LifeLines: a population-based study
to study disease overriding risk factors for the development of multifactorial diseases during lifetime.

Multifactorial diseases are by definition the result of multiple risk factors
that are both genetically and environmentally determined. Examples of
multifactorial diseases are depression, COPD, cancer, cardiovascular and
endocrine diseases. Together they comprise the most common disorders in
adulthood and are responsible for the use of the majority of health care
resources. Biomedical and epidemiological research on the etiology of
multifactorial diseases frequently focuses on single determinant-outcome
relations, without taking into account other risk factors, other diseases and
time dependent effects. This has been recognized over the last years, and
resulted in new study designs, sometimes referred to as "life course
epidemiology".
Multifactorial diseases may have more in common than generally recognized,
since some risk factors are associated with multiple diseases, as has been
shown for example by low birth weight. A risk factor like smoking results in
lung cancer in some individuals and myocardial infarction in others, whereas it
has a protective effect on dementia, suggesting an individual susceptibility
for specific risk factors. The individual differences that determine which
disease occurs in the presence of a given risk factor are called modifiers.
Since different diseases share identical risk factors, it is clear that a
continuing exclusive focus on associatons between single risk factors and
single outcomes will not unravel the unresolved issues of etiology and
individual prognosis of multifactorial diseases. Instead, research has to focus
on the underlying mechanisms why individuals with similar (established) risk
factors develop different diseases, i.e. the modification of the universal risk
factors for multiple disorders.

The main objective is to unravel the interaction between genetic and
environmental factors in the development of multifactorial diseases, their
concurrent development in individuals, and their complications as a complex
trait.
Which are the disease overriding risk factors which predict the development of
a multifactorial disease during lifetime? How are these universal risk factors
modified, or what determines the effect of a universal risk factor in an
individual? Specific research questions will focus on risk factors and
modifiers (genetic, environmental and combined or complex factors) for single
and multiple diseases. In addition to co-morbidity, LifeLines focuses on
co-determinants.

LifeLines is an observational cohort study in a large sample of the population
of the northern provinces of the Netherlands, covering three generations:
proband and partner (if present), parents (in law) (if alive) and children (if
applicable). This protocol only describes the study of the two oldest
generations and not the children. The part of the study concerning the children
will be separately submitted.
The study population will be followed for 30 years, in which period the
participants will be examined every 4 to 5 years, using questionnaires,
measurements (BMI, blood pressure, ECG, pulmonary function, RFFT, AGE-reader)
and blood- and urine-sampling. Methods of data collection are standardized with
other ongoing biobank studies (a.o. via an international collaboration of the
P3G consortium), which will make it possible in time to combine datasets in
order to construct larger study populations with even more statistical power,
for even less frequently occuring diseases.
The advantage of including more generations is the possibility to separate
genetic and environmental factors. This design has statistical advantages with
respect to the power and precision, multiple-level information, separation of
non-genetic and genetic familial transmission and direct haplotype assessment.
In addition, because of the inclusion of step-family members, the design
enables to quantify genetic effects. Furthermore, it opens unique possibilities
to study social characteristics (socioeconomic mobility, partner preferences,
between-generation similarities), and offers practical benefits (lower
non-response).
A cohort studie, in contrast to a case-control study, enables the prospective
investigation of risk factors, which is crucial in the study of environmental
and other time-varying exposures, as well as interactions between environmental
factors. For genetic studies, a case-control desing is often more appropriate,
but in such a design it is virtually impossible to investigate gene-environment
interactions.

Participants of the study will have to fill in several questionnaires.
Furthermore, their length, weight, waist and hip circumferences and blood
pressure will be measured. Their pulmonary function will be tested, an ECG
performed, the autofluorescence of the skin will be measured with a
non-invasive AGE-reader, and two psychological tests will be taken. Also, we
will ask them to collect urine, and have a blood sample taken. The main results
of these tests will be sent to the participants and their general
practitioners, so that measures can be taken if necessary. There are no risks
involved.