Mosaic chromosomal alterations detected in men living with HIV and the relationship to non-Hodgkin lymphoma.

OBJECTIVES: People with HIV (PWH) have an elevated risk of non-Hodgkin lymphoma (NHL) and other diseases. Studying clonal hematopoiesis (CH), the clonal expansion of mutated hematopoietic stem cells, could provide insights regarding elevated NHL risk. DESIGN: Cohort analysis of participants in the Multicenter AIDS Cohort Study ( N  = 5979). METHODS: Mosaic chromosomal alterations (mCAs), a type of CH, were detected from genotyping array data using MoChA. We compared CH prevalence in men with HIV (MWH) to HIV-uninfected men using logistic regression, and among MWH, assessed the associations of CH with NHL incidence and overall mortality using Poisson regression. RESULTS: Comparing MWH to HIV-uninfected men, we observed no difference in the frequency of autosomal mCAs (3.9% vs. 3.6%, P -value = 0.09) or mosaic loss of the Y chromosome (mLOY) (1.4% vs. 2.9%, P -value = 0.13). Autosomal mCAs involving copy-neutral loss of heterozygosity (CN-LOH) of chromosome 14q were more common in MWH. Among MWH, mCAs were not associated with subsequent NHL incidence (autosomal mCA P -value = 0.65, mLOY P -value = 0.48). However, two MWH with diffuse large B-cell lymphoma had overlapping CN-LOH mCAs on chromosome 19 spanning U2AF2 (involved in RNA splicing), and one MWH with Burkitt lymphoma had high-frequency mCAs involving chromosome 1 gain and chromosome 17 CN-LOH (cell fractions 22.1% and 25.0%, respectively). mCAs were not associated with mortality among MWH (autosomal mCA P -value = 0.52, mLOY P -value = 0.93). CONCLUSIONS: We found limited evidence for a relationship between HIV infection and mCAs. Although mCAs were not significantly associated with NHL, mCAs detected in several NHL cases indicate a need for further investigation.

Characteristics of Patients With Chronic Hepatitis B Virus Infection With Genotype E Predominance in Burkina Faso.

Hepatitis B virus (HBV) genotype E (HBV-E) accounts for the majority of chronic hepatitis B (CHB) infections in West Africa. We aimed to determine factors associated with HBV-E-induced hepatocellular carcinoma (HCC) in West Africa. Data on patients from Burkina Faso who were hepatitis B surface antigen positive (HBsAg+) and had CHB were analyzed. HBV viral load and hepatitis B e antigen (HBeAg) status were measured in 3,885 individuals with CHB without HCC (CHB HCC-) and 59 individuals with CHB with HCC (CHB HCC+). HBV genotyping was performed for 364 subjects with CHB HCC- and 41 subjects with CHB HCC+. Overall, 2.5% of the CHB HCC- group was HBeAg+ compared with 0% of the CHB HCC+ group. Of the 364 patients who were CHB HCC- with available genotyping, the frequencies of HBV genotypes E and C/E were 70.3% and 12.9%, respectively. Age (odds ratio [OR] for older age, 1.08; 95% confidence interval [CI], 1.06-1.10 per 1-year increase in age), male sex (OR, 2.03; 95% CI, 1.11-3.69), and HBV viremia (OR, 1.48; 95% CI, 1.31-1.67 per 1 log10 IU/mL) were each associated with HCC diagnosis. Patients with genotype E had a lower HBeAg prevalence (6.3% vs. 14.9%), lower HBV viral load, and higher prevalence of cirrhosis (14.5% vs. 4.8%) than patients with genotype C/E. Conclusion: HBV-E is the most common circulating strain (70.3%) in West African patients. HCC was associated with older age, male sex, and high HBV viral load. It is expected that these results will further inform guidance on clinical management of HBV infection in West Africa.

Alterations in Oral Microbiota in HIV Are Related to Decreased Pulmonary Function.

