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Inhibitory KIR2DL2 Gene: Risk for Deep Endometriosis in Euro-descendants

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Abstract

Endometriosis (EDT) is an inflammatory disease characterized by implantation/growth of endometrial tissue, glands, and/or stroma, outside the uterus. Reduced NK cell cytotoxic activity has been implicated in its pathogenesis, together with other immunologic alterations. We investigated the influence of KIR gene polymorphisms and their HLA ligand combinations in deep endometriosis (DE) susceptibility. One hundred sixty women with a histological diagnosis of DE and 202 control women without the disease, who underwent laparoscopy, were enrolled. The DE group was subdivided into initial (I/II; n = 60) and advanced stages (III/IV, n = 100). KIR and HLA class I gene polymorphisms were typed by PCR-SSP and sequence-based-typing (SBT), respectively. We observed a significant association of KIR2DL2, an inhibitory gene of B haplotype, conferring risk for DE in Euro-descendants. Positive associations of Bx haplotype and centromeric AB segments were also found. However, no association with KIR-HLA ligand combination was observed. Our data suggest KIR2DL2 gene to be a relevant factor favoring NK inhibition in DE in Euro-descendants, contributing to the defective NK cytotoxic activity and impaired clearance of ectopic endometrial cells in the disease.

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Acknowledgments

The authors thank Danilo Augusto Franceschi (State University of Maringá, PR, Brazil) and Claudia Borba Rosales (Heart Institute, Universidade de São Paulo, SP, Brazil) for their relevant technical KIR and HLA typing assistance and analyses of data.

Authors’ Collaborations

M.L.C.M.: conception and design; sample collection; technical processing; acquisition, analysis, and interpretation of data; drafting manuscript. V.C.: analysis and interpretation of data and drafting manuscript. J.E.L.V., H.V.A., and K.F.K.: analysis and interpretation of data. M.R.R.: sample collection and drafting manuscript. M.S.A. and J.K: conception and interpretation of data. All authors had revised for critical content and final approval of the submitted manuscript.

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant number: 2010/10338-0).

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Author notes

  1. Mauricio Simões Abrão and Jorge Kalil contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Immunology, Heart Institute (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Maria Lucia Carnevale Marin, Verônica Coelho, Karen Francine Köhler, Marici Rached Rached & Jorge Kalil

  2. Histocompatibility and Cellular Immunology Laboratory, LIM-19, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Maria Lucia Carnevale Marin, Verônica Coelho & Jorge Kalil

  3. Institute for Investigation in Immunology, National Institute of Science and Technology (iii-INCT), São Paulo, SP, Brazil

    Verônica Coelho & Jorge Kalil

  4. Division of Clinical Immunology and Allergy, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Verônica Coelho & Jorge Kalil

  5. Laboratory of Immunogenetics, Department of Basic Health Sciences, State University of Maringá, Maringá, PR, Brazil

    Jeane Eliete Laguila Visentainer & Hugo Vicentin Alves

  6. Obstetrics and Gynecology Department, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Mauricio Simões Abrão

  7. Gynecologic Division, BP - A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil

    Mauricio Simões Abrão

  8. Rua São Sebastião 550, São Paulo, 04708-001, Brazil

    Mauricio Simões Abrão

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  1. Maria Lucia Carnevale Marin
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Correspondence to Mauricio Simões Abrão.

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Abrão MS is a Consultant for Myovant Sciences and for Abbvie Pharmaceutical. The other authors declare that they have no conflict of interest.

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Supplementary Fig 1

Distribution of KIR genotypes according to AA and Bx haplotypes in women with DE and controls DE, deep endometriosis, including DE in the presence of endometrioma; KIR, killer cell immunoglobulin-like receptors. Hapl. G, Haplotype group; Gen. ID, Genotype ID assigned by the Allele Frequencies Net Database (http://www.allelefrequencies.net/kir60012.asp, April 2018); NAS, Not yet Assigned ID; ns, not significant; black box, gene detected; white box, gene absent/no detected. (DOCX 48 kb)

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Marin, M.L.C., Coelho, V., Visentainer, J.E.L. et al. Inhibitory KIR2DL2 Gene: Risk for Deep Endometriosis in Euro-descendants. Reprod. Sci. 28, 291–304 (2021). https://doi.org/10.1007/s43032-020-00255-x

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