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203 A mismatch repair genetic variant is linked to the development of lupus
  1. Joann B Sweasy1,
  2. Rithy Meas2,
  3. Joanne Nititham3,
  4. Kimberly Taylor3 and
  5. Lindsey Criswell4
  1. 1Yale University School of Medicine
  2. 2Yale University
  3. 3Division of Rheumatology, Department of Medicine, University of California, San Francisco
  4. 4University of California, San Francisco


Background Recent analysis of exome chip data indicates that genetic variants (GVs) in DNA repair genes are enriched in individuals diagnosed with systemic lupus erythematosus (SLE).

Methods Specifically, we analyzed 1364 single nucleotide polymorphisms (SNPs) within 41 genes that function in DNA repair. In a comparison of 1,201 SLE cases to 597 controls, corrected for ancestry, we identified 9 GVs with odds ratios (ORs) ranging from 1.1–4.6 in genes that function in mismatch repair as being significantly enriched in SLE cases versus controls. We followed up this analysis with replication studies, by analyzing a second cohort of individuals with 1298 SLE cases and 633 controls, and we were able to replicate our initial findings with full ORs ranging from 2 to 8.393.

Results One of the variants that emerged from our exome chip (eChip) studies is the MSH6 GV. This variant is a single amino acid change in the DNA binding domain of the MSH6 protein that is predicted to be damaging using the POLYPHEN algorithm. The MSH6 GV is eight times more prevalent in human SLE versus control cases after correcting for ancestry (odds ratio [OR]=8.393; p=0.0398). Remarkably, among the 2499 cases in the combined cohort, patients harboring the MSH6 GV are diagnosed with lupus 11.2 years earlier than SLE patients not harboring this allele (p=0.004). To determine if the MSH6 GV is linked to the development of lupus, we employed CRISPr/cas9 gene-editing technology to construct a mouse harboring this variant. Initial characterization of the mice shows that they develop significantly increased levels of antinuclear antibodies versus wild-type controls. Our data also suggest that the MSH6 GV identified in lupus-prone individuals results in the accumulation of mutations at A in the WA hotspot (W is A or T; adenine or thymine, respectively; A is adenine) motif. Therefore, these mutations are likely to be the result of processing of the activation induced cytidine deaminase (AID)-generated U:G mispair by the MSH2/6 complex followed by error-prone DNA synthesis by DNA polymerase eta.

Abstract 203 Figure 1

High levels of ANA in MSH6 GV mice

Conclusions Importantly, these types of mutations likely result in an overall increase in positively charged amino acids in the autoantibodies that are produced, a trait that is commonly found in anti-DNA antibodies. In summary, our results suggest that the MSH6 GV has strong potential to be associated with the development of lupus.

Funding Source(s): 5 R01 ES019179-08 ; R21 AI124055-01

The MSH6GV mice develop antinuclear antibodies at 6 months of age. +/+are WT; Mut/+are heterozygotes and Mut/Mut are homozygotes.

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