Rationale: Mechanisms of HIV-associated chronic obstructive pulmonary disease (COPD) are poorly understood. The oral microbiome shapes the lung microbiome, and gut dysbiosis can affect lung diseases; however, relationships of the oral and gut microbiome to COPD in HIV have not been explored.Objectives: To examine alterations in the oral and gut microbiome associated with pulmonary disease in persons with HIV (PWH).Methods: Seventy-five PWH and 93 HIV-uninfected men from the MACS (Multicenter AIDS Cohort Study) performed pulmonary function testing. Sequencing of bacterial 16S ribosomal RNA in saliva and stool was performed. We used nonmetric multidimensional scaling, permutational multivariate ANOVA, and linear discriminant analysis to analyze communities by HIV and lung function.Measurements and Main Results: Oral microbiome composition differed by HIV and smoking status. Alterations of oral microbial communities were observed in PWH with abnormal lung function with increases in relative abundance of Veillonella, Streptococcus, and Lactobacillus. There were no significant associations between the oral microbiome and lung function in HIV-uninfected individuals. No associations with HIV status or lung function were seen with the gut microbiome.Conclusions: Alterations of oral microbiota in PWH were related to impaired pulmonary function and to systemic inflammation. These results suggest that the oral microbiome may serve as a biomarker of lung function in HIV and that its disruption may contribute to COPD pathogenesis.

Increasing Levels of Serum Heat Shock Protein 70 Precede the Development of AIDS-Defining Non-Hodgkin Lymphoma Among Carriers of HLA-B8-DR3.

BACKGROUND: We hypothesized that carriage of presumably high Hsp70-producing gene variants on a specific human major histocompatibility complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-non-Hodgkin lymphoma (NHL). SETTING: We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n = 151 pairs) nested in the Multicenter AIDS Cohort Study. METHODS: We tested the impact of 8.1AH-specific single-nucleotide polymorphism (SNP) and joint SNP-human leukocyte antigen extended haplotypes previously associated with AIDS-NHL in the Multicenter AIDS Cohort Study on the circulating Hsp70 levels in mixed linear models. RESULTS: We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH, but not in noncarrier cases and not in carrier- or non-carrier-matched controls. The strongest predictor of higher serum Hsp70 was the haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster, and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; standard error = 0.182; P = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing tumor necrosis factor-alpha haplotype rs909253(G)-rs1800629(A) (beta = 0.308; standard error = 0.140; P = 0.032) were observed only with NHL identified as an AIDS-defining condition, but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases. CONCLUSION: Our combined genetic and functional approach suggests that the altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy.

GlycA, a novel inflammatory marker, is associated with subclinical coronary disease.

OBJECTIVE: GlycA, a novel NMR biomarker of inflammation, has been associated with incident cardiovascular disease (CVD) in the general population, but its association with CVD among HIV-infected individuals is unknown. We examined the associations between GlycA and subclinical coronary plaque among HIV-infected and HIV-uninfected men participating in Multicenter AIDS Cohort Study (MACS). DESIGN: Cross-sectional analysis of 935 men with plasma measurement of GlycA and noncontrast cardiac computed tomography (CT) and/or coronary CT angiography. METHODS: We used multivariable Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively. RESULTS: Mean ±â€ŠSD age was 54 ±â€Š7 years; 31% were black; 63% HIV-infected. GlycA levels were higher in HIV-infected compared with HIV-uninfected men (397 ±â€Š68 vs. 380 ±â€Š60 µmol/l, P = 0.0001) and higher for men with detectable viral load vs. undetectable (413 ±â€Š79 vs. 393 ±â€Š65 µmol/l, P = 0.004). After adjusting for HIV serostatus, demographic and CVD risk factors, every 1SD increment in GlycA level was associated with a higher prevalence of coronary artery calcium (CAC >0) [prevalence ratio 1.09 (95% CI 1.03-1.15)] and coronary stenosis at least 50% [1.20 (1.02-1.41)]. These associations were not significantly altered after adjusting for traditional inflammatory biomarkers or differ by HIV serostatus. Among men with plaque, GlycA was positively associated with the extent of CAC and total plaque. CONCLUSION: HIV infection was associated with higher GlycA levels. In both HIV-infected and HIV-uninfected individuals, GlycA was significantly associated with several measures of subclinical coronary atherosclerosis, independent of other CVD risk factors and inflammatory biomarkers. These findings suggest the potential role of GlycA in CVD risk stratification among HIV patients.

