Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype

OBJECTIVES: Several natural polymorphisms in the genes for the human CC-chemokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are not resistant to sexual transmission of HIV-1, but progress significantly more slowly to HIV-1 disease. It is therefore important to determine the global distributions of CCR2-64I and CCR5-59653T genetic variants and define the degree of linkage between them. DESIGN AND METHODS: We have developed molecular beacon-based, real-time PCR allele discrimination assays for all three chemokine receptor mutations, and used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations. RESULTS: CCR2-64I and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest (approximately 35%) in Africa and Asia but decrease in Northern Europe. We confirm that CCR2-64I is in strong linkage disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for both CCR2-64I and CCR5-59653T polymorphisms). CONCLUSIONS: The greater geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with that of CCR5-delta32 suggests that it is a much older mutation whose origin predates the dispersal of modern humans.     

CCR2b-64I allelic polymorphisms in advanced HIV-infected Koreans accelerate disease progression

Genetic polymorphisms of chemokine genes and chemokine-receptor genes in HIV-infected patients have been associated with delayed progression of this disease. The allelic frequencies of these genetic variants also differ between ethnic groups. To investigate the effects of the SDF1 and CCR2b genotypes on disease progression, survival of 200 HIV-infected persons for whom at least four subsequent immunologic data items had been collected was analyzed. A genotyping assay of SDF1 and CCR2b genes was carried out using polymerase chain reaction-restriction fragment length polymorphism analyses. HIV-infected persons heterozygous for the SDF1-3'A or CCR2b-64I alleles were included in the survival analysis, but homozygotes were excluded because of a very small sample number. Neither the CCR2b-+/64I allele nor the SDF1-+/3'A allele, separately or in combination, had a significant impact on survival during the asymptomatic period of HIV infection. However, CCR2b-+/64I alleles were associated with accelerated disease progression during the advanced period of HIV infection. The survival time of HIV-infected people with CCR2b-+/64I and SDF1-+/+ genotypes was significantly shorter than those of the other groups (p < 0.01), but this effect was not apparent in persons with CCR2b-+/64I alleles and SDF1-+/3'A genotypes. These results suggest that the effect of CCR2b-64I polymorphisms on disease progression may differ according to the stage of HIV infection and interactions with other gene variants.     

A CCR2-V64I polymorphism affects stability of CCR2A isoform

OBJECTIVE: A valine to isoleucine substitution at position 64 of CCR2 (CCR2-64I) is associated with a delay in progression to AIDS in HIV-1-infected individuals. The aim of the present study is to elucidate the molecular mechanism underlying the effect of this allele. DESIGN: We analysed the effect of the 64I substitution on levels of expression of CCR2A and CCR2B, two CCR2 isoforms produced by alternative splicing. METHODS: Sendai virus vector was used to express CCR2 molecules. RESULTS: While CCR2B trafficked well to the cell surface, CCR2A, which differs from CCR2B only by the sequence of its C-terminal cytoplasmic tail, was detected predominantly in the cytoplasm. The level of expression of CCR2A-64I was significantly higher than that of CCR2A without the substitution. On the other hand, the 64I substitution did not affect levels of CCR2B expression. Pulse-chase experiments revealed that the 64I substitution increased the half-life of CCR2A in cells. When co-expressed with CCR5, CCR2A-64I interfered more severely with cell surface expression of CCR5 than did wild-type CCR2A. Furthermore, immunoprecipitation experiments showed that CCR2A co-precipitated with an immature form of CCR5. CONCLUSION: These results suggest that CCR2A binds to CCR5 in the cytoplasm and down-modulates its surface expression. We propose that the increased ability of CCR2A-64I to down-modulate CCR5 expression might be a possible cause of a delay in HIV-1 disease progression in patients with this allele.     

C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis

RATIONALE: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin. OBJECTIVES: We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells. METHODS: In addition to the known CCR5 Delta 32 insertion/deletion, we evaluated a further eight single-nucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects. MEASUREMENTS AND MAIN RESULTS: In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage >or= II versus stages 0 and I) at presentation (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.96-13.7; corrected p = 0.02), at 2 (OR, 6.6; 95% CI, 2.5-17.6; corrected p = 0.006), and at 4 years follow-up (OR, 6.8; 95% CI, 2.5-18.0; corrected p = 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8-16.4; corrected p = 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5-23.1; corrected p = 0.0009). CONCLUSIONS: No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between CCR5 haplotype HHC and persistent lung involvement in sarcoidosis.     

