Disease-specific target selection: a critical first step down the right road.
Relevance of a drug target for a disease is often inferred with strong belief but fragile evidence. Here, a program for early identification of human disease-specific drug targets using high-throughput genetic associations is described. Large numbers of well-characterized patients (>1000) and matched controls are screened for genetic associations using several thousand (>7000) single nucleotide polymorphisms from more than 1500 genes. The genes were selected because they are members of target classes for which there are precedents for high-throughput chemical screening technology. This review summarizes the methods and intensive data analyses leading to target gene identification for type 2 diabetes mellitus, including the statistical permutation methodology used to correct for many variables.
Roses
Allen D
AD
GlaxoSmithKline R&D, Research Triangle Park, NC 27709, USA. allen.d.roses@gsk.com
Burns
Daniel K
DK
Chissoe
Stephanie
S
Middleton
Lefkos
L
St Jean
Pamela
P
D001249:Asthma / Q000188:drug therapy / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D015195:Drug Design; D023281:Genomics / Q000379:methods*; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013223:Statistics as Topic; D013678:Technology, Pharmaceutical / Q000379:methods*