Interferon Gamma 13-CA-Repeat Homozygous Genotype and a Low Proportion of CD4+ Lymphocytes Are Independent Risk Factors for Cytomegalovirus Reactivation with a High Number of Copies in Hematopoietic Stem Cell Transplantation Recipients

Abstract

Cytomegalovirus (CMV) reactivation was analyzed in 92 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) in relation to the proportion of CD4(+) lymphocytes in blood and a microsatellite polymorphism within the first intron of the interferon-gamma (IFNG) gene. CMV reactivation was found in 50% of the HSCT recipients; in 30% of these individuals, the level of CMV copies exceeded 100 per 10(5) peripheral blood (PB) cells on at least one occasion during the 100-day post-HSCT observation period. This high CMV copy level was most frequently found between 31 and 60 days post-HSCT (P = .021). Patients with > or = 100 CMV copies/10(5) cells were characterized by poorer overall survival (OS) compared with those lacking CMV copies or having < 100 CMV copies/10(5) cells (P = .04), and they suffered from severe post-HSCT complications, including acute graft-versus-host disease (aGVHD) and relapse. Thus, patients with > or = 100 CMV copies/10(5) cells were designated as having clinically significant CMV reactivation. Patients with < 10% CD4(+) lymphocytes had a higher number of CMV DNA copies than those with higher proportions of CD4(+) lymphocytes (0.62 vs 0.21, P = .001; mean +/- SEM, 4422 +/- 1667 vs 937 +/- 662 CMV copies/10(5) cells, P < .001, for the proportion of cases with reactivation and numbers of copies, respectively). Similarly, patients carrying 2 IFNG 13-CA-repeat alleles (homozygotes) had more frequent CMV reactivation (0.50 vs 0.26; P = .039) and a higher CMV load (4111 +/- 1699 vs 950+/-591 CMV copies/10(5) cells; P = .041) compared with those with other IFNG microsatellite allele constellations. Multivariate analysis demonstrated that the IFNG 13-CA-repeat homozygous genotype (odds ratio [OR] = 0.221; P = .044), a low proportion of CD4(+) lymphocytes (OR = 0.276; P = .050), and a lack of optimal (10/10 alleles) donor-recipient HLA match (OR = 15.19; P = .006) were independent risk factors for CMV reactivation with a high number of copies.

A polymorphism linked to elevated levels of interferon-γ is associated with an increased risk of cytomegalovirus disease among Caucasian lung transplant recipients at a single center

“…2,3 Our genotype data, on the other hand, were more remarkable. A relationship between a polymorphism associated with increased levels of IFN-␥ and decreased CMV viral load was reported in a study of hematopoietic stem cell transplant (HSCT) recipients, 35 but it has not been described following solid-organ transplantation. Moreover, an association between the IFN-␥ ϩ874T/T genotype and CMV disease has not been reported previously.…”

“…33,34 In a recent study of 92 allogeneic HSCT recipients, homozygosity for a 13-CA-repeat microsatellite polymorphism within the first intron of the IFN-␥ gene was an independent risk factor for CMV reactivation with high serum viral loads within 100 days. 35 The 13-CA-repeat allele is in linkage disequilibrium with the ϩ874T/A SNP, such that there is an absolute association with the ϩ874A allele. [33][34][35] Thus, both the HSCT study and ours suggest that a genetic predisposition to the production of high levels of IFN-␥ is associated with heightened control of CMV viral replication.…”

“…35 The 13-CA-repeat allele is in linkage disequilibrium with the ϩ874T/A SNP, such that there is an absolute association with the ϩ874A allele. [33][34][35] Thus, both the HSCT study and ours suggest that a genetic predisposition to the production of high levels of IFN-␥ is associated with heightened control of CMV viral replication. Our study is unique, however, for suggesting that the protective effects of the ϩ874T/T genotype were more striking among R Ϫ than R ϩ patients.…”

Beneficial effect of the CXCL12-3′A variant for patients undergoing hematopoietic stem cell transplantation from unrelated donors

“…Cytomegalovirus (CMV), Human Herpes Virus-6 (HHV-6), and Epstein-Barr Virus (EBV) reactivations were monitored in patients after transplantation using quantitative PCR as previously described [7][8][9][10]. In brief, DNA was extracted from peripheral blood (QiAmp Blood Kit; Qiagen, Hilden, Germany) according to the manufacturer's instructions.…”

Can determination of gene polymorphism be of practical value in tailoring the treatment of HSCT patients?

“…Indeed, 13 CA microsatellite polymorphism at position +875 within the first intron of the IFNγ gene of the patients influences the risk of CMV reactivation, but this effect is only clinically relevant if the polymorphic feature, representing a low level of IFNγ production, 1 goes together with low CD4+ lymphocyte count. 2 On studying the NOD2/CARD15 gene polymorphism we learned that the presence of SNP 13 (3020insC, Leu1007 fsins C) mutation in patients as well as donors constitutes a risk factor of septic complications in HSCT patients exposed to deadly bacteria. 3 NOD2/CARD15, if triggered by muramyl dipeptide, activates two pathways: one going to mitochondrial antiviral-signaling protein/ Interferon regulatory factors (MAVS/IFR) and the other to nuclear factor κB and activating protein-1; the latter ones are the transcription factors of several molecules involved in the immune response including IFNγ.…”