Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3′UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
To assess whether arthropod bites promote Kaposi sarcoma (KS), we determined the seroprevalence of Sicilian (SFSV) and Toscana (TOSV) phlebovirus antibodies in 30 patients with classic KS and 100 controls in Sicily. Nine (6.9%) subjects, all controls, were positive for SFSV, whereas 41 (31.5%) were positive for TOSV. Seroprevalence with immunoglobulin (Ig) M or IgG against either virus was significantly higher in controls (43% vs 13.3% in case patients; P < .01). Adjusted for age, IgG seroprevalence was significantly lower in KS patients compared to controls (adjusted odds ratio, 0.22; 95% confidence interval, .07–.72). Low phlebovirus seroprevalence in patients with KS may reflect incapacity to produce robust, persistent antibody responses, and suggests that arthropod bites do not promote KS.
We sequenced the genomes of ten unrelated individuals and identified heterozygous stop gain variants in protein-coding genes: we then sequenced their transcriptomes and assessed the expression levels of the stop gain alleles. An ANOVA showed statistically significant differences between their expression levels (p=4×10-16). This difference was almost entirely accounted for by whether the stop gain variant had a second, non-protein-truncating function in or near an alternate transcript: stop gains without alternate functions were generally not found in the cDNA (p=3×10-5). Additionally, stop gain variants in two intronless genes were not expressed, an unexpected outcome given previous studies. In this study, stop gain variants were either well expressed in all individuals or were never expressed. Our finding that stop gain variants were generally expressed only when they had an alternate function suggests that most naturally occurring stop gain variants in protein-coding genes are either not transcribed or have their transcripts destroyed.
Nonsense-mediated decay; whole-genome sequencing; RNA-Seq; premature termination codons
Kaposi sarcoma (KS) may develop because of incompetent immune responses, both nonspecifically and specifically against the KS-associated herpes virus (KSHV). Peripheral blood mononuclear cells from 15 classic (non-AIDS) KS cases, 13 KSHV seropositives (without KS), and 15 KSHV-seronegative controls were tested for interferon-γ T-cell (Elispot) responses to KSHV-LANA, KSHV-K8.1, and CMV/EBV peptide pools. The forearm and thigh of each participant also was tested for delayed-type hypersensitivity (DTH) against common recall antigens. Groups were compared with Fisher exact test and multinomial logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). KSHV Elispot response was detected in 10 (67%) classic KS cases, 11 (85%) KSHV seropositives (without KS), and 2 (13%) seronegative controls. All 4 cases with KSHV-LANA responses had current KS lesions, whereas 5 of 6 cases with KSHV-K8.1 responses had no lesions (P=0.048). No case responded to both LANA and K8.1. Compared to seronegative controls, risk for classic KS was inversely related to DTH in the thigh (OR 0.71, 95% CI 0.55–0.94, P=0.01), directly associated with DTH in the forearm (OR 1.35, 95% CI 1.02–1.80, P=0.04), and tended to be increased 5-fold per KSHV Elispot response (OR 5.13, 95% CI 0.86–30.77, P=0.07). Compared to KSHV seropositives (without KS), risk for classic KS, was reduced 5-fold (OR 0.20, CI 0.03–0.77, P=0.04) per KSHV response. CMV/EBV Elispot responses were irrelevant. Deficiency of both KSHV-specific and –nonspecific immunity is associated with classic KS. This may clarify why Kaposi sarcoma responds to immune reconstitution.
Kaposi sarcoma; T-cell immunity; delayed-type hypersensitivity; case-control study; Italy
Cytokine dysregulation and decontrol of Epstein-Barr virus (EBV) latency by human immunodeficiency virus (HIV) infection are potential mechanisms for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). We therefore assessed circulating blood levels in pre-diagnosis plasma or serum from 63 AIDS-related NHL cases 0.1 – 2.0 (median 1.0) years pre-NHL and 181 controls matched for CD4+ T-cell count. Cytokines were measured by Millipore 30-plex Luminex assays and cell-free EBV DNA detected by polymerase chain reaction (PCR). Correlations in multiplex cytokine levels were summarized by factor analysis. Individual cytokines and their principal factors were analyzed for associations with NHL by conditional logistic regression. Cases had higher levels for 25 of the 30 cytokines. In analyses of cytokine profiles, cases had significantly higher scores for a principal factor primarily reflecting levels of interleukin (IL)-4, IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (four gene products with coordinated transcription in vitro), as well as IL-1alpha. Epstein-Barr viremia was not significantly associated based on 113 evaluable samples without PCR inhibition. We found increases of T-helper type 2 interleukins and generalized elevations of other inflammatory cytokines and growth factors up to two years before AIDS-NHL. Cytokine-mediated hyperstimulation of B-cell proliferation may play a role in AIDS-related lymphomagenesis.
