Identification of Candidate Loci at 6p21 and 21q22 in a Genome-Wide Association Study of Cardiac Manifestations of Neonatal Lupus

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 x 10(-10), OR 3.34 [95% CI 2.29-4.89]), followed by a missense variant within C6orf10 (rs7775397; P(dom) = 1.35 x 10(-9), OR 3.30), which lies between NOTCH4 and BTNL2, and several SNPs near the tumor necrosis factor alpha gene, including rs2857595 (P(add) = 1.96 x 10(-9), OR 2.37), rs2230365 (P(add) = 1.00 x 10(-3), OR 0.46), and rs3128982 (P(add) = 6.40 x 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 x 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.