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.
BACKGROUND
Single-nucleotide polymorphisms (SNPs) associated with active cytomegalovirus (CMV) infections after lung transplantation have not been identified.


METHODS
SNPs associated with varying levels of interferon (IFN)-γ (+874T/A), tumor necrosis factor-α (-308G/A), interleukin-10 (-1082G/A, -819C/T, -592C/A) and interleukin-6 (-174G/C) were characterized for 170 Caucasian lung transplant recipients who received alemtuzumab induction and valganciclovir prophylaxis against CMV.


RESULTS
Patients were followed for a median of 34 months post-transplant, and 66% (113 of 170), 24% (40 of 170) and 10% (17 of 170) had no CMV infection, CMV viremia and CMV disease, respectively. Median times to CMV viremia and disease were 7 and 10 months, respectively. For each gene, there was no significant deviation from Hardy-Weinberg equilibrium. Independent risk factors for the development of CMV disease were IFN-γ +874 T/T genotype (associated with high levels of IFN-γ production), CMV donor-positive/recipient-negative (D(+)/R(-)) serostatus and acute cellular rejection requiring augmented immunosuppression (p = 0.001, 0.003 and 0.049, respectively). The association between IFN-γ +874 T/T genotype and CMV disease was most striking among R(+) patients (p = 0.02). D(+)/R(-) serostatus was also a significant risk factor for CMV viremia (p = 0.0005). IFN-γ +874 T/T genotype was associated with significantly lower peak CMV viral loads (p = 0.03). There were no associations between tumor necrosis factor-α, interleukin-10 or interleukin-6 SNPs and CMV infections.


CONCLUSIONS
A genetic predisposition to elevated IFN-γ levels may play a dual role in controlling active CMV infection among lung transplant recipients receiving alemtuzumab induction and valganciclovir prophylaxis, limiting the extent of viral replication in serum but increasing the risk of CMV disease.
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Dimitra
D
Mitsani
M Hong
MH
Nguyen
Diana M
DM
Girnita
Kathleen
K
Spichty
Eun J
EJ
Kwak
Fernanda P
FP
Silveira
Yoshiya
Y
Toyoda
Joseph M
JM
Pilewski
Maria
M
Crespo
Jay K
JK
Bhama
Rima
R
Abdel-Massih
Diana
D
Zaldonis
Adriana
A
Zeevi
Cornelius J
CJ
Clancy
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D003587:Cytomegalovirus / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000097:blood / Q000453:epidemiology* / Q000517:prevention & control; D005260:Female; D005500:Follow-Up Studies; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics*; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D016040:Lung Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D000077562:Valganciclovir; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D044465:White People / Q000235:genetics*; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000998:Antiviral Agents; D015415:Biomarkers; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000074323:Alemtuzumab; D007371:Interferon-gamma; D000077562:Valganciclovir; D015774:Ganciclovir