Genomewide Association Study of HLA Alloimmunization in Previously Pregnant Blood Donors

Overview

Journal Transfusion

Specialty Hematology

Date 2017 Nov 24

PMID 29168253

Citations 1

Authors

Mark Seielstad

Grier P Page

Nathan Gaddis

Marion Lanteri

Tzong-Hae Lee

Ram Kakaiya

Lisa F Barcellos

Lindsey A Criswell

Darrell Triulzi

Philip J Norris

Michael P Busch

Affiliations

Soon will be listed here.

Abstract

Background: Alloimmunization through blood transfusion, transplantation, or circulating fetal cells during pregnancy is a significant concern. Some exposed individuals make alloantibodies while others do not, implying variation in genetic risk factors.

Study Design And Methods: We conducted a genomewide association study (GWAS) of 9,427,497 single-nucleotide polymorphisms (SNPs) to identify genetic variants for HLA alloimmunization in previously pregnant blood donors with (n = 752) and without (n = 753) HLA Class I or II alloantibodies.

Results: A SNP in the neurexophilin 2 (NXPH2) gene surpassed genome-wide significance (p = 2.06 × 10 ), with multiple adjacent markers p < 10 , for women with anti-Class I alloantibodies only. Little is currently known about the function of NXPH2, although gene family members have been shown to impact immunity. SNPs in the E2F7 gene, a transcription factor related to cell cycle control and cellular proliferation, also approached genomewide significance (p = 2.5 × 10 ).

Conclusion: Further work to extend the GWAS approach and to characterize variants in NXPH2 and E2F7 in the context of alloantibody formation is warranted.

Citing Articles

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References

Brantley S, Ramsey G . Red cell alloimmunization in multitransfused HLA-typed patients. Transfusion. 1988; 28(5):463-6. DOI: 10.1046/j.1537-2995.1988.28588337338.x. View

Schonewille H, Haak H, van Zijl A . Alloimmunization after blood transfusion in patients with hematologic and oncologic diseases. Transfusion. 1999; 39(7):763-71. DOI: 10.1046/j.1537-2995.1999.39070763.x. View

Heal J, Phipps R, Blumberg N . One big unhappy family: transfusion alloimmunization, thrombosis, and immune modulation/inflammation. Transfusion. 2009; 49(6):1032-6. DOI: 10.1111/j.1537-2995.2009.02182.x. View

Villegas V, Zaphiropoulos P . Neighboring gene regulation by antisense long non-coding RNAs. Int J Mol Sci. 2015; 16(2):3251-66. PMC: 4346893. DOI: 10.3390/ijms16023251. View

de Bruin A, Maiti B, Jakoi L, Timmers C, Buerki R, Leone G . Identification and characterization of E2F7, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem. 2003; 278(43):42041-9. DOI: 10.1074/jbc.M308105200. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Di Stefano L, Jensen M, Helin K . E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes. EMBO J. 2003; 22(23):6289-98. PMC: 291854. DOI: 10.1093/emboj/cdg613. View

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View

Gatault P, Jollet I, Rabot N, Boulanger M, Taupin J, Barbet C . Mothers without HLA antibodies before transplantation have a low risk of alloimmunization post-transplantation. Tissue Antigens. 2011; 78(4):241-8. DOI: 10.1111/j.1399-0039.2011.01757.x. View

10.

Bruder D, Probst-Kepper M, Westendorf A, Geffers R, Beissert S, Loser K . Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol. 2004; 34(3):623-630. DOI: 10.1002/eji.200324799. View

11.

Missler M, Hammer R, Sudhof T . Neurexophilin binding to alpha-neurexins. A single LNS domain functions as an independently folding ligand-binding unit. J Biol Chem. 1998; 273(52):34716-23. DOI: 10.1074/jbc.273.52.34716. View

12.

Blumberg N, Heal J, Gettings K . WBC reduction of RBC transfusions is associated with a decreased incidence of RBC alloimmunization. Transfusion. 2003; 43(7):945-52. DOI: 10.1046/j.1537-2995.2003.00443.x. View

13.

Higgins J, Sloan S . Stochastic modeling of human RBC alloimmunization: evidence for a distinct population of immunologic responders. Blood. 2008; 112(6):2546-53. DOI: 10.1182/blood-2008-03-146415. View

14.

Jackman R, Deng X, Bolgiano D, Lebedeva M, Heitman J, Busch M . Low-level HLA antibodies do not predict platelet transfusion failure in TRAP study participants. Blood. 2013; 121(16):3261-6. PMC: 3630837. DOI: 10.1182/blood-2012-12-472779. View

15.

Slichter S . Platelet refractoriness and alloimmunization. Leukemia. 1998; 12 Suppl 1:S51-3. View

16.

King A, Boocock C, Sharkey A, Gardner L, Beretta A, Siccardi A . Evidence for the expression of HLAA-C class I mRNA and protein by human first trimester trophoblast. J Immunol. 1996; 156(6):2068-76. View

17.

Vichinsky E, Earles A, Johnson R, HOAG M, Williams A, Lubin B . Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Engl J Med. 1990; 322(23):1617-21. DOI: 10.1056/NEJM199006073222301. View

18.

Yazer M, Triulzi D, Shaz B, Kraus T, Zimring J . Does a febrile reaction to platelets predispose recipients to red blood cell alloimmunization?. Transfusion. 2009; 49(6):1070-5. DOI: 10.1111/j.1537-2995.2009.02116.x. View

19.

Kinzfogl J, Hangoc G, Broxmeyer H . Neurexophilin 1 suppresses the proliferation of hematopoietic progenitor cells. Blood. 2011; 118(3):565-75. PMC: 3142901. DOI: 10.1182/blood-2010-12-325381. View

20.

Morris A, Riley J, Fleming W, Boss J . MHC class II gene silencing in trophoblast cells is caused by inhibition of CIITA expression. Am J Reprod Immunol. 1999; 40(6):385-94. DOI: 10.1111/j.1600-0897.1998.tb00423.x. View