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Microsatellite scanning of the immunogenome associates MAPK14 and ELTD1 with graft-versus-host disease in hematopoietic stem cell transplantation

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Abstract

Graft-versus-host disease (GVHD) is the main complication after hematopoietic stem cell transplantation (HSCT). Evidence for non-HLA gene polymorphisms as a cause of GVHD lacks consistency, which is, in part, due to methodological issues of previous candidate gene association studies and small effect size of their results, demanding for larger scale and more robust approaches. Here, non-HLA gene polymorphisms were studied on a large population (922 HSCT pairs) from a homogeneous ethnic background with selection/correction for important clinical confounders. A methodology was applied exploiting the strength of confirmatory typing in an independent study cohort. Targeting an immunogenome of 2,909 genes, an approach of pooled DNA typing of 4,321 microsatellite (MS) markers in two independent screening steps and confirmation of associated markers by further individual genotyping on combined screening cohorts was used to identify genetic susceptibility loci for moderate to severe GVHD (grades 2–4). Ten MS loci (D5S424, D6S0035i, D1S0818i, DXS0151i, D17S0219i, DXS0629i, DXS0324i, D17S0271i, D6S0330i, and D1S1335i) passed the two pooled DNA typing steps and confirmation by individual sample genotyping; two of these (D1S0818i–ELTD1 and D6S0035i–MAPK14) remain associated following application of Bonferroni’s correction and multivariate analysis. The MAPK14 locus was exemplarily explored by typing of haplotype single nucleotide polymorphisms (SNP) confirming this association. This study identified several new MS susceptibility loci for GVHD that warrant further investigation. Immunogenome scanning using MS markers is a useful method for the identification of non-HLA gene loci associating with HSCT outcomes.

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Acknowledgments

The authors are greatly indebted to the staff members of the transplantation centers, donor centers, and the JMDP office for their generous cooperation. This work was supported by the Research on Allergic Disease and Immunology (Health and Labor Science Research Grant H20-014, H23-010) from the Ministry of Health, Labor, and Welfare of Japan, and a grant (3224–22133011) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, through JMDP. The authors want to express their gratitude to the Daiwa Foundation, which contributed to the cost of custom MS marker design with a small grant. CH was supported during this research by a fellowship from the Kay Kendall Leukaemia Fund UK (KKLF) (grant nos. 291 and 297). We thank laboratory staff at the Division of Molecular Life Sciences at Tokai University for their kind support: Mr. Hayashi for technical advice, and Ms. Yamaguchi, Ms. Matsushita, and Ms. Higuchi for supporting the genotyping work.

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Authors and Affiliations

  1. Division of Molecular Life Sciences, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Christian Harkensee, Akira Oka, Makoto Onizuka, Hidetoshi Inoko & Hirofumi Nakaoka

  2. Institute of Cellular Medicine, University of Newcastle, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Christian Harkensee, Peter G. Middleton & Andrew R. Gennery

  3. Department of Hematology and Oncology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Makoto Onizuka & Kiyoshi Ando

  4. Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Yata 111, Mishima, Shizuoka, 411-8540, Japan

    Hirofumi Nakaoka

  5. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden Chikusaku, Nagoya, 646-8681, Japan

    Yasuo Morishima

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  1. Christian Harkensee
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Correspondence to Christian Harkensee.

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Harkensee, C., Oka, A., Onizuka, M. et al. Microsatellite scanning of the immunogenome associates MAPK14 and ELTD1 with graft-versus-host disease in hematopoietic stem cell transplantation. Immunogenetics 65, 417–427 (2013). https://doi.org/10.1007/s00251-013-0691-z

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  • DOI: https://doi.org/10.1007/s00251-013-0691-z

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