Validating therapeutic targets through human genetics, Robert M. Plenge, Edward M. Scolnick and David Altshuler. Nature Reviews Drug Discovery. 2013 Aug;12(8):581-94. doi: 10.1038/nrd4051. Epub 2013 Jul 19. PMID: 23868113
We describe a strategy to use human genetics as a powerful tool to validate therapeutic targets for drug discovery. We frame the concept of “genotype-phenotype dose-response curves”.View article PDF
Human genetics in rheumatoid arthritis guides of high-throughput drug screen of the CD40 signaling pathway, Li G, Diogo D, Wu D, Spoonamore J, Dancik V, Franke F, Kurreeman F, Rossin EJ, Duclos G, Hartland C, Zhou X, Li K, Liu J, De Jager PL, Siminovitch KA, Zhernakova A, Raychaudhuri S, Bowes J, Eyre S, Padyukov L, Gregersen PK, Worthington J, Rheumatoid Arthritis Consortium International (RACI), Gupta N, Clemons PA, Stahl E, Tolliday N, Plenge RM. PLoS Genetics. 2013 May, in progress.
We demonstrate how to leverage human genetics for drug discovery. Genetics of risk of RA points to a pathway (CD40-CD40L signaling) and a HTS assay (NF-kB luciferase-reporter in a B cell line), which was used in a pilot small molecule drug screen at the Broad Institute.
Rare, Low-Frequency, and Common Variants in the Protein-Coding Sequence of Biological Candidate Genes from GWAS Contribute to Risk of Rheumatoid Arthritis, Diogo D, Kurreeman F, Stahl EA, Liao KP, Gupta N, Greenberg JD, Rivas MA, Hickey B, Flannick J, Thomson B, Guiducci C, Ripke S, Adzhubey I, Barton A, Kremer JM, Alfredsson L; Consortium of Rheumatology Researchers of North America; Rheumatoid Arthritis Consortium International, Sunyaev S, Martin J, Zhernakova A, Bowes J, Eyre S, Siminovitch KA, Gregersen PK, Worthington J, Klareskog L, Padyukov L, Raychaudhuri S, Plenge RM. Am J Hum Genet. 2013 Jan 10;92(1):15-27. Epub 2012 Dec 20. PMID: 23261300
We provide evidence that protein-coding variants from GWAS identified by GWAS contribute to risk of RA independent from non-coding variants discovered by GWAS. The same approach can be used to identify an allelic series that could be useful in identifying drug targets.
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C, Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, Davila S, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; Wellcome Trust Case Control Consortium, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Arlsetig L, Martin J, Rantapää-Dahlqvist S, Plenge RM*, Raychaudhuri S*, Klareskog L*, Gregersen PK*, Worthington J*. Nat Genet. 2012 Dec;44(12):1336-40. PMID: 23143596 *contributed equally
The “iChip” manuscript – we use data from Illumina’s Immunochip (iChip) to discover 14 new RA risk loci, as well as fine-map existing risk loci. One new RA risk locus is contains the gene IL6R (the protein product of IL6R is the target of the drug tocilizumab), which further emphasizes that concept genetics can identify drug targets.
Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, Gianniny L, Korman BD, Padyukov L, Kurreeman FA, Chang M, Catanese JJ, Ding B, Wong S, van der Helm-van Mil AH, Neale BM, Coblyn J, Cui J, Tak PP, Wolbink GJ, Crusius JB, van der Horst-Bruinsma IE, Criswell LA, Amos CI, Seldin MF, Kastner DL, Ardlie KG, Alfredsson L, Costenbader KH, Altshuler D, Huizinga TW, Shadick NA, Weinblatt ME, de Vries N, Worthington J, Seielstad M, Toes RE, Karlson EW, Begovich AB, Klareskog L, Gregersen PK, Daly MJ, Plenge RM. Nat Genet. 2008 Oct;40(10):1216-23. PMID: 18794853.
This study represents one of the first GWAS meta-analysis for RA, leading to the discovery of the CD40 risk locus. We have further evaluated CD40 signaling as a drug target.