Analysis of CCR5-Delta 32 and CCR2-V64I polymorphisms in a cohort of Spanish HCV patients using real-time polymerase chain reaction and fluorescence resonance energy transfer technologies

Summary.  Nowadays it is clear that chemokine–chemokine receptor interactions are important in chronic hepatitis C virus (HCV) infection. The objective of the present study was to elucidate the involvement of the CCR5 -Δ32 and CCR2- V64I polymorphisms in the response to the HCV infection, as well as in the histological damage and the outcome of the infection. A cohort of 139 patients with hepatitis C and 100 healthy blood donors were analysed for both polymorphisms using real-time polymerase chain reaction (PCR) and LightCycler^TM technology. We have detected the CCR5 -Δ32 allele in 15 of 278 HCV chromosomes (5.4%) and 15 of 200 control chromosomes (7.5%). The CCR2- V64I allele was present in 24 of 278 HCV chromosomes (8.6%) and 19 of 200 control chromosomes (9.5%). Analysis of the histological parameters showed no statistical significance when comparing the patients carrying the variants vs the cases with the wild-type allele. Our results seem to indicate that the CCR5 -Δ32 and CCR2 -V64I polymorphisms are not related to the response to HCV infection, histological damage and outcome of infection in our cohort of Spanish HCV patients.     

Association of CCR5-59029 A/G and CCR2-V64I Variants with Renal Allograft Survival

Background: Despite advances in the medical care of renal transplant recipients which have led to an improvement in allograft survival, renal allograft rejection is still a major ob-stacle to successful organ transplantation. Understanding the mechanisms contributing to allograft rejection will be of great importance for the development of efficient antirejection strategies. Objective: The aim of current investigation was to study the impact of polymor-phisms of CCR5Δ32, CCR5- 59029 A/G and CCR2-V64I on renal allograft survival. Methods: Using PCR and PCR-RFLP methods in 84 renal transplant recipients, the influ-ence of CCR5Δ32, CCR5- 59029 A/G and CCR2-V64I polymorphisms on renal allograft survival in two rejector and non-rejector groups were examined. Rejector group was de-fined as having rejection before 1 year and non-rejector group had stable graft function at least for 5 years. Results: Significant reductions were found in the risk of renal transplant rejection in recipients possessing the CCR2-64I (A) allele (p=0.03) or 59029-A allele (p=0.03) compared to non-rejector group. There were no significant differences in the fre-quency of CCR5Δ32 polymorphism in rejector group compared to non-rejector group (p>0.05). Conclusion: It was possible to conclude that the chemokine receptors CCR2-V64I (A) and CCR5- 59029 A alleles may influence renal allograft survival.     

Genetic variations in CC chemokine receptors and hypertension

BACKGROUND: CC-chemokine receptor 5 (CCR5) is a co-receptor for human immunodeficiency virus type 1 (HIV-1) infection. Homozygosity for a 32-base pair (bp) deletion (Delta32) in the CCR5 gene confers resistance to HIV-1. Previous studies found an increased prevalence of hypertension among CCR5-Delta32 homozygotes and among carriers of a polymorphism (CCR2-64I) found on the gene that codes a closely related chemokine receptor. The present study was carried out to verify these associations. METHODS: Subjects in this cross-sectional study were selected from the Global Repository at Genomics Collaborative, which includes patients and healthy control subjects enrolled at multiple clinical sites in the United States and other nations. The current study includes 2842 subjects with hypertension and 2893 nonhypertensive control subjects from white populations in the United States and Poland. Case and control subjects were frequency matched by age, gender, and birthplace. All subjects were genotyped for CCR5-Delta32 and CCR2-64I polymorphisms by established Taqman assays. RESULTS: The CCR5-Delta32 genotype was not found to be associated with hypertension (CCR5-Delta32 heterozygosity: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.87 to 1.14; CCR5-Delta32 homozygosity: OR 1.07, 95% CI 0.68 to 1.67) among these subjects. There was also no association between CCR2-64I genotype and hypertension (CCR2-64I heterozygosity: OR 0.96, 95% CI 0.83 to 1.10; CCR2-64I homozygosity: OR 1.18, 95% CI 0.73 to 1.92). These results changed little after adjustment for potential confounding variables. CONCLUSION: The results of the present study, which is much larger than previously published studies, provide no evidence that either CCR5-Delta32 or CCR2-64I is associated with hypertension.     

