Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus

Abstract

Objective: Cardiac manifestations of neonatal lupus, comprising atrioventricular conduction defects and cardiomyopathy, occur in fetuses exposed to anti-Ro/SSA antibodies, and carry substantial mortality. There is strong evidence of a genetic contribution to the risk. This study was undertaken to evaluate single-nucleotide polymorphisms (SNPs) for associations with cardiac neonatal lupus.

Methods: Children of European ancestry with cardiac neonatal lupus (n = 116) were genotyped using the Illumina 370K SNP platform and merged with 3,351 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for association with cardiac neonatal lupus were determined.

Results: The 17 most significant associations with cardiac neonatal lupus were found in the HLA region. The region near the MICB gene showed the strongest variant (rs3099844; P(dom) = 4.52 × 10(-10) , OR 3.34 [95% CI 2.29-4.89]), followed by a missense variant within C6orf10 (rs7775397; P(dom) = 1.35 × 10(-9) , OR 3.30), which lies between NOTCH4 and BTNL2, and several SNPs near the tumor necrosis factor α gene, including rs2857595 (P(add) = 1.96 × 10(-9) , OR 2.37), rs2230365 (P(add) = 1.00 × 10(-3) , OR 0.46), and rs3128982 (P(add) = 6.40 × 10(-6) , OR 1.86). Outside the HLA region, an association was detected at 21q22, upstream of the transcription regulator ets-related isoform 1 (rs743446; P = 5.45 × 10(-6) , OR 2.40). HLA notwithstanding, no individual locus previously implicated in autoimmune diseases achieved genome-wide significance.

Conclusion: These results suggest that variation near genes related to inflammatory and apoptotic responses may promote cardiac injury initiated by passively acquired autoantibodies.

Copyright © 2010 by the American College of Rheumatology.

Figures

Figure 1

Q–Q plot of the genome-wide association study of cardiac neonatal lupus. The number and magnitude of observed associations (data quantile) were compared with expectations under no association (normal quantile). Each point represents 1 single-nucleotide polymorphism (of 346,110).

Figure 2

Combined association results for the entire genome. Each point represents 1 single-nucleotide polymorphism (of 370,000) versus the P value.

Figure 3

Graphic analysis of the HLA–A and HLA–B single-nucleotide polymorphisms with P < 0.1. OR = odds ratio.