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1.  F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort 
Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk.
Design and Methods
Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed.
H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development.
H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
PMCID: PMC3521089  PMID: 22958194
F8 haplotype; FVIII inhibitors; haplotype mismatch
2.  Genome wide association study of spontaneous resolution of hepatitis C virus infection 
Annals of internal medicine  2013;158(4):235-245.
Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood.
To evaluate the host genetic basis for spontaneous resolution of HCV infection.
Two-stage genome wide association study (GWAS).
13 international multicenter study sites.
919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence).
Frequencies of 792,721 SNPs.
Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015).
Epigenetic effects were not studied.
IL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.
PMCID: PMC3638215  PMID: 23420232
3.  KIR2DL2 Enhances Protective and Detrimental HLA Class I-Mediated Immunity in Chronic Viral Infection 
PLoS Pathogens  2011;7(10):e1002270.
Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.
Author Summary
Hepatitis C virus (HCV) and human T-cell leukemia virus (HTLV-I) infect millions of people worldwide. Some HCV-infected individuals spontaneously clear the virus and many HTLV-1-infected people remain asymptomatic; however, in both cases the infection can lead to serious illness such as cancer. The factors which determine outcome are still elusive. We have found that a gene that encodes a receptor (KIR2DL2) enhances both protective and detrimental HLA class I-mediated immunity to HCV and HTLV-1. Strikingly, although KIRs are primarily associated with innate immunity, our observations suggest that they also have a major impact on the efficiency of the adaptive immune response. This work helps to explain why one individual infected with a virus remains healthy but another, infected with the same virus develops disease; it also helps to explain why particular HLA class I molecules do not always protect or cause susceptibility as expected. Interestingly, the impact of the KIR is entirely context dependent: if an HLA class I molecule is protective then protection is enhanced, but in the context of a detrimental HLA then susceptibility is enhanced. This study reveals a novel role for inhibitory KIRs in adaptive immunity.
PMCID: PMC3192839  PMID: 22022261
4.  Genetic variation in IL28B and spontaneous clearance of hepatitis C virus 
Nature  2009;461(7265):798-801.
Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide1. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
PMCID: PMC3172006  PMID: 19759533
5.  Evaluation of IL10, IL19, and IL20 gene polymorphisms and chronic hepatitis B infection outcome 
Hepatitis B viral infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNPs, n = 42) from the IL10, IL19, and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005–0.04). The SNP, rs1518108, in IL20 nominally deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20, as well as an IL20 haplotype were associated with HBV recovery (P = 0.01–0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.
PMCID: PMC2874896  PMID: 18479293
Interleukin-10; Inflammation; African American; Immunogenetics; Hepatitis b; HIV co-infection
6.  Naturally occurring dominant resistance mutations to HCV protease and polymerase inhibitors in treatment-naïve patients 
Hepatology (Baltimore, Md.)  2008;48(6):1769-1778.
Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir, the NS5B polymerase inhibitor AG-021541, and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.6% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses in vivo.
Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous non-response to peginterferon and ribavirin.
PMCID: PMC2645896  PMID: 19026009
NS3 protease inhibitor; NS5B polymerase inhibitor; Telaprevir; Boceprevir

Results 1-6 (6)