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

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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; Pdom = 4.52 × 10−10, OR 3.34 [95% CI 2.29–4.89]), followed by a missense variant within C6orf10 (rs7775397; Pdom = 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 (Padd = 1.96 × 10−9, OR 2.37), rs2230365 (Padd = 1.00 × 10−3, OR 0.46), and rs3128982 (Padd = 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.