many of which are based mainly on this cohort and the rest from Consortia in which SardiNIA was a major contributor. The overall goals are
1) Measures of genetic variation, quantitative traits, and of longitudinal trends for traits and outcomes, focusing on the longitudinal dimension of the study, aiming at determining individual trajectories and features of the aging process, as well as the identification of longer-term health-related outcomes; and
2) Gene variation associated with phenotypic traits, prevalent diseases, and age-related trends, based on increasingly complete recovery of the range of trait variability and genetic variation in the population.
Specific Aim 1. Measures of genetic variation, quantitative traits, and of longitudinal data for traits and outcomes.
We have maintained a primary concentration on risk factors for age-related diseases and traits/risk factors. For traits, we have specifically profited from the experience in long-standing epidemiological studies at the NIA (for example, incorporating frailty-related tests), and have made trait lists concordant with the lists of traits studied in the Baltimore Longitudinal Study of Aging and the AGES and InCHIANTI studies to facilitate cross-replication and meta-analyses among the studies sponsored by the NIA.
The focus is on cardiovascular traits, personality traits, sensory capacity (retinal scans and hearing tests); levels of immune system cells, frailty-related traits (walking speed, grip strength, and bone density); and kidney ultrasound features.
Data collection has been completed for multiple sclerosis, Type1 Diabetes, and breast cancer cases and controls and efforts continue to assemble data to assess chronic kidney disease.
To identify health related events that can be correlated with genetic and environmental risk factors and their interactions, a system has been set up to ascertain major health-related outcomes. The sources of information start with the self-reports of individuals at visits, but depend more on three more reliable sources: 1) medical records from local primary care physicians (every Sardinian has a local physician); 2) an extensive database maintained by the Sardinia Region for all health and social services delivered by the health care system, including hospitalization, treatment, and all pharmaceuticals taken by each individual; and 3) death certificates on file locally.Specific Aim 2. Analyses of gene variation associated with phenotypic traits and/or prevalent diseases, and of age-related trends and outcomes.
a) Loci and gene variation associated with traits
b. Epidemiological and longitudinal trends: outcome study
With the completion of the fourth visit data analyses can start estimating age-related trajectories for most of the major traits and ask definitively 1) whether differential rates of change are predicted by polymorphisms in specific genes and 2) whether any such genes are the same that were found associated with same traits in the cross-sectional analysis. In a first example that used aggregate groups of individuals, a genetic score was generated from thirteen reported eGFR- and related loci. Both uni- and multivariable analyses were then assessed to query the relationship between clinical, ultrasound, and genetic variables with three outcomes: CKD, change in eGFR, and fast eGFR decline. Genetic risk score, in addition to classical factors, was determined to impose independent risk.