Several genes that modify risk of factor VIII inhibitors in hemophilia A patients have been identified. Aside from the underlying mutations that cause hemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators, including IL10, TNFα, and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk.
We sought to confirm previous observations on factor VIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal factor VIII gene polymorphisms affect inhibitor risk in Caucasians.
We studied 915 Caucasian, severe hemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls) Genes were analyzed using 368 tagging SNPs starting 20kb 5′ and ending 10kb 3′ of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated.
Haplotypes that increased inhibitor risk were found in IL10 (OR 1.33, P = 0.04), IL12 (OR 1.31, P = 0.04), and IL1α (OR 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR 0.69, P = 0.008) and IL1β (OR 0.75, P = 0.02). One rare haplotype in the factor VIII gene increased the risk of inhibitor development by nearly four-fold (OR 3.8, P = 0.004).
We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare factor VIII haplotype in Caucasians that is associated with increased inhibitor risk.
hemophilia A; inhibitor; factor VIII; IL10; IL2; IL12; IL1
Few microbial functions have been compared to a comprehensive survey of the human fecal microbiome. We evaluated determinants of fecal microbial β-glucuronidase and β-glucosidase activities, focusing especially on associations with microbial alpha and beta diversity and taxonomy. We enrolled 51 healthy volunteers (26 female, mean age 39) who provided questionnaire data and multiple aliquots of a stool, from which proteins were extracted to quantify β-glucuronidase and β-glucosidase activities, and DNA was extracted to amplify and pyrosequence 16S rRNA gene sequences to classify and quantify microbiome diversity and taxonomy. Fecal β-glucuronidase was elevated with weight loss of at least 5 lb. (P = 0.03), whereas β-glucosidase was marginally reduced in the four vegetarians (P = 0.06). Both enzymes were correlated directly with microbiome richness and alpha diversity measures, directly with the abundance of four Firmicutes Clostridia genera, and inversely with the abundance of two other genera (Firmicutes Lactobacillales Streptococcus and Bacteroidetes Rikenellaceae Alistipes) (all P = 0.05–0.0001). Beta diversity reflected the taxonomic associations. These observations suggest that these enzymatic functions are performed by particular taxa and that diversity indices may serve as surrogates of bacterial functions. Independent validation and deeper understanding of these associations are needed, particularly to characterize functions and pathways that may be amenable to manipulation.
Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.
Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.
Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).
Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
Effective antiretroviral therapy has reduced the risk of AIDS and dramatically prolonged the survival of HIV-infected people in the United States. Consequently, an increasing number of HIV-infected people are at risk of non-AIDS-defining cancers that typically occur at older ages. We estimated the annual number of cancers in the HIV-infected population, both with and without AIDS, in the United States.
Incidence rates for individual cancer types were obtained from the HIV/AIDS Cancer Match Study by linking 15 HIV and cancer registries in the United States. Estimated counts of the US HIV-infected and AIDS populations were obtained from Centers for Disease Control and Prevention surveillance data. We obtained estimated counts of AIDS-defining (ie, Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers in the US AIDS population during 1991–2005 by multiplying cancer incidence rates and AIDS population counts, stratified by year, age, sex, race and ethnicity, transmission category, and AIDS-relative time. We tested trends in counts and standardized incidence rates using linear regression models. We multiplied overall cancer rates and HIV-only (HIV infected, without AIDS) population counts, available from 34 US states during 2004–2007, to estimate cancers in the HIV-only population. All statistical tests were two-sided.
The US AIDS population expanded fourfold from 1991 to 2005 (96 179 to 413 080) largely because of an increase in the number of people aged 40 years or older. During 1991–2005, an estimated 79 656 cancers occurred in the AIDS population. From 1991–1995 to 2001–2005, the estimated number of AIDS-defining cancers decreased by greater than threefold (34 587 to 10 325 cancers; Ptrend < .001), whereas non-AIDS-defining cancers increased by approximately threefold (3193 to 10 059 cancers; Ptrend < .001). From 1991–1995 to 2001–2005, estimated counts increased for anal (206 to 1564 cancers), liver (116 to 583 cancers), prostate (87 to 759 cancers), and lung cancers (875 to 1882 cancers), and Hodgkin lymphoma (426 to 897 cancers). In the HIV-only population in 34 US states, an estimated 2191 non-AIDS-defining cancers occurred during 2004–2007, including 454 lung, 166 breast, and 154 anal cancers.
