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Lindsey A. Criswell M.D., M.P.H.

Genetics and epidemiology of human autoimmune disease

Lindsey A. Criswell M.D., M.P.H.

The focus of my research program is the genetics and epidemiology of human autoimmune disease, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). My research unit has devoted substantial effort to the performance of genome wide association (GWA) and other genetics studies, which have led to the identification of over 30 genes that contribute to risk and outcome of these disorders. This work has also highlighted key biologic pathways responsible for disease onset and progression, which can inform more basic research to define the mechanism of these genetic associations. Given the heterogeneity of these disorders, we are also devoting substantial effort to the refinement of genotype-phenotype associations, such as the specificity of genetic associations for serologic or clinical subphenotypes. Several genes we have been studying, including STAT4 and TNFAIP3, are also of interest due to emerging evidence supporting their association with multiple autoimmune disorders and phenotypes. Given the strong association of the major histocompatibility complex (MHC) region with multiple autoimmune disorders, we are performing fine mapping studies of this region in order to further define the complex genetic associations of this region with SLE, RA and related phenotypes. We are also pursuing studies designed to better understand ethnic differences in autoimmune disease risk and outcome. Lastly, we have initiated several recent studies that seek to define the contribution of epigenetic factors, particularly DNA methylation patterns, to autoimmune disease risk and outcome.

Selected publications:

Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD. A genome wide association study of systemic lupus erythematosus. Nature Genetics, 2008: 40(2): 204-10.

Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira R, Pant PVK, Ballinger DG, Kosoy R, Demirci FY, Kamboh I, Kao AH, Tian C, Gunnarsson I, Bengtsson AA, Rantapää-Dahlquist S, Petri M, Manzi S, Seldin MF, Rönnblom L, Syvänen A-C, Criswell LA, Gregersen PK, Behrens TW. Association of systemic lupus erythematosus with C8orf13/BLK and ITGAM/ITGAX. The New England Journal of Medicine, 2008: 358(9): 900-9.

Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C, Chung SA, Nititham J, Hom G, Kao AH, Demirci FY, Kamboh MI, Petri M, Manzi S, Kastner DL, Seldin MF, Gregersen PK, Behrens TW, Criswell LA. Specificity of the STAT4 genetic association for severe disease manifestations of SLE. PLoS Genetics, 2008; 4 (5): e1000084.

Musone SL, Taylor KE, Lu T, Nititham J, Ferreira RC, Ortmann W, Shiffrin N, Petri MA, Kamboh MI, Manzi S, Seldin MF, Gregersen PK, Behrens TW, Ma A, Kwok P-Y, Criswell LA. Multiple Polymorphisms in the TNFAIP3 Region are Independently Associated with Systemic Lupus Erythematosus. Nature Genetics, 2008: 40 (9): 1062-4.

Kaiser R, Barton JL, Chang MN, Catanese JJ, Li YN, Begovich A, Criswell LA. Factor V Leiden and thrombosis in patients with systemic lupus erythematosus: a meta-analysis. Genes and Immunity, 2009; 10 (5): 495-502.

Chung SA, Tian C, Taylor KE, Lee AT, Ortmann WA, Hom G, Graham R, Nititham J, Kelly JA, Morrisey J, Wu H, Yin H, Alarcón-Riquelme ME, Tsao BP, Harley JB, Gaffney PM, Moser KL, Manzi S, Petri M, Gregersen PK, Langefeld CD, Behrens TW, Seldin MF, Criswell LA. Substructure in European-derived populations is associated with mucocutaneous manifestations and autoantibody production in systemic lupus erythematosus. Arthritis and Rheumatism, 2009; 60 (8): 2448-56.

Gregersen PK, Amos CI, Lee AT, Lu E, Remmers EF, Kastner D, Seldin MF, Criswell LA, Plenge RM, Holers VM, Mikuls T , Sokka T, Bridges SL, Begovich A, Siminovitch K. C-Rel, a member of the NF-ĸB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nature Genetics, 2009; 41 (7): 820-3.

