Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease

Abstract

Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III–IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1β, IFNγ, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

“…We discovered pathways associated with aGvHD pathogenesis, implicating immunological responses in processes such as T cell function, cytokines, JAK-STAT signaling, and regulation of the TRAF6 gene. The risk for GvHD has mainly been investigated during past decades by concentrating on the MHC region and specific candidate genes (10,11), and only in recent years has the use of genome-wide approaches emerged in the field (16,17,(19)(20)(21)(22). These studies have shown the importance of genetic component in HSCT complications, but the results remain diverse, and their replication is incomplete.…”

“…Finnish Cohort 1 and Spanish Cohort 1 have been described previously in detail (11). Briefly, Finnish Cohort 1 consisted of 239 donor-recipient pairs, 23 individual recipients, and 28 individual donors with available clinical data and imputed genotype.…”

“…The genotyping and imputation procedures have been previously described in detail (11). Briefly, Finnish Cohort 1 was genotyped using an Illumina Immunochip and Spanish Cohort 1 and Finnish Cohort 2 with Illumina were genotyped with an Immunoarray v2.0.…”

“…However, both HLA and minor histocompatibility antigen disparities have been shown to result in the beneficial graft-vs.-leukemia effect reducing the risk of relapse (7,8). Emphasizing the complex genetic background of the condition, the susceptibility to GvHD is also potentially altered by donor or recipient polymorphisms in genes involved in immune responses (9)(10)(11) and drug metabolism (12,13), common deletions (14), and regulatory elements (15). Nevertheless, owing to the lack of replication of many of the results in large independent cohorts, a full understanding of relevant genetic factors remains elusive.…”

FinDonor 10 000 study: A cohort to identify iron depletion and factors affecting it in Finnish blood donors

“…DNA samples from the Finnish cohort were extracted using the QIAamp DNA Blood Mini Kit (Qiagen, Germany). Imputation was carried out as in 17 according to instructions of 18 using plink 1.90b3.29 19 for quality filtering and IMPUTE2 20 for the actual imputation with 1000 Genomes Phase 3 21 as a phased reference. Post-imputation filtering excluded variants having an IMPUTE2 INFO-field <0.5.…”