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.

Exome Resequencing in a Densely Affected Multigenerational SLE Pedigree.

Wiley2,  Graham, Lin2,  Chee Paul, Adrianto3,  Indra, Kelly3,  Jennifer A., Moser2,  Kathy L., Kaufman3,  Kenneth M., Harley4,  John B.

Oklahoma Med Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation
Univ of OK Hlth Sci Ctr, Oklahoma City, OK


Systemic lupus erythematosus (SLE) is a complex autoimmune disease that has heretofore been the subject of intense genetic scrutiny. While genome-wide association studies in SLE have successfully identified approximately 30 new risk loci the low odds ratios of associated loci leave a substantial portion of the estimated heritability of SLE unexplained. By comparison, the high odds ratios of highly penetrant rare polymorphisms (e.g. TREX1, OR=25) suggest the possibility that some of the missing heritability of SLE may exist in the form of rare variants.


To begin to explore the role of rare variants in SLE susceptibility we resequenced the exome in a unique, densely affected multigenerational SLE pedigree with 7 affected individuals. A densely affected pedigree was specifically chosen with the assumption that rare variations conferring higher SLE risk are more likely to be represented within such a family as opposed to the general population. The entire exonic region for the individuals within this family were captured through the use of the Agilent SureSelect sequence capture system and sequenced to 15x coverage using an Illumina GAIIx second-generation sequencer. Assembly of sequence to reference, variant calling, and other analysis were carried out using the CLC Genomics Workbench bioinformatics suite. Variants were verified with Illumina Omni1 Quad genotyping assays. Identified variants were screened using effect on protein function as determined by the SIFT algorithm.


Over 1700 coding variations were identified as shared between all case subjects within the family with approximately 40% encoding a nonsynonymous amino acid change. Of these amino acid changes approximately 7% are predicted to be damaging to the encoded protein. We have identified several nonsynonymous changes in proteins previously associated with SLE (TNIP1) as well as in loci not previously implicated in SLE including NFKBIL1 and NOTCH1.


We have identified a number of potentially rare variants that appear to preferentially segregate with case samples within a densely affected SLE pedigree. These variants, in some cases, are predicted to cause a nonsynonymous amino acid change which will damage the affected protein. Several of these damaging variants are within genes which have been previously associated with SLE while others are within associated pathways. We believe the identification of these variants may assist in the identification of causal variants as well as shed some light on missing heritability within recent GWAS studies.

To cite this abstract, please use the following information:
Wiley, Graham, Lin, Chee Paul, Adrianto, Indra, Kelly, Jennifer A., Moser, Kathy L., Kaufman, Kenneth M., et al; Exome Resequencing in a Densely Affected Multigenerational SLE Pedigree. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2144
DOI: 10.1002/art.29908

Abstract Supplement

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