The Genetic Basis of Complex Human Disease: Extending the Utility of Twin Studies (P05.123)

Abstract

Objective: To develop a mathematical Model that uses readily-available epidemiological data to provide quantitative estimates for many parameters, associated with disease-pathogenesis, that cannot be directly-observed. Background Disease-pathogenesis generally involves both environmental-events and genetic-risk, although quantifying each influence is difficult. Design/Methods: We define the subsets of genetically-susceptible individuals (G); women (F); men (M); and carriers (HLA+), carriers of one-copy (1HB+), carriers two-copies (2HB+), and non-carriers (HLA–) of the DRB1*1501 allele. We assume only that mono-zygotic (MZ)-twins are genetically similar to the general-population and that the probability of a person9s co-twin developing MS {P(MZ MS )} is equal to P(MS). Results: Using the example of multiple sclerosis (MS) and these definitions, we can conclude that:0.019≤P(G)≤0.0220.94≤P(G l MS)≤10.044≤P(G l HLA+)≤0.0490.012≤P(G l HLA–)≤0.0140.039≤P(G l 1HB+)≤0.0450.122≤P(G l 2HB+)≤0.1400.010≤P(G l F)≤0.0130.025≤P(G l M)≤0.0310.28≤P(F l G)≤0.480.52≤P(M l G)≤0.720.54≤P(HLA+ l G)≤0.55P(2HB+ l G)∼0.100.15≤P(MS l F,G)≤0.180.031≤P(MS l M,G)≤0.034P(MS l G,2HB+)∼P(MS l G,1HB+)∼P(MS l G,HLA–)∼P(MS l G)0.067≤P(MS l G)≤0.077And, furthermore, we conclude that:1. For practical purposes, purely-genetic MS does not exist (i.e., specific environmental-triggers are always necessary).2. For most susceptible-individuals (∼59%), the DRB1*1501 allele, even when present, doesn9t contribute to susceptibility.3. Each DRB1*1501 allele and each “(HLA–) allele” impacts susceptibility independently.4. The mean allelic frequency of DRB1*1501 in MS-women is consistently greater than in MS-men. This imbalance is primarily due to gender-differences the in the composition of the subset (G). Conclusions: These conclusions demonstrate that easily-obtained epidemiological data can provide considerable insight to the nature of the genetic and environmental bases of complex human diseases. Disclosure: Dr. Goodin has received personal compensation for activities with Merck Serono, Novartis, Berlex Laboratories, Bayer Pharmaceuticals Corporation, Biogen Idec, Schering AG and Teva Neuroscience as speaker, consultant and participant in clinical trials. Dr. Goodin has received research support from Novartis.