PhD ThesisNon-HLA gene polymorphisms contribute to the immune response,
leading to complications of haematopoietic stem cell transplantation
(HSCT). A systematic approach using 4,321 microsatellite (MS) markers
typing for 2,909 immune response genes (‘immunogenome’) on pooled
DNA of 922 Japanese donors and recipients of HSCT was used to identify
recipient and donor risk loci for graft-versus-host disease (GVHD).
Splitting the population into discovery and confirmation cohorts (460/462
pairs), DNA pools were created for a 2-step pooled DNA screening.
Fisher’s exact test for 2x2 (each MS allele) and 2xm Chi Square tests
were performed, comparing allele frequencies of recipient/donor pools
with GVHD grade 0-1 with those of GVHD grade 2-4.
The independent, 2-step pooled DNA screening process has effectively
reduced false-positive associations. In the final pooled DNA analysis, 17
(recipient) and 31 (donor) MS loci remained associated with risk or
protection from GVHD and were further investigated by individual
genotyping in the combined cohorts.
Ten of these loci were confirmed to have consistent associations with
GVHD; of these, two associations remained when applying multiple
testing correction and multivariate statistics: D6S0035i (MAPK14,
p=0.00035, OR=0.68) and D1S0818i (ELTD1, p=0.000078, OR=1.52).
These findings implicate important new immunoregulatory genes with the
process of moderate to severe acute GVHD. These data show that
genetic susceptibility to GVHD following HSCT is complex and depends
on multiple recipient and donor risk loci. Large-scale genomic screening
with microsatellites on pooled DNA, here described for the first time in a
HSCT population, is a useful method for the systematic evaluation of
multigeneic traits.Research on Allergic Disease and
Immunology (Health and Labor Science Research Grant H20-014, H23-
010), the Ministry of Health, Labor, and Welfare of Japan, through JMDP. Post-doctoral
Fellowship from the Japan Society for Promotion of Science (JSPS), International Fellowship from the Kay
Kendall Leukaemia Fund UK (KKLF) (grants No 291,297),The Great Britain
Sasakawa Foundation (GBSF) Butterfield Award, Daiwa Anglo-Japanese Foundation
