The SardiNIA Project

For the Project (called Progenia for the Sardinian public), this poster shows one of the participants , who lived to over 100 through a vigorous old age

 For the Project (called Progenia for the Sardinian public), this poster shows one of the participants , who lived to over 100 through a vigorous old age

Welcome to SardiNIA Project

Finding longevity genes is only one of many goals for gerontologists. An equally important mission is unraveling the genetic processes involved in age-related traits and diseases. NIA and Italian investigators are focusing their attention on the Mediterranean island of Sardinia. Why? We quote directly from the rationale and background for the initiation of the study in 2001, which also apply to follow-up studies in the course of the Project:

To identify genetic bases for prominent age-associated changes, including cardiovascular risk factors and determinants of personality traits, in a founder population. The results of the study will extend the studies of aging-associated conditions of outbred populations.

Recent reports form the Baltimore Longitudinal Study on Aging (BLSA) and other population studies have identified some epidemiological and genetic risk factors for aging-associated diseases; but the majority of studies have been observational, determining the range of values for a phenotype as a function of aging. Further examination of the genetics of aging-associated conditions such as cardiovascular and personality-related features is especially difficult because 1) they are 'late-onset' conditions, affecting older individuals; and 2) they are 'complex traits', with a number of genes individually tipping the balance toward a phenotype in one or another subgroup of an outbred population

As one way to help overcome these obstacles, attention has increasingly focused on the promise of 'founder populations' for the simplification of complex trait analysis. Such rare populations arise from a delimited group living in a defined region for many centuries with minimal admixture from outside populations. The Sardinian population is one of the few that is both numerous and accessible enough, and one of the most extreme in its relative homogeneity. It can thus be studied for a wide variety of both frequent and relatively rare traits. The targeted region for the present study, Ogliastra, has a particularly isolated population of 60,000, in an area enclosed by two mountain ranges and the sea.

The proposed study will test critically the notion that such a population can indeed help to analyze the complex vascular and personality traits proposed for the study.

Concerning the choice and progress of the Project:

    Constant environment (in rural towns)
    High level of altruism and interest in sharing genetic patrimony
    Support of the local Bishop, Mayors, and Health Authorities
    Local clinic location that facilitates rapid and repeated visits: e.g., 3,500 were recalled in 1 year for fractionation of white cells into 95 subtypes within 90 min of blood draw.
    Structures of more than 750 families embedded in a large cohort of individuals, permitting
    Accurate estimates of genetic heritability.
    Lower cost sequencing and genotyping coverage: 2,000 sequenced individuals yield the imputed DNA sequence for 7,000 in the cohort.
    Reliable detection of true DNA sequence rare variants in individuals vs. background sequencing errors by checking DNA sequence of relatives.
    Assessment of diagnostic/prognostic strength of genetic factors in a longitudinal study with medical outcomes.
    Analysis of mitochondrial variation and its transmission.
    Straightforward formulation and testing of imputation algorithms.
    Easier discovery of interactions of traits, including pleiotropy.

In a first survey, the project team recruited over 6,100 subjects from a catchment area including four towns in east-central Sardinia and assessed a first list of >200 traits. The baseline survey has been followed by follow-up visits that collected longitudinal data on the same traits collected at baseline but added assessment of frailty-related traits, namely measures of bone density and geometry, muscle strength, and gait speed, and additional cardiovascular measures (see below). In the course of SardiNIA3, along with the expansion of the cohort and the addition of more traits (see below), increases in testing efficiency and additional cost-sharing funds from Sardinian sources permit the completion of both Fourth Visits for the entire cohort and Fifth Visits for half the cohort. Also in current actions, DNA sequencing has recovered essentially all of the genetic variation in the cohort, and further arrangements for an Outcome Study have also been made (see Course of the Project).
       
The infrastructure for the clinic and phenotypic testing has been stable, with stringent quality control, which is reflected in the high quality of the database. The initial sample cohort included over 62% of the eligible population living in the region (age 14-102 years), and at least 96% of the initial cohort have all grandparents born in the same province. The initial group included 4,933 phenotyped sib pairs, 4,266 phenotyped parent-child pairs, >4,069 phenotyped cousin pairs, and >6,459 phenotyped avuncular pairs (95). Additional recruitment has increased the cohort substantially (see below), and results have shown that for essentially every trait, most of the associated genes and variants would be involved in determining variance in both young and old and in men and women. Thus, genetic analyses can draw on data from all ages and both genders.

The longitudinal study, now in its 12th year, focuses on residents of a cluster of towns to collect longitudinal information on more than 400 age-related quantitative traits ("endophenotypes" or "quantitative risk-related genetic or environmental factors") that can be scored on a continuous scale, as well as  >200 dichotomous traits (including major diseases and risk factors such as smoking). The use of quantitative traits permits the study of the entire range of allelic variation in a population, with particular interest in a range of cardiovascular risk factors, anthropometric measurements, blood test values, facets of personality, and
bone-density and frailty-related variables.

 
The longitudinal study of a broad range of phenotypes in a founder population is distinctive in this study, and stable environmental/epidemiological factors combined with the simplification of genetic analyses also aid in proposed joint investigations of relative risk. Furthermore, because we are collecting risk factor data, we can also analyze, in an Outcome Study, the prognostic power and/or pathophysiological relevance of earlier predictors for the onset of serious risk factors [e.g., increases in pulse wave velocity as a function of earlier (predictor) lipid and inflammatory markers].