Genetic correlations among psychiatric and immune-related phenotypes based on genome-wide association data.

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

Frailty and subclinical coronary atherosclerosis: The Multicenter AIDS Cohort Study (MACS).

BACKGROUND AND AIMS: Frailty and cardiovascular disease share many risk factors. We evaluated whether frailty is independently associated with subclinical coronary atherosclerosis and whether any relationships differ by HIV-serostatus. METHODS: We studied 976 [62% HIV-infected] male participants of the Multicenter AIDS Cohort Study who underwent assessment of frailty and non-contrast cardiac CT scanning; of these, 747 men also underwent coronary CT angiography (CCTA). Frailty was defined as having ≥3 of 5 of the following: weakness, slowness, weight loss, exhaustion, and low physical activity. Coronary artery calcium (CAC) was assessed by non-contrast CT, and total plaque score (TPS), mixed plaque score (MPS), and non-calcified plaque score (NCPS) by CCTA. Multivariable-adjusted regression was used to assess the cross-sectional associations between frailty and subclinical coronary atherosclerosis. RESULTS: Mean (SD) age of participants was 54 (7) years; 31% were black. Frailty existed in 7.5% and 14.3% of HIV-uninfected and HIV-infected men, respectively. After adjustment for demographics, frailty was significantly associated with prevalence of any CAC (CAC>0), any plaque (TPS>0), and mixed plaque (MPS>0) in HIV-uninfected but not in HIV-infected men (p-interactionHIV<0.05 for all). Among HIV-uninfected men, after adjustment for cardiovascular risk factors, frailty was significantly associated only with CAC>0 [Prevalence Ratio 1.27 (95%CI 1.02, 1.59)] and TPS>0 [1.19 (1.06, 1.35)]. No association was found for NCPS. CONCLUSIONS: Frailty was independently associated with subclinical coronary atherosclerosis among HIV-uninfected men, but not among HIV-infected men. Further work is needed to ascertain mechanisms underlying these differences and whether interventions that improve frailty (i.e. strength training) can improve cardiovascular outcomes.

Lipid levels in HIV-positive men receiving anti-retroviral therapy are not associated with copy number variation of reverse cholesterol transport pathway genes.

BACKGROUND: The exacerbation of HIV-1 associated dyslipidemia seen in a subset of patients receiving anti-retroviral therapy suggests that genetic factors put these individuals at greater risk of cardiovascular disease. Single nucleotide polymorphisms (SNPs) within genes of and influencing the reverse cholesterol transport (RCT) pathway are associated with lipid levels but little is known regarding their copy number variation (CNV). This form of quantitative genetic variation has the potential to alter the amount of gene product made, thereby also influencing lipid metabolism. RESULTS: To examine if CNV in RCT pathway genes was associated with altered serum lipid profiles in HIV-positive individuals receiving therapy, we designed a custom multiplex ligation-dependent probe amplification assay to screen 16 RCT genes within a subset of individuals from the Multicenter AIDS Cohort Study who show extreme lipid phenotypes. Verification of CNV was performed using a custom NanoString assay, and the Illumina HT-12 mRNA expression microarray was used to determine the influence of copy number on gene expression. Among the RCT genes, CNV was observed to be extremely rare. The only CNV seen was in the CETP gene, which showed a loss of copy in 1 of the 320 samples (0.3%) in our study. The genes in our study showed little variation in expression between individuals, and the variation seen was not related to any detected CNV. CONCLUSIONS: Whole gene CNV is uncommon in RCT pathway genes, and not a major factor in the development of highly active antiretroviral therapy (HAART) associated dyslipidemia.