Gateva V, Sandling J, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira R, Nordmark G, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jönsen A, Bengtsson A, Rantapää-Dahlqvist S, Baechler EC, Brown EE, Alarcón GS, Edberg JC, Ramsey-Goldman R, McGwin, Jr.G, Reveille JD, Vilá LM, Kimberly RP, Manzi S, Petri MA, Lee A, Gregersen PK, Seldin MF, Rönnblom L, Criswell LA, Syvänen A-C, Behrens TW, Graham RR. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1, and IL10 asnovel risk loci for systemic lupus erythematosus. Nature Genetics, 2009; 41 (11): 1228-33.

Barcellos LF, May SL, Ramsay PP, Quach H, Lane JA, Nititham J, Noble JA, Taylor KE, Quach D, Chung SA, Kelly JA, Moser KL, Behrens TW, Seldin MF, Thomson G, Harley JB, Gaffney PM, Criswell LA. High density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genetics, 2009; 5 (10): e1000696.

Richman IB, Chung SA, Taylor KE, Kosoy R, Tian C, Ortmann WA, Nititham J, Lee AT, Rutman S, Petri M, Manzi S, Behrens TW, Gregersen PK, Seldin MF, Criswell LA. European population substructure correlates with systemic lupus erythematosus endophenotypes in North Americans of European descent. Genes Immun. 2010 Sep;11(6):515-21. Epub 2009 Oct 22. PubMed PMID: 19847193.

Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT, Ortmann WA, Jacob CO, Alarcón-Riquelme ME, Tsao BP, Harley JB, Gaffney PM, Moser KL; SLEGEN, Petri M, Demirci FY, Kamboh MI, Manzi S, Gregersen PK, Langefeld CD, Behrens TW, Criswell LA. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet. 2011 Mar;7(3):e1001323. Epub 2011 Mar 3. PubMed PMID: 21408207; PubMed Central PMCID: PMC3048371.

Taylor KE, Chung SA, Graham RR, Ortmann WA, Lee AT, Langefeld CD, Jacob CO, Kamboh MI, Alarcón-Riquelme ME, Tsao BP, Moser KL, Gaffney PM, Harley JB, Petri M, Manzi S, Gregersen PK, Behrens TW, Criswell LA. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet. 2011 Feb;7(2):e1001311. Epub 2011 Feb 17. PubMed PMID: 21379322; PubMed Central PMCID: PMC3040652.

Musone SL, Taylor KE, Nititham J, Chu C, Poon A, Liao W, Lam ET, Ma A, Kwok PY, Criswell LA. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. Genes Immun. 2011 Apr;12(3):176-82. Epub 2011 Feb 17. PubMed PMID: 21326317.

Ramos PS, Criswell LA, Moser KL, Comeau ME, Williams AH, Pajewski NM, Chung SA, Graham RR, Zidovetzki R, Kelly JA, Kaufman KM, Jacob CO, Vyse TJ, Tsao BP, Kimberly RP, Gaffney PM, Alarcón-Riquelme ME, Harley JB, Langefeld CD for SLEGEN. A comprehensive analysis of shared loci between Systemic Lupus Erythematosus (SLE) and sixteen other autoimmune diseases reveals limited genetic overlap. PLoS Genetics, 2011; 7(12): e1002406. doi:10.1371/journal.pgen.1002406.

Wang J, Bansal AT, Martin M, Germer S, Benayed R, Essioux L, Lee JS, Begovich A, Hemmings A, Kenwright A, Taylor KE, Upmanyu R, Cutler P, Harari O, Marchini J, Criswell LA, Platt A. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for treatment of rheumatoid arthritis. Pharmacogenomics, 2012 Apr 10. doi: 10.1038/tpj.2012.8 [Epub ahead of print].