Chemokine receptor gene polymorphisms and risk of human T lymphotropic virus type I infection in Jamaica

Polymorphisms of some chemokine receptor genes and their ligands are associated with susceptibility and progression of human immunodeficiency virus infection. This study assessed whether these variants are also responsible for susceptibility to infection with human T lymphotropic virus (HTLV) type I. Frequencies of CCR5-Delta 32, CCR2-64I, and SDF-1-3'A genotype among 116 HTLV-I-positive and 126 HTLV-I-negative persons of African descent in Jamaica were 1.0%, 14.9%, and 5.4%, respectively. The association of HTLV-I infection with the most common variant, CCR2-64I, was examined in 532 subjects. Thirteen (5.4%) of 241 HTLV-I-negative subjects were homozygous for CCR2-64I, versus 3 (1.0%) of 291 HTLV-I-positive subjects (P=.005). Among HTLV-I carriers, provirus load and antibody titer were not significantly different in persons with CCR2-+/64I or CCR2-+/+. These findings suggest that CCR2-64I, or alleles in linkage disequilibrium with it, may affect the risk of HTLV-I infection in a recessive manner.     

The codon 64 polymorphism of the beta3-adrenergic receptor gene is not associated with coronary heart disease or insulin resistance in nondiabetic subjects and non-insulin-dependent diabetic patients.

Hyperinsulinemia has been shown to predict coronary heart disease (CHD) events in both nondiabetic subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, defects in genes that regulate insulin action could be responsible for an increased risk of CHD. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene has been linked with abdominal obesity, insulin resistance, and early-onset NIDDM. Therefore, we screened for this polymorphism among 185 unrelated nondiabetic subjects (101 men and 84 women; age, 56+/-1 years [mean +/- SEM]; body mass index [BMI], 27.8+/-0.3 kg/m2) with angiographically confirmed CHD (stenosis > 50% in > or = two coronary arteries), among 119 unrelated patients with NIDDM (90 men and 29 women; age, 62+/-1 years; BMI, 28.7+/-0.4 kg/m2; 95 had CHD by the same criteria and 24 had definite myocardial infarction [MI]), and among 82 healthy men (age, 54+/-1 years; BMI, 26.3+/-0.4 kg/m2) from our previous study. The frequency of the Trp64Arg allele of the beta3-adrenergic receptor gene was similar in nondiabetic patients with CHD (8%), NIDDM patients with CHD (7%), and nondiabetic subjects without CHD (7%). No association was found between cardiovascular risk factors and the codon 64 polymorphism of the beta3-adrenergic receptor gene in patients with CHD. Similarly, this polymorphism was not significantly related to insulin resistance in nondiabetic and NIDDM subjects with CHD evaluated by the euglycemic clamp technique. These results indicate that the Trp64Arg allele of the beta3-adrenergic receptor gene does not contribute to the risk of CHD in nondiabetic subjects and NIDDM patients.     

Effects of CCR5-delta32 and CCR2-64I alleles on disease progression of perinatally HIV-1-infected children: an international meta-analysis

OBJECTIVE: Among perinatally infected children, the effects of certain alleles of the CCR5 and CCR2 genes on the rate of disease progression remain unclear. We addressed the effects of CCR5-delta32 and CCR2-64I in an international meta-analysis. METHODS: Genotype data were contributed from 10 studies with 1317 HIV-1-infected children (7263 person-years of follow-up). Time-to-event analyses were performed stratified by study and racial group. Endpoints included progression to clinical AIDS, death, and death after the diagnosis of clinical AIDS. The time-dependence of the genetic effects was specifically investigated. RESULTS: There was large heterogeneity in the observed rates of disease progression between different cohorts. For progression to clinical AIDS, both CCR5-delta32 and CCR2-64I showed overall non-significant trends for protection [hazard ratios 0.84, 95% confidence interval (CI) 0.58-1.23; and 0.87, 95% CI 0.67-1.14, respectively]. However, analyses of survival showed statistically significant time-dependence. No deaths occurred among CCR5-delta32 carriers in the first 3 years of life, whereas there was no protective effect (hazard ratio 0.95; 95% CI 0.43-2.10) in later years (P=0.01 for the time-dependent model). For CCR2-64I, the hazard ratio for death was 0.69 (95% CI 0.39-1.21) in the first 6 years of life and 2.56 (95% CI 1.26-5.20) in subsequent years (P<0.01 for the time-dependent model). CCR5-delta32 and CCR2-64I offered no clear protection after clinical AIDS had developed. CONCLUSION: The CCR5-delta32 and CCR2-64I alleles are associated with a decreased risk of death among perinatally infected children, but only for the first years of life.     