The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status.

BACKGROUND: Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study. METHODS: We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses. RESULTS: Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], -3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001). CONCLUSIONS: Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects.

No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death.

The ε4 allele of the apolipoprotein E (ApoE) gene may have important interactions with physical health and cognitive function among individuals with HIV disease. The purpose of this study is to examine the relationships between ε4, HIV disease, age, neuropsychological impairment, and death in a large, well-characterized study sample. A total of 2846 men participating in the Multicenter AIDS Cohort Study had ApoE genotyping and neuropsychological test data available for analysis. We found a significant association between HIV infection and time to death (from any cause), as well as older age, race, and education. But, ApoE status was not significantly associated with time to death. Similarly, we found a significant association between HIV infection and time to incident cognitive impairment, as well as age, education, and HIV serostatus; Apoε4 status was not related to incident cognitive impairment. There were no significant interactions between ApoE, HIV infection, and age on cognitive impairment. These data replicate and strengthen prior findings of the lack of association between ApoE ε4 and cognitive outcomes in HIV disease. We conclude that within the specific constraints of an exclusively male study in which the majority of participants were less than 65 years of age (range 22-87 years), it appears reasonable to conclude that the ε4 allele is not significantly interacting with HIV serostatus.

HIV therapy, metabolic and cardiovascular health are associated with glomerular hyperfiltration among men with and without HIV infection.

OBJECTIVE: Diabetes and hypertension, common conditions in antiretroviral-treated HIV-infected individuals, are associated with glomerular hyperfiltration, which precedes the onset of proteinuria and accelerated kidney function decline. In the Multicenter AIDS Cohort Study, we examined the extent to which hyperfiltration is present and associated with metabolic, cardiovascular, HIV and treatment risk factors among HIV-infected men. DESIGN: Cross-sectional cohort using direct measurement of glomerular filtration rate by iohexol plasma clearance for 367 HIV-infected men and 241 HIV-uninfected men who were free of chronic kidney disease. METHODS: Hyperfiltration was defined as glomerular filtration rate above 140-1 ml/min per 1.73 m per year over age 40. Multivariate logistic regression was used to estimate the odds ratios (ORs) of prevalent hyperfiltration for metabolic, cardiovascular, HIV and cumulative antiretroviral exposure factors. RESULTS: Among individuals without chronic kidney disease, the prevalence of hyperfiltration was higher for HIV-infected participants (25%) compared to uninfected participants (17%; P = 0.01). After adjustment, HIV infection remained associated with hyperfiltration [OR 1.70, 95% confidence interval (CI) 1.11-2.61] and modified the association between diabetes and hyperfiltration, such that the association among HIV-uninfected men (OR 2.56, 95% CI 1.33-5.54) was not observed among HIV-infected men (OR 1.19, 95% CI 0.69-2.05). These associations were independent of known risk factors for hyperfiltration. Indicators of hyperglycemia and hypertension were also associated with hyperfiltration as was cumulative zidovudine exposure. CONCLUSION: Hyperfiltration, a potential modifiable predictor of kidney disease progression, is significantly higher among antiretroviral-treated HIV-infected men. Furthermore, HIV-infection nullifies the association of diabetes and hyperfiltration present in HIV-uninfected men.

HAART-associated dyslipidemia varies by biogeographical ancestry in the multicenter AIDS cohort study.

