Promoter variant of PIK3C3 is associated with autoimmunity against Ro and Sm epitopes in African-American lupus patients

Abstract

The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-alpha). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34-3.73), P = 2.0 x 10(-3)]. This autoantibody profile was associated with higher serum IFN-alpha (P = 7.6 x 10(-6)). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 x 10(-5)), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients.

Figure 1

Principal component (PC) analysis including all cases and controls. A. shows the first PC (x-axis) versus the second PC (y-axis) for each subject. Each dot represents one subject and is color-coded by self-reported ancestral background (AA : African-American, His : Hispanic American, EA : European-American).

Figure 2

Distribution of the number of different autoantibody specificities in African-American SLE patients stratified by rs3813065 genotype. no. of specificities = the sum of the number of positive test results for anti-Ro, anti-La, anti-Sm, anti-RNP, and anti-dsDNA for a given subject (thus every subject is assigned a number 0 through 5). The horizontal line in the middle of the box indicates the median, boundaries of the boxes indicate the interquartile range, and the error bars show the 10th and 90th percentile, respectively. The P value for the Kruskall-Wallis test is shown.

Figure 3

Serum IFN-α activity in African-American SLE patients stratified by rs3813065 genotype and presence or absence of the anti-Ro positive/anti-Sm positive serologic phenotype. Serum IFN-α is represented in relative units on the Y-axis, as described in Methods. “Anti-Ro+/Anti-Sm+” indicates SLE patients who have positive tests for both anti-Ro and anti-Sm, and “All others” indicates all of the other SLE patients who lack one or both of these autoantibodies. Line drawn at the median and error bars show the interquartile range. P value by Mann-Whitney U test for a difference between subjects with CT genotype with versus without the anti-Ro+/anti-Sm+ serology.