LLAS: Large Lupus Association Study An article by Jennifer Kelly, M.P.H., Data Analyst Originally Published in the study's annual Newsletter: Lupus Linkage , vol XII, 2007 Updated for website posting March 2008
Lupus genetics is on the verge of being completely transformed. We have just conducted the largest genetic experiment performed in lupus to date. In fact, it is even one of the largest carried out in a complex disease. This experiment is the product of more than 15 years of lupus research and its goals are more than ten-fold greater than our goals of only two years ago.
This experiment was a major collaborative effort with other lupus researchers around the world. We have come together with our individual knowledge and intuitions about what genes are involved in SLE to perform this one experiment. It came at a time when the genomic technologies, our SLE patient collections, and the progress to this point intersect for explosive progress. We evaluated ~22,000 single nucleotide polymorphisms (SNPs) in 12,043 participants with SLE and unrelated participants without SLE, generating greater than 252 million genotypes. We have begun to evaluate the known and suspected candidate genes for their potential to cause SLE, particularly with regard to the variables that influence the genetic association (genetic effects that occur in lupus patients) including sex, race, clinical criteria, autoantibodies, and other genetic effects. In fact, the Lupus Genetics Studies, in cooperation with the International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) and other lupus scientists, recently published some results from the LLAS in a paper in Nature Genetics (Feb. 2008) documenting the genetic association of four new lupus-linked chromosomal regions (16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269)). This paper also found evidence for association of three other previously-known lupus- and autoimmune disease-linked regions (FCGR2A, PTPN22 and STAT4) and indicated nine or more additional areas of the human genome that may predispose to lupus.
To give you an idea of the scope of this experiment, between 1992 and 2005 we performed 343 genotypes per day. In 2005-2006 we performed approx. 19,000 genotypes per day. This experiment produced over 1 million genotypes per day at a more than 200-fold decrease in specific unit costs and a more than 1000-fold increase in the rate of data generation.
Our goal in this work is to bring the new genetic revolution to SLE. The infrastructure (the samples, the clinical data, the inventory systems, the data management informatics, the analysis capabilities, and the commitment to the project) are all in place at the Oklahoma Medical Research Foundation to be successful in this endeavor. We hope to have the maximum impact possible upon the generation of new understanding of the genetics of SLE. The capacity to identify genetic subsets and tailor pharmaceutics is unparalleled. In sum, the significance of the advances made will be substantial and fundamental.
Definitions of Terms:
International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H, Baechler EC, Li QZ, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA. “Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci.” Nat Genet. 2008 Jan; 40(2):204-10.
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