Effects of CCR5-Delta32 and CCR2-64I alleles on HIV-1 disease progression: the protection varies with duration of infection

OBJECTIVE: To examine temporal variation in the effects of CCR5-Delta32 and CCR2-64I chemokine receptor gene polymorphisms on HIV-1 disease progression. DESIGN: Pooled analysis of individual patient data from 10 cohorts of HIV-1 seroconverters from the United States, Europe, and Australia. METHODS: We studied HIV-1 seroconverters of European (n = 1635) or African (n = 215) ancestry who had been genotyped for CCR5-Delta32 and CCR2-64I. We used Cox proportional hazards models with time-varying coefficients to determine whether the genetic protection against AIDS (1987 case definition) and death varied with time since seroconversion. RESULTS: Protection against AIDS conferred by CCR5-Delta32 held constant at a 31% (RH 0.69, 95% CI 0.54, 0.88) reduction in risk over the course of HIV-1 infection, whereas protection against death held constant at a 39% reduction in risk (RH 0.61, 95% CI 0.45, 0.88). When the period from AIDS to death was isolated, the survival benefit of CCR5-Delta32 diminished 2 years after AIDS. Protection against AIDS conferred by CCR2-64I was greatest early in the disease course. Compared with individuals without CCR5-Delta32 or CCR2-64I, individuals with one or two copies of CCR2-64I had a 58% lower risk of AIDS during the first 4 years after seroconversion (RH 0.42, 95% CI 0.23, 0.76), a 19% lower risk during the subsequent 4 years (RH 0.81, 95% CI 0.59, 1.12), and no significant protection thereafter. CONCLUSION: The protection against AIDS provided by CCR5-Delta32 is continuous during the course of infection. In contrast, the protection provided by CCR2-64I is greatest early in the course of infection.     

Increased macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosis.

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are two CC chemokines that induce lymphocyte migration. MIP-1alpha preferentially mediates chemotaxis of CD8 rather than CD4 lymphocytes, whereas the reverse is true for MIP-1beta. Both these chemokines recognize CCR5 as a cellular receptor in T lymphocytes and alveolar macrophages. We measured the concentrations of MIP-1alpha and MIP-1beta in bronchoalveolar lavage fluid (BALF) of 30 subjects affected by different stages of pulmonary sarcoidosis and 18 healthy normal subjects. We also evaluated the expression of CCR5 in alveolar macrophages and lymphocytes. The BALF concentrations of MIP-1alpha were significantly increased only in Stage II and III sarcoidosis. On the contrary, the concentrations of MIP-1beta were significantly increased at all stages. A striking increase of CCR5 expression was observed in both lymphocytes and macrophages of all patients, along with a trend to decreased positivity from Stage I to III of the disease. The MIP-1beta concentrations correlated with the number of total (r = 0.65, p = 0.0001) and both CD4 (r = 0.64, p = 0.0001) and CD8 (r = 0.62, p = 0.0001) lymphocytes; on the contrary, the MIP-1alpha concentrations correlated only with CD8 lymphocytes (r = 0.45, p = 0.002). Finally, significant negative correlations were observed between the neutrophil percentage and CCR5 expression in alveolar macrophages (r = -0.53, p = 0.005) and lymphocytes (r = -0.43, p = 0.01). Our results help to explain the mechanism of CD4 and CD8 recruitment and the possible involvement of CC chemokines in the fibrotic progression of sarcoidosis.     

