Universal risk factors for multifactorial diseases: LifeLines: a three-generation population-based study.

Area of Science:

• Epidemiology
• Genetics
• Public Health

Background:

• Multifactorial diseases arise from universal risk factors, but individual susceptibility remains incompletely understood.
• Current research often examines single determinant-outcome relationships, neglecting the crucial role of effect modification.

Purpose of the Study:

• To present a novel model for investigating universal risk factors in multifactorial diseases, emphasizing effect modification.
• To propose a three-generation study design as optimal for dissecting genetic and environmental influences on disease risk over the life course.

Main Methods:

• The proposed model utilizes a single risk factor, a single outcome measure, and multiple effect modifiers (risk-factor, outcome, and generic modifiers).
• A three-generation study design is recommended to separate genetic and environmental factors, enabling long-term follow-up and analysis of familial transmission.
• The LifeLines study, a large-scale initiative in the Netherlands, will implement this design with 165,000 participants.

Main Results:

• The model allows for the investigation of how universal risk factors are modified, influencing individual susceptibility across different life stages.
• A three-generation design offers statistical advantages, including precision and the separation of genetic and non-genetic familial transmission.
• The LifeLines study aims to provide comprehensive data on cumulative risk factor effects over a lifetime.

Conclusions:

• Shifting research focus to effect modification of universal risk factors is crucial for understanding multifactorial diseases.
• A three-generation design is superior for studying the complex interplay of genetic and environmental factors in disease etiology.
• The LifeLines study will significantly advance our knowledge of life course epidemiology and individual susceptibility to chronic diseases.