Genome-wide association study of cardiac manifestations of neonatal lupus identifies risk variants in the ERG, TCF19,C6orf10 and MICB-TNF-AIF1 region

Abstract

Objectives: Isolated congenital heart block (CHB) is highly associated with maternal anti-Ro/SSA antibodies. CHB carries a substantial mortality, approaching 30%, and morbidity, with over 60% of surviving affected children requiring lifelong pacemakers. To date, complete atrioventricular (AV) block is irreversible. This is a rare disease and factors beyond requisite maternal autoantibody are unknown. Data from twin studies and the 10-fold increased recurrence rate of cardiac neonatal lupus (NL) in subsequent pregnancies indicate a strong genetic contribution to risk. We posit that fetal genes influence the response to maternal autoantibodies. Methods: Children of European ancestry (n=116) with cardiac NL were identified from the U.S. Research Registry for Neonatal Lupus. Cases were genotyped using the Illumina 370K SNP platform and merged with 3351 controls from the International Consortium on Systemic Lupus Erythematosus Genetics (SLEGEN). Standard quality control and admixture-adjusted tests of association were computed. Results: Outside the HLA region, a strong association was detected at 21q22, upstream from the transcriptional regulator ERG (rs743446, p=5.45E-06, OR = 2.40). Within the HLA, associated regions include PSORS1C1 (rs3130544, p = 1.94E-07, OR = 2.77) and a missense mutation (proline to serine) at TCF19 (rs7750641, p = 1.58E-07, OR = 2.79), at Class I; several variants in the MICB-NFKBIL1- LTA-TNF-LTB-AIF1 region at Class III (rs2230365, p= 1.00E-03, OR=0.46; rs2857595, p= 1.96E-09, OR = 2.37; rs3128982, p= 6.40E-06, OR=1.86; and rs3099844, p= 4.52E-10, OR= 3.34; and the C6orf10 locus at class II (rs3115553, p=2.69E-05, OR=1.81; rs6457536, pa=1.74E-05, OR=1.84; and rs7775397 (p = 1.35E-09, OR=3.30). These are consistent with our previous results (Clancy 2002). With the exception of the HLA region, no loci previously implicated in autoimmune diseases achieved genome-wide significance in the CHB children. Conclusion: These results suggest that genetic variation near ERG, PSORS1C1, LTA/TNF/LTB and C6orf10 in the fetus may promote an abnormal tissue response initiated by exposure to maternal autoantibodies. Identification of risk loci is an incremental step towards discovery of a fetal genetic component that contributes to the anti-SSA/Ro associated development of life-long cardiac damage.