Genome-wide association study of cardiac manifestations of neonatal lupus identifies candidate loci at 6p21 and 21q22

Clancy RM, Marion MC, Kaufman KM, Ramos PS, Adler A; Slegen, Harley JB, Langefeld CD, Buyon JP.

Department of Medicine, New York University Langone School of Medicine, Wake Forest University Health Sciences.

Abstract

OBJECTIVE: Cardiac manifestations of neonatal lupus (NL) comprising atrioventricular conduction defects and cardiomyopathy, occur in fetuses exposed to anti-SSA/Ro antibodies, and carry substantial mortality. There is strong evidence of a genetic contribution to the risk.

METHODS: Cardiac- NL children of European ancestry (n=116) were genotyped using the Illumina 370K SNP platform and merged with 3351 controls.

RESULTS: The seventeen most significant associations with cardiac NL reside in the HLA region. The region near the MICB gene shows the strongest variant (rs3099844, pdom = 4.52 x 10(-10), OR=3.34 (2.29-4.89)), followed by a missense variant within C6orf10 (rs7775397, pdom =1.35x10(-9), OR=3.30), which lies between NOTCH4 and BTNL2, and several SNPs near the TNFalpha gene (rs2857595, padd =1.96x10(-9), OR=2.37; rs2230365, padd =1.00x10(-3), OR=0.46; rs3128982, padd = 6.40 x 10(-6), OR=1.86). Outside HLA, an association was detected at 21q22, upstream from the transcriptional regulator ERG (rs743446, p=5.45x10(-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.

PMID: 20662065

If you are interested in participating in this study or simply want more information, please contact Zoey Smith at: zoey.smith@nyumc.org or call 212-263-2255.

Preventive IVIG Therapy for Congenital Heart Block (PITCH Study)
Sponsored through peer reviewed grant from the Alliance for Lupus Research

PITCH study has concluded and is closed to enrollment.

Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial.

Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, Cummiskey K, Dooley MA,
Foley J, Graves C, Hendershott C, Kates R, Komissarova EV, Miller M, Paré E, Phoon CK,
Prosen T, Reisner D, Ruderman E, Samuels P, Yu JK, Kim MY, Buyon JP.

New York Medical College, Valhalla, NY, USA.

Abstract

OBJECTIVE: The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.

METHODS: A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB.

RESULTS: Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.

CONCLUSION: This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

PMID: 20391423

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For more information, please contact:

Jill P. Buyon, M.D., Rheumatologist
212-263-0746
jill.buyon@nyumc.org

Deborah M. Friedman, M.D., Pediatric Cardiologist
914-594-4370

deborah_friedman@nymc.edu

Thank you for your cooperation, and we look forward to hearing from you.

Jill P. Buyon, M.D.
Deborah M. Friedman, M.D.