Association of Natural Killer Cell Ligand Polymorphism, HLA-C Asn80Lys, with the Development of Anti-SSA/Ro Associated Congenital Heart Block

Hannah C. Ainsworth¹, Miranda C Marion¹, Antonio Brucato², Nathalie Costedoat-Chalumeau³, Tiziana Bertero⁴, Rolando Cimaz⁵, Micaela Fredi⁶, Patrick M. Gaffney⁷, Jennifer A. Kelly⁷, Kateri Levesque⁸, Alice Maltret⁸, Nathalie Morel⁸, Véronique Ramoni⁹, Amelia Ruffatti¹⁰, Carl D Langefeld¹, Jill P. Buyon¹¹ and Robert M Clancy¹¹, ¹Wake Forest University, Winston Salem, NC, ²Ospedale Papa Giovanni XXIII, Bergamo, Italy, ³Service de médecine interne Pôle médecine, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares de l’île de France, Paris, France, ⁴Ospedale Mauriziano, Torino, Italy, ⁵Department of Paediatrics, University of Florence and Anna Meyer Children's Hospital, Florence, Italy, Florence, Italy, ⁶Department of Rheumatology and Clinical Immunology, Rheumatology and Clinical Immunology, Rheumatology and Clinical Immunology, Spedali Civili of Brescia, Brescia, Italy, ⁷Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁸Université Paris Descartes-Sorbonne Paris Cité, Paris, France, ⁹Ospedale Papa Giovanni XXIII of Bergamo, Policlinico San Matteo of Pavia, Bergamo, Pavia, Italy, ¹⁰Unità di Reumatologia, Dipartimento di Medicina-DIMED, Università di Padova., Padova, Italy, ¹¹NYU Langone Medical Center, New York, NY

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: autoimmune diseases, genetics, heart block, human leukocyte antigens (HLA) and natural killer (NK) cells

Session Information

Date: Sunday, November 5, 2017

Title: Genetics, Genomics and Proteomics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Fetal exposure to maternal anti-SSA/Ro antibodies is necessary but insufficient for the development of congenital heart block (CHB), suggesting the potential of a fetal genetic predisposition. Prior studies identified an association of HLA and CHB risk providing a possible avenue into pathogenesis involving an interactive genetic effect between 6p21 and 19q13 wherein HLA-C acts as a ligand for the checkpoint receptor killer cell immunoglobulin-like receptors (KIR). A dimorphism at position 80 in HLA-C creates two epitope subgroups, defined by their KIR interactions: C1 (Asn80) and C2 (Lys80). We tested whether C2, which binds with high affinity to an inhibitory KIR rendering an NK cell incapable of restricting inflammation, contributes to CHB.

Methods:

192 pedigrees from the US, Italy, and France (194 CHB, 91 unaffected siblings, 152 fathers, 167 mothers) and 1073 out-of-study controls were genotyped on the Immunochip single nucleotide polymorphism (SNP) microarray. There were 79 discordant CHB sibling pairs. HLA-C Asn80Lys and KIR imputation was completed. Tests for association used logistic regression, and matched analyses between affected and unaffected children employed McNemar’s test.

Results:

The C1 allele was enriched (and C2 allele reduced) in mothers compared to female controls (P=0.0014; OR=0.63). In contrast, C2 was increased in fathers compared to male controls (P=0.0123; OR=1.40). This gender-by-C2 interaction was statistically significant (P=0.0002). CHB offspring had comparable C2 frequencies to the fathers (affected offspring frequency=0.42; fathers frequency=0.45) while unaffected C2 offspring frequencies were comparable to the mothers (unaffected frequency=0.31; mothers frequency=0.29). Formal assessment of C2 differences within a pedigree showed a significant increase in the C2 allele in affected vs. unaffecteds (P=0.0027; OR=4.00). Results were comparable in the CHB discordant sibling pairs in which mothers were homozygous for C1 (n=46 pairs, P=0.07; OR=2.75). When the paired-sibling analysis was stratified by geographic region the results remained significant in each stratum (U.S. P=0.0325; OR=3.67; Europe P=0.0348; OR=4.50). There was no difference in the inhibitory KIR genotype (AA KIRs) between affected and unaffected children (P=0.55).

Conclusion:

The HLA-C–encoded supertypic epitope C2 was significantly enriched in CHB vs. unaffected offspring, establishing C2 as a novel genetic risk factor associated with disease. This observation supports a model in which anti-SSA/Ro exposed fetuses expressing C2 ligands may have impaired NK surveillance resulting in unchecked cardiac inflammation and scarring.

Disclosure: H. C. Ainsworth, None; M. C. Marion, None; A. Brucato, None; N. Costedoat-Chalumeau, None; T. Bertero, None; R. Cimaz, None; M. Fredi, None; P. M. Gaffney, None; J. A. Kelly, None; K. Levesque, None; A. Maltret, None; N. Morel, None; V. Ramoni, None; A. Ruffatti, None; C. D. Langefeld, None; J. P. Buyon, None; R. M. Clancy, None.

To cite this abstract in AMA style:

Ainsworth HC, Marion MC, Brucato A, Costedoat-Chalumeau N, Bertero T, Cimaz R, Fredi M, Gaffney PM, Kelly JA, Levesque K, Maltret A, Morel N, Ramoni V, Ruffatti A, Langefeld CD, Buyon JP, Clancy RM. Association of Natural Killer Cell Ligand Polymorphism, HLA-C Asn80Lys, with the Development of Anti-SSA/Ro Associated Congenital Heart Block [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/association-of-natural-killer-cell-ligand-polymorphism-hla-c-asn80lys-with-the-development-of-anti-ssaro-associated-congenital-heart-block/. Accessed .

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