Over a 15-year period (1991–2005), increases in non-AIDS-defining cancers were mainly driven by growth and aging of the AIDS population. This growing burden requires targeted cancer prevention and treatment strategies.
Background. High-throughput genome-wide techniques have facilitated the identification of previously unknown host proteins involved in cellular human immunodeficiency virus (HIV) infection. Recently, 3 independent studies have used small interfering RNA technology to silence each gene in the human genome to determine the importance of each in HIV infection. Genes conferring a significant effect were termed HIV-dependency factors (HDFs).
Methods. We assembled high-density panels of 6380 single-nucleotide polymorphisms (SNPs) in 278 HDF genes and tested for genotype associations with HIV infection and AIDS progression in 1633 individuals from clinical AIDS cohorts.
Results. After statistical correction for multiple tests, significant associations with HIV acquisition were found for SNPs in 2 genes, NCOR2 and IDH1. Weaker associations with AIDS progression were revealed for SNPs within the TM9SF2 and EGFR genes.
Conclusions. This study independently verifies the influence of NCOR2 and IDH1 on HIV transmission, and its findings suggest that variation in these genes affects susceptibility to HIV infection in exposed individuals.
Hepatitis C virus (HCV) treatment failure and disease progression are more likely with high HCV-RNA load. Correlates of high HCV-RNA load in individuals with hemophilia are largely unknown.
Among 1,266 interferon naïve HCV-infected individuals with hemophilia, we compared those with high (> 2×106 HCV RNA copies/ml) to lower viral load, overall and stratifying on HIV co-infection status using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI).
Overall, high HCV load was independently associated with longer duration of HCV infection (Ptrend=0.0001), body mass index ≥25 kg/m2 (OR= 1.4, 95% CI=1.1-1.9), and HIV co-infection (OR=1.4, 95% CI=1.0-1.8). Among 795 HIV-negative participants, high HCV- RNA load was associated with older age at HCV acquisition (OR=1.9 for >15 years vs ≤2 years, Ptrend=0.008), and lower AST/platelet ratio (Ptrend=0.01), in addition to longer duration of HCV infection (Ptrend=0.0008), and body mass index ≥25 kg/m2 (OR=1.6, P=0.005). Among 471 HIV-positive individuals, anti-retroviral therapy (ART) was the only variable associated with high HCV-RNA load (OR=1.8, CI=1.1-2.9 for combination ART; OR=1.8, CI=0.9-3.4, for other ART vs. no treatment).
High HCV-RNA load with hemophilia is more likely with longer duration of infection, older age at infection, higher body mass index, and antiretroviral therapy. These findings may help identify individuals at increased risk of HCV treatment failure and progression to end-stage liver disease.
HCV load; HCV/HIV co-infection; hemophilia
An IL28B haplotype strongly determines the outcome of natural and interferon-α treated HCV infection. To assess if the polymorphism marking the haplotype (rs12979860) also affects other interferon-α responsive chronic viral illnesses, namely hepatitis B virus (HBV) and human immunodeficiency virus-1 (HIV), we genotyped 226 individuals with HBV persistence, 384 with HBV recovery, and 2548 with or at high-risk for HIV infection. The C/C genotype of rs12979860 was not associated with HBV recovery (OR 0.99), resistance to HIV infection (0.97), or HIV disease progression (P>0.05). This IL28B SNP affects the immune response to HCV but not to HBV or HIV.
IL28B; HIV; HBV; genetics; polymorphism
An IL28B haplotype strongly determines the outcome of natural and interferon-α treated hepatitis C virus (HCV) infection. To assess whether the polymorphism marking the haplotype (rs12979860) also affects other interferon-α responsive chronic viral illnesses, namely hepatitis B virus (HBV) and human immunodeficiency virus (HIV) type 1 infections, we genotyped 226 individuals with HBV persistence, 384 with HBV recovery, and 2548 with or at high risk for HIV infection. The C/C genotype of rs12979860 was not associated with HBV recovery (odds ratio, 0.99), resistance to HIV infection (odds ratio, 0.97), or HIV disease progression (P>.05). This IL28B single-nucleotide polymorphism affects the immune response to HCV but not to HBV or HIV.
