Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.

Targeted Resequencing in Systemic Lupus Erythematosus Genetic Risk Loci: Initial Results from the REVEAL (Resequencing Variants Enhancing Autoimmunity and Lupus) Resource.

Gaffney1,  Patrick M., Wiley2,  Graham, Kelly2,  Jennifer A., Kaufman2,  Kenneth M., Harley3,  John B., Rai4,  Ekta, Wakeland4,  Edward K.

Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation, Oklahoma City, OK
Univ of OK Hlth Sci Ctr, Oklahoma City, OK
University of Texas Southwestern Medical Center, Dallas, TX


Genetic predisposition is a potent element in susceptibility to SLE. Previous studies by the International Consortium for Systemic Lupus Erythematosus (SLEGEN) and others have associated more than 20 genomic segments with SLE susceptibility. These studies have localized causative genes into small genomic segments, but have not identified the precise genetic variations responsible for the functional changes that cause SLE. To elucidate the genetic lesions that are causative for SLE susceptibility, we have initiated deep sequencing studies of all of the genomic segments exhibiting suggestive or significant association with susceptibility to SLE.


DNA samples for sequencing were obtained from the Lupus Family Registry and Repository (LFRR) at the Oklahoma Medical Research Foundation. Samples were ranked based on their content of SLE associated SNP haplotypes at defined susceptibility alleles and samples with the highest content of SLE-associated SNP haplotypes were prioritized for sequencing. Isolation of 86 SLE associated genomic segments was performed using either solid-phase microarray capture (Nimblegen) or solution-based capture (Agilent SureSelect) followed by sequencing on the Illumina GAIIx platform. Custom software scripts were used to de-convolute multiplexed samples, eliminate redundant reads and assess for overall sequence coverage. Polished reads were aligned to the human genome reference (hg18) and variants (SNPs and deletion/insertion polymorphisms (DIPs)) were called using CLC Genomics Workbench Software (v4.0).


We have completed sequencing of more than 100 SLE cases. Of the over 40 gigabases of total sequence reads aligning to the human genome in this study, 60–80% mapped to the targeted regions, yielding 35–45-fold average coverage. A comparison of 50 SNP genotypes previously determined in 5 samples with these sequences revealed concordance > 0.95. Further analysis of data from the first 32 European-American samples has revealed more than 2000 novel SNPs or DIPs in 2.9 megabases derived from 25 genomic segments showing significant associations with SLE. Our ongoing analysis of the organization of these polymorphisms, utilizing phylogenetic algorithms to network the SNP haplotypes formed in strong linkage disequilibrium with SNPs associated with SLE, has delineated multiple allele lineages with novel variants in haplotypes that are associated with susceptibility to SLE. These preliminary results suggest that identification of novel, potentially functional variants, in SLE-associated risk haplotypes will significantly improve our understanding of the functional changes that mediate disease susceptibility and ultimately lead to identification the precise causal variants.


We have initiated a large-scale, targeted resequencing resource (REVEAL) to identify and disseminate novel functional variants in 86 regions of SLE susceptibility. Production sequencing is currently underway with a goal of completing 600 subjects (1200 chromosomes) by the end of 2011. Public access to the REVEAL data will parallel policies similar to the ENCODE project.

To cite this abstract, please use the following information:
Gaffney, Patrick M., Wiley, Graham, Kelly, Jennifer A., Kaufman, Kenneth M., Harley, John B., Rai, Ekta, et al; Targeted Resequencing in Systemic Lupus Erythematosus Genetic Risk Loci: Initial Results from the REVEAL (Resequencing Variants Enhancing Autoimmunity and Lupus) Resource. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2146
DOI: 10.1002/art.29910

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