Philippa L. Roddam

Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection

Experimental and computational evidence suggests that HLAs preferentially bind conserved regions of viral proteins, a concept we term “targeting efficiency,” and that this preference may provide improved clearance of infection in several viral systems. To test this hypothesis, T-cell responses to A/H1N1 (2009) were measured from peripheral blood mononuclear cells obtained from a household cohort study performed during the 2009–2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFN-γ enzyme-linked immunosorbent spot responses (P = 0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality (r = 0.37, P = 0.031) and are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. HLA efficiency scores and HLA use are associated with CD8 T-cell magnitude in humans after influenza infection. The computational tools used in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons. Population-based studies of the relative frequency of these alleles in severe vs. mild influenza cases might advance clinical practices for severe H1N1 infections among genetically susceptible populations.

Viral Specific Factors Contribute to Clinical Respiratory Syncytial Virus Disease Severity Differences in Infants

Background There is a wide range of severity of respiratory syncytial viral (RSV) disease in previously healthy infants. Host factors have been well demonstrated to contribute to disease severity differences. However the possibility of disease severity differences being produced by factors intrinsic to the virus itself has rarely been studied. Methods Low-passage isolates of RSV collected prospectively from infants with different degrees of RSV disease severity were evaluated in vitro, holding host factors constant, so as to assess whether isolates induced phenotypically different cytokine/chemokine concentrations in a human lung epithelial cell line. Sixty-seven RSV isolates from previously healthy infants (38 hospitalized for acute RSV infection (severe disease) and 29 never requiring hospitalization (mild disease)) were inoculated into A549, lung epithelial cells at precisely controlled, low multiplicity of infection to mimic natural infection. Cultures were evaluated at 48 hours, 60 hours, and 72 hours to evaluate area under the curve (AUC) cytokine/chemokine induction. Results Cells infected with isolates from severely ill infants produced higher mean concentrations of all cytokine/chemokines tested (IL-1α, IL-6, IL-8 and RANTES) at all-time points tested. RSV isolates collected from infants with severe disease induced significantly higher AUCIL-8 and AUCRANTES secretion in infected cultures than mild disease isolates (p=0.028 and p=0.019 respectively). IL-8 and RANTES concentrations were 4 times higher at 48 hours for these severely ill infant isolates. Additionally, 38 isolates were evaluated at all-time points for quantity of virus. RSV concentration significantly correlated with both IL-8 and RANTES at all-time points. Neither cytokine/chemokine concentrations nor RSV concentrations were associated with RSV subgroup. Discussion Infants’ RSV disease severity differences may be due in part to intrinsic viral strain-specific characteristics.