Lung cancer risk is significantly increased among persons with AIDS (PWA), and increased smoking may not explain all of the elevated risk, suggesting a role for additional co-factors. We investigated whether AIDS-defining pulmonary infections [recurrent pneumonia, Pneumocystis jirovecii pneumonia (PCP), and pulmonary tuberculosis] affected the risk of subsequent lung cancer over 10 years after AIDS onset among 322,675 PWA whose records were linked with cancer registries in 11 U.S. regions. We assessed lung cancer hazard ratios (HR) using Cox regression, and indirectly adjusted HRs for confounding by smoking. Individuals with recurrent pneumonia (n=5317) were at significantly higher lung cancer risk than those without [HR=1.63, 95%CI=1.08-2.46, adjusted for age, race, sex, HIV acquisition mode, CD4 count, and AIDS diagnosis year]. This association was especially strong among young PWA (<50 years HR=1.99 vs. ≥50 years HR=1.10) and was significantly elevated during 5-10 years after recurrent pneumonia diagnosis (HR= 2.41; 95%CI=1.07-5.47). Although attenuated, HRs for recurrent pneumonia remained non-significantly elevated after indirect adjustment for smoking. Lung cancer risk was unrelated to tuberculosis [(n=13,878) HR=1.12, 95%CI=0.82-1.53] or PCP [(n=69,771) HR=0.97, 95%CI=0.80-1.18]. The increased lung cancer risk associated with recurrent pneumonia supports the hypothesis that chronic pulmonary inflammation arising from infections contributes to lung carcinogenesis.
HIV/AIDS; Lung cancer; Pulmonary infections; Inflammation; Recurrent pneumonia; Tuberculosis; Pneumocystis jirovecii pneumonia
Previous studies describe decreased prostate cancer risk in HIV-infected men. In the U.S., prostate-specific antigen (PSA) screening is common and increases detection of prostate cancer. We evaluated whether the prostate cancer deficit among men with AIDS reflects differential PSA screening.
Data from the U.S. HIV/AIDS Cancer Match Study were used to calculate standardized incidence ratios (SIRs) for prostate cancer, comparing men with AIDS (N=287,247) to the general population. Further, we estimated PSA testing rates in the Johns Hopkins HIV Clinical Cohort.
Prostate cancer rates increased over time in the general population and beginning in the 1990s were consistently higher than among men with AIDS. Men with AIDS had the same prostate cancer risk as the general population in the pre-PSA era (<1992, SIR=1.00), but significantly reduced risk during the PSA era overall (1992–2007, SIR=0.50) and across age, race, HIV risk group, antiretroviral therapy era, and CD4 counts. Local and regional stage prostate cancer risk was lower among men with AIDS (SIRs 0.49 and 0.14, respectively), but distant stage cancer risk did not differ (SIR=0.85). Among HIV-infected men ≥40 years old, PSA testing was uncommon (18.7% per year), but increased 2.4-fold from 2000 to 2008, after age adjustment.
Prostate cancer risk was decreased by 50% among men with AIDS compared to the general population. This deficit was limited to the PSA era and early stage cancers.
Our findings suggest that the prostate cancer deficit in HIV-infected men is largely due to differential PSA screening.
Prostate cancer; HIV; PSA; AIDS; screening
Chromosome 3p21–22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28–6.31) among four major AIDS–defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.
Human chemokine receptors are cell surface proteins that may be utilized by HIV-1 for entry into host cells. DNA variation in the HIV-1 major coreceptor CCR5 affects HIV-1 infection and progression. This study comprehensively assesses the role of genetic variation of multiple chemokine receptor genes clustered in the chromosome 3p21 and 3p22 on HIV-1 disease outcomes in HIV-1 natural history cohorts. The multivariate survival analyses identified functional variants that altered disease progression rate in CCRL2, CCR3, and CCR8. CCRL2-F167Y affects the rate to AIDS development through a specific protection against pneumocystis pneumonia (PCP), a common AIDS–defining condition. Our study identified this atypical chemokine receptor CCRL2 as a key factor involved in PCP, possibly through inducing inflammation in the lung.