Highly active antiretroviral therapy (HAART) has been successful in delaying the progression to AIDS in HIV-1-infected individuals. Exposure to HAART can result in metabolic side effects, such as dyslipidemia, in a subset of recipients. Longitudinal data and frozen peripheral blood mononuclear cell pellets were obtained from 1,945 men enrolled in the Multicenter AIDS Cohort. Individuals were genotyped for ancestry informative markers (AIMs) and stratified by biogeographical ancestry (BGA). Then serum levels of total cholesterol (TCHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TRIG) were examined controlling for a number of HIV and HAART-related covariates using multivariate mixed-effects linear regression. HIV-1 infection, in the absence of HAART, was associated with altered lipid levels for all phenotypes tested when compared to HIV-negative men. HIV-1-infected men receiving HAART also had significantly different lipid levels compared to HIV-negative men, except for LDL-C. There were statistically significant interactions between BGA and HIV/HAART status for all lipids tested. BGA remained significantly associated with lipid levels after controlling for other HIV and HAART-related covariates. There was low concordance between self-reported race (SRR) and BGA in admixed populations. BGA performed better than SRR in our statistical models. Lipid profiles in untreated HIV-1-positive men and HIV-1-positive men receiving HAART differ from HIV-negative men and this effect varies by BGA. BGA performed better in our statistical analysis as a racial classifier but SRR remains a good clinical surrogate for BGA.

Replication of RYR3 gene polymorphism association with cIMT among HIV-infected whites.

To replicate the association of variants in RYR3 gene with common carotid intima-media thickness (cIMT), a surrogate marker of atherosclerosis, we genotyped single nucleotide polymorphisms (SNPs) rs2229116 and rs7177922 in a sub-population of 244 HIV-positive and HIV-negative men. SNP rs2229116 was associated with common cIMT in HIV infected white men after adjusting for age and use of stavudine (d4T). The association was more evident at younger ages and decreased among older individuals.

Copy number variation of KIR genes influences HIV-1 control.

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.

Investigation of association between PFO complicated by cryptogenic stroke and a common variant of the cardiac transcription factor GATA4.

Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke.

Screening low-frequency SNPS from genome-wide association study reveals a new risk allele for progression to AIDS.

BACKGROUND: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance. METHODS: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections. RESULTS: Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10⁻6), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10⁻¹5, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10⁻¹°, OR = 2.9) and NOTCH4 (9.08 × 10⁻°7, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10⁻°6, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant. CONCLUSIONS: Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.

Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study.

BACKGROUND: Cytokine stimulation of B-cell proliferation may be an important causative mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus (EBV) may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine-signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. PATIENTS AND MATERIALS: We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N = 160) or post-AIDS diagnosis (N = 90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR = 0.3; 95% CI 0.1, 0.7) but not systemically (CC vs. CT/TT: OR = 1.0; 95% CI 0.5, 1.9) (Pheterogeneity = 0.03). Carriage of two copies of the 'low IL10' haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend = 0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. CONCLUSION: Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important causative pathway for EBV-related lymphomagenesis.

Common genetic variation and the control of HIV-1 in humans.

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

MIF (macrophage migration inhibitory factor) promoter polymorphisms and susceptibility to severe malarial anemia.

BACKGROUND: Severe malarial anemia (SMA) resulting from Plasmodium falciparum infection is one of the leading causes of childhood mortality in sub-Saharan Africa. The innate immune mediator macrophage migration inhibitory factor (MIF) plays a critical role in the pathogenesis of SMA. METHODS: To investigate the influence of MIF genetic variation on susceptibility to SMA, haplotypes of the MIF -173G/C and -794CATT5-8 polymorphisms were examined in a cohort of Kenyan children. RESULTS: A statistically significant relationship between increasing frequencies of longer CATT repeats at -794 and increasing severity of malarial anemia was observed. In addition, there was a strong association between lower MIF concentrations and longer CATT repeats. Multivariate logistic regression analyses demonstrated that the 6G haplotype (ie, MIF -794CATT6/-173G) was associated with protection against SMA, whereas carriers of the 7C or 8C haplotype had increased risk of developing SMA. Furthermore, carriers of the 7C or 8C haplotype had reduced plasma MIF levels during acute disease. CONCLUSIONS: The findings demonstrate that variation in the MIF promoter influences susceptibility to SMA and peripheral MIF production. However, the MIF -173 and -794 polymorphisms appear to have both independent and interactive effects on different measures of disease severity, suggesting that MIF plays a complex role in malarial pathogenesis.