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Abstract Number: 2955

The Impact of Northern European Ancestry and Susceptibility Loci on the Risk of Lupus Nephritis

Sarah French1, Kimberly E. Taylor2, Sharon A. Chung1, Joanne Nitiham3, Michelle Petri4, Peter K. Gregersen5, Ward Ortmann6, Annette T. Lee7, Timothy W. Behrens6, Susan Manzi8, F. Yesim Demirci9, M. Ilyas Kamboh10, Robert R. Graham6, Michael F. Seldin11 and Lindsey A. Criswell3, 1School of Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, 2Department of Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, 3Medicine, University of California, San Francisco, Rosalind Russell / Ephraim P. Engleman Rheumatology Research Center, San Francisco, CA, 4Johns Hopkins University School of Medicine, Baltimore, MD, 5Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, 6ITGR Human Genetics, Genentech, Inc., South San Francisco, CA, 7Genomics & Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, 8Division of Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 9University of Pittsburgh, Pittsburgh, PA, 10Human Genetics, University of Pittsburgh, Pittsburgh, PA, 11Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: genetics and lupus nephritis, SLE

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Session Information

Session Title: Genetics, Genomics and Proteomics II: Genetics of Autoimmunity

Session Type: Abstract Submissions (ACR)

Background/Purpose

Lupus nephritis (LN) has a higher prevalence among African Americans, Hispanics, and Asians compared to Caucasians. Significant differences in SLE severity also exist within continental groups, with northern European genetic ancestry conferring protection against autoantibody production and renal disease, which we have previously shown to be independent of socioeconomic status (SES). The goal of our study was to test whether the effect of northern European ancestry is mediated by known SLE risk alleles or recently identified LN susceptibility loci.

Methods

We studied 1142 SLE patients from four independent case collections with genotype data obtained from a previous genome-wide association study (GWAS). A set of continental and intra-European ancestry informative markers (AIMs) was analyzed using the program STRUCTURE to define percent European and northern European ancestry. Subjects with <90% European ancestry were excluded. Multivariate logistic regression of LN risk was performed including percent northern European and other covariates (Table 1). Susceptibility loci were incorporated as potential mediators of the effect of genetic ancestry on the risk of LN. Forty-nine established SLE susceptibility loci and 12 single nucleotide polymorphisms (SNPs) with the strongest association with LN in a recent renal GWAS of SLE subjects were tested for association with LN. A p<0.05 was required for SNPs in multivariate logistic regression with other putative risk SNPs to be included in the model of LN risk. A polygenic risk score (PRS), a statistical method for calculating the effect of many common variants in aggregate, was generated from a random 2/3 of individuals using the program PLINK to select 12,935 SNPs with evidence of cumulative association with LN (p<0.05).

Results

The overall rate of LN in the study population was 27.3%. A 25% increase in the proportion of northern European ancestry was associated with a 16% reduction in the odds of having renal disease, after adjustment for disease duration and gender (OR 0.84, 95% CI 0.72-0.99, p=0.04). Two previously reported SLE susceptibility loci (BANK1, HLA-DR3) and 7 of 12 LN risk SNPs were significantly associated with LN in our dataset. Adjustment for all 9 putative LN susceptibility loci did not substantially alter the association between northern European ancestry and LN (Table 1). Exploratory analyses incorporating the PRS were underpowered in our study but suggested that a more comprehensive set of genetic variants, as captured by the PRS, may explain more of the effect of Northern European ancestry on the risk of LN.

Conclusion

Northern European ancestry has a significant protective effect for renal disease among SLE patients of European ancestry; this appears to be independent of currently known SLE risk alleles and LN susceptibility loci, but may be partially explained by a PRS.


Disclosure:

S. French,
None;

K. E. Taylor,
None;

S. A. Chung,
None;

J. Nitiham,
None;

M. Petri,
None;

P. K. Gregersen,
None;

W. Ortmann,

Genentech Inc.,

3;

A. T. Lee,
None;

T. W. Behrens,

Genentech Inc.,

3;

S. Manzi,
None;

F. Y. Demirci,
None;

M. I. Kamboh,
None;

R. R. Graham,

Genentech Inc.,

3;

M. F. Seldin,
None;

L. A. Criswell,
None.

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