Better CD4+ T cell recovery in Brazilian HIV-infected individuals under HAART due to cumulative carriage of SDF-1-3'A, CCR2-V64I, CCR5-D32 and CCR5-promoter 59029A/G polymorphisms

Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3'A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3'A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/microl/month, respectively). Regression logistic analysis showed that the CCR5-D32/CCR2-V64I association was predictor of positive CD4+ T cell slope after HAART. The distribution of polymorphisms did not differ between HIV-1-infected and uninfected individuals, but differed from more homogenous ethnic groups probably reflecting the miscegenation of the Brazilian population. We add further evidence of the role of these polymorphisms by showing that the CD4 gain was influenced by carriage of one or more of the polymorphisms studied here. These results highlight the possibility that these genetic traits can be useful to identify patients at risk for faster progression to AIDS or therapeutic failure.     

C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome

Sarcoidosis is thought to result from the interaction between an unknown environmental antigenic trigger and the host's genetic susceptibility. We hypothesized that sarcoidosis, or one of the disease subsets, could be associated with single nucleotide polymorphisms of C-C chemokine receptor 2 (CCR2) gene. Eight single-nucleotide polymorphisms in CCR2 were studied in a total of 304 Dutch individuals (90 non-L?fgren sarcoidosis, 47 L?fgren's syndrome, 167 control subjects). From the investigated CCR2 polymorphisms, nine haplotypes were deduced (haplotypes 1-9). In patients with L?fgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position -6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects (74% vs. 38% respectively, p < 0.0001), whereas no difference was found between non-L?fgren sarcoidosis and control subjects (both 38%). The association between CCR2-haplotype 2 carriage frequency and L?fgren's syndrome (odds ratio, 4.4; p < 0.0001) remained significant after adjustment for human leukocyte antigen haplotype DRB1*0301-DQB1*0201 (odds ratio, 11.5; p < 0.0001) and female sex (odds ratio, 3.2; p = 0.003), two known risk factors for L?fgren's syndrome. In conclusion, this report describes a strong association between CCR2-haplotype 2 and L?fgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association.     

CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis.

CC chemokines play an important role in the pathogenetic mechanisms of interstitial lung disease, while a downregulation of CC chemokine receptor (CCR)5 in the fibrotic stages of sarcoidosis has been observed. To evaluate the involvement of CC chemokines and the expression of CCR5 in idiopathic pulmonary fibrosis (IPF) and, more specifically, in usual interstitial pneumonia, 35 subjects were studied. CC chemokine ligand (CCL)2, CCL3 and CCL4 levels were measured in the bronchoalveolar lavage fluid (BALF) of 18 nonsmoker control subjects and 17 patients affected by IPF. CCR5 expression was evaluated in alveolar macrophages and lymphocytes. The BALF levels of all chemokines were significantly increased in IPF: median (range) CCL3 1.6 (1.0-11.1) versus 1.2 (0.0-3.8) pg x mL(-1); CCL4 6.2 (1.3-96.0) versus 3.4 (0.3-6.8) pg x mL(-1); and CCL2 60.1 (16.7-251.3) versus 4.6 (0.5-119.4) pg x mL(-1). CCL2 levels correlated negatively with the carbon monoxide diffusing capacity of the lung (D(L,CO)) and arterial oxygen tension. CCR5 expression was significantly reduced in lymphocytes from IPF compared with controls. The CC chemokines investigated are involved in the inflammatory mechanisms of idiopathic pulmonary fibrosis, and the results are in agreement with the hypothesis of a downregulation of the T-helper 1 immunological response in this disease.     

CC chemokine receptor 5 delta32 and CC chemokine receptor 2 64I polymorphisms do not influence the virologic and immunologic response to antiretroviral combination therapy in human immunodeficiency virus type 1-infected patients

To investigate the influence of the CC chemokine receptor 2 64I and CC chemokine receptor 5 delta32 polymorphisms on the virologic and immunologic response of human immunodeficiency virus type 1 (HIV-1)-infected patients to highly active antiretroviral therapy, data from 4 clinical studies were pooled. The prevalence of the CCR5 delta32 polymorphism was 21% (27 of 130 subjects), and the prevalence of the CCR2 64I polymorphism was 15% (19 of 130 subjects). There were no major differences between subjects with and without polymorphisms in the CCR5 and/or CCR2 genes with respect to the rate of initial viral clearance, proportion of subjects with plasma HIV-1 RNA levels below the lower limit of quantification, rate of virologic treatment failure, immunologic responses, and disease progression during 96 weeks of follow-up.     

Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.     

Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals

Normal B-lymphocyte maturation and proliferation are regulated by chemotactic cytokines (chemokines), and genetic polymorphisms in chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1-infected persons were examined for associations of previously described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and CCR2 chemokine receptor gene variants with the risk of B-cell non-Hodgkin's lymphoma (NHL). The SDF1-3'A chemokine variant, which is carried by 37% of whites and 11% of blacks, was associated with approximate doubling of the NHL risk in heterozygotes and roughly a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3'A/3'A homozygotes and 22 (10%) of 202 SDF1-+/3'A heterozygotes, compared with 24 (5%) of 514 wild-type subjects. The acquired immunodeficiency syndrome (AIDS)-protective chemokine receptor variant CCR5-triangle up32 was highly protective against NHL, whereas the AIDS-protective variant CCR2-64I had no significant effect. Racial differences in SDF1-3'A frequency may contribute to the lower risk of HIV-1-associated NHL in blacks compared with whites. SDF-1 genotyping of HIV-1-infected patients may identify subgroups warranting enhanced monitoring and targeted interventions to reduce the risk of NHL.     

Decreased serum osteoprotegerin levels in patients with cardiac syndrome X

Receptor activator of nuclear factor KB (RANK) and osteoprotegerin (OPG) represent the ligand and decoy receptor, respectively, of a pleiotropic cytokine system that regulates bone metabolism and vascular biology. Several studies supported systemic microvascular abnormalities in patients with cardiac syndrome X (CSX). This study investigates serum OPG levels in healthy obese subjects and healthy lean controls affected by cardiac syndrome X. METHODS: We compared the OPG levels in 8 patients with cardiac syndrome X [2 males, 6 females; age: 46+/-6 yr; body mass index (BMI): 30+/-5 kg/m2] with 24 obese subjects (8 males, 16 females; age: 38+/-5 yr; BMI: 35+/-5 kg/m2) and 15 healthy lean controls (6 males, 9 females; age: 36+/-5 yr; BMI: 23+/-2 kg/m2; BMI<25kg/m2). RESULTS: Serum OPG levels in patients with cardiac syndrome X were lower than those in obese subjects and lean controls (11.45+/-8.36 pg/ml, 14.78+/-8.22 pg/ml, 19.24+/-6.96 pg/ml, respectively, cardiac syndrome X vs lean controls, p=0.039). CONCLUSIONS: Serum OPG levels are lower in patients with CSX. Further studies on the mechanisms of OPG in microangiopathy may help to evaluate the OPG system role as a marker for disease activity, prognosis and response to therapy in cardiovascular diseases.     

CC chemokine receptor 5 and interleukin-1 receptor antagonist gene polymorphisms in patients with primary Sjögren's syndrome

OBJECTIVE: Interleukin-1 receptor antagonist (IL-1Ra) and also mononuclear cell-attractant chemokines CCL3, CCL4 and CCL5 have been implicated in the immunopathogenesis of primary Sj?gren syndrome (pSS). Both the gene coding for receptor CCR5 binding the aforementioned CCL ligands and the gene for IL-1Ra are polymorphic. We have therefore in a case control study assessed the putative role of these "candidate" polymorphic genes in the inflammatory process in Sj?gren syndrome. METHODS: DNA was obtained from 39 unrelated patients with primary Sj?gren's syndrome and 76 unrelated healthy controls; all subjects were Caucasians of Slovak origin. CCR5 delta 32 and IL-1Ra VNTR polymorphisms were genotyped by PCR-SSP. RESULTS: The frequencies of CCR5 delta 32 in patients with pSS were different from that in control subjects: there was an apparent decrease of the mutant allele in the patient group. CCR5 delta 32/CCR5 heterozygosity was associated with a reduced relative risk of pSS (OR 0.35, p = 0.043). There was no difference in the distribution of the alleles of the IL-1Ra VNTR polymorphism between the groups of pSS patients and control subjects. CONCLUSION: In this population of patients with Sj?gren's syndrome, the frequency of CCR5 delta 32/CCR5 genotype is significantly decreased. The data suggests that carrier status for the CCR5 delta 32 allele may contribute to protection from the development of primary Sj?gren's syndrome. In contrast, IL-1Ra VNTR polymorphism does not confer susceptibility to primary Sj?gren's syndrome in Slovak Caucasians.