Both clinical experience and a growing medical literature indicate that there are persons who have been exposed to HIV infection who have remained uninfected. While in some instances this may represent good fortune, cohorts of uninfected persons have been reported where risks for infection are thought to be high. In these cohorts a variety of characteristics have been proposed as mediating protection but to date only the 32 base pair deletion in the CCR5 gene that results in complete failure of cell surface expression of this co-receptor has been associated with high level protection from HIV infection. With this in mind, there are likely numerous other factors that may individually or in combination provide some level of protection from acquisition of HIV infection. As some of these factors are likely incompletely protective or inconsistently active, identifying them with confidence will be difficult. Nonetheless, clarifying the determinants of protection against HIV infection is a high priority that will require careful selection of high risk uninfected cohorts to which targeted studies of plausible mediators and broad screening for unexpected determinants of protection should be applied.
HIV infection; Exposed Seronegatives; High Risk Seronegatives; Interferon; Restriction factors; CCR5
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.
HLA class I polymorphism is known to affect the rate of progression to AIDS after infection with HIV-1. Here we test the consistency of HLA-B allelic effects on progression to AIDS, heterosexual HIV transmission and ‘setpoint’ viral levels.
We used adjusted Cox proportional hazard models in previously published relative hazard (RH) values for the effect of HLA-B alleles on progression to AIDS (n=1089). The transmission study included 303 HIV-1-infected men with hemophilia and their 323 female sex partners (MHCS cohort). Among 259 HIV-1 seroconverters (MACS cohort), HIV RNA levels at ‘setpoint’ were determined in stored plasma samples by a reverse-transcription polymerase chain reaction assay. HLA-B genotyping was performed by sequence-specific-oligonucleotide-hybridization and DNA sequencing.
Several HLA-B alleles showed consistent associations for AIDS risk, infectivity and ‘setpoint’ HIV RNA. HLA-B*35 was associated with more rapid progression to AIDS (RH 1.39; p = 0.008), greater infectivity (OR 3.14; p = 0.002), and higher HIV RNA (p = 0.01), whereas the presence of either B*27 or B*57 associated with slower progression to AIDS (B*27: RH 0.49, p < 0.001; B*57: RH 0.40, p <0.0001), less infectivity (OR 0.22 and 0.31, respectively, though not significant) and lower viral levels (p <0.0001). Importantly, HLA-B polymorphism in female partners was not associated with susceptibility to HIV-1 infection.
HLA-B polymorphisms that affect the risk of AIDS may also alter HIV-1 infectivity, probably through the common mechanism of viral control, but they do not appear to protect against infection in our cohort.
HIV; AIDS; HLA; viral load; HIV transmission; AIDS progression; MHC diversity
Chronic inflammation could play a role in lung carcinogenesis, underscoring the potential for lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP, an inflammation biomarker) and CRP single nucleotide polymorphisms (SNPs) with prospective lung cancer risk.
Patients and Methods
We conducted a nested case-control study of 592 lung cancer patients and 670 controls with available prediagnostic serum and 378 patients and 447 controls with DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 77,464). Controls were matched to patients on age, sex, entry year, follow-up time, and smoking. We measured CRP levels in baseline serum samples and genotyped five common CRP SNPs.
Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR], 1.98; 95% CI, 1.35 to 2.89; P-trend < .001 for fourth quartile [Q4, ≥ 5.6 mg/L] v Q1 [< 1.0 mg/L]). The CRP association did not differ significantly by histology, follow-up time, or smoking status, but was most apparent for squamous cell carcinomas (OR, 2.92; 95% CI, 1.30 to 6.54), 2 to 5 years before lung cancer diagnosis (OR, 2.33; 95% CI, 1.24 to 4.39), and among former smokers (OR, 2.48; 95% CI, 1.53 to 4.03) and current smokers (OR, 1.90; 95% CI, 1.06 to 3.41). Although CRP SNPs and haplotypes were associated with CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels among former smokers (Q4: 2.55%; 95% CI, 1.98% to 3.27% v Q1: 1.39%; 95% CI, 1.07% to 1.81%) and current smokers (Q4: 7.37%; 95% CI, 5.81% to 9.33% v Q1: 4.03%; 95% CI, 3.01% to 5.40%).
Elevated CRP levels are associated with subsequently increased lung cancer risk, suggesting an etiologic role for chronic pulmonary inflammation in lung carcinogenesis.