Joan Fibla

Vitamin D Receptor Gene Haplotypes and Susceptibility to HIV-1 Infection in Injection Drug Users

Vitamin D receptor (VDR) participates in multiple immune functions. Here, we determined whether VDR gene-sequence variations are associated with intersubject differences in the risk of acquiring human immunodeficiency virus type 1 (HIV-1) infection. We assessed this in 460 males exposed to HIV-1 by injection drug use (335 infected and 125 uninfected) and 124 seronegative healthy subjects. Multilocus logistic regression analysis revealed haplotypes for rs11568820, rs4516035, rs10735810, rs1544410, and rs17878969 polymorphisms showing association with protection to HIV-1 infection (odds ratio, 0.4 [95% confidence interval, 0.22-0.72]; P = .0025), which remained significant after correction for multiple testing. We infer that VDR haplotypes might influence the risk of HIV-1 acquisition.

Host Genetic Background at CCR5 Chemokine Receptor and Vitamin D Receptor Loci and Human Immunodeficiency Virus (HIV) Type 1 Disease Progression among HIV-Seropositive Injection Drug Users

The effect of polymorphisms on genes encoding the CCR5 chemokine receptor and vitamin D receptor (VDR) in human immunodeficiency virus (HIV) type 1 disease progression was analyzed in a cohort of 185 HIV-seropositive injection drug users. Results confirmed a lack of association in patients with HIV disease between CCR5 wtDelta32 heterozygosity and a slow progression to AIDS and to a CD4 cell count <200 cells/microL. In contrast, a more rapid disease progression was associated with the VDR-BB genotype. A higher proportion of this genotype was found in patients with <200 CD4 cells/microL (P=.009; odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3-4.7), as well as a faster progression both to AIDS (1993 CDC classification [CDC 1993]) and to a CD4 cell count <200 cells/microL. When the analysis was restricted to patients with a VDR-bb genetic background, patients with CCR5 wtDelta32 heterozygosity were overrepresented in CDC 1993 nonprogressors (P=.033; OR, 0.28; 95% CI, 0.08-0.92) and in those with >200 CD4 cells/microL (P=.062; OR, 0.26; 95% CI, 0.06-1.08). Also, patients with CCR5 wtDelta32 heterozygosity showed a slow progression both to AIDS CDC 1993 and to a CD4 cell count <200 cells/microL.

Association of androgen receptor gene, CAG and GGN repeat length polymorphism and impulsive-disinhibited personality traits in inmates: the role of short-long haplotype.

Objective This study analyses the association between impulsive-disinhibited personality traits and the androgen receptor CAG and GGN repeat polymorphisms in both inmates and control samples. Methods We used two samples: 153 inmates (mean age= 33.31 years; standard deviation: 8.6; range: 20–63) and 108 controls (mean age= 26.71 years; standard deviation: 9.68; range: 17–53). A disinhibited personality construct was measured using the following personality scales: Sensation Seeking, Aggression-Hostility, Psychoticism, Sensitivity to Reward, Novelty Seeking and Impulsivity. A factor analysis of the six scales provided a normalized z index that was taken as a measure of impulsive-disinhibited personality. Results Our data show that inmates carrying CAG short and GGN long haplotype group (short–long haplotype) obtained higher scores on all personality scales. Differences were found for the Impulsive Sensation-Seeking scale (age-adjusted multivariate analysis, P<0.016) and z index (P<0.036). When comparing extreme groups in the impulsive-disinhibited personality index (taking the 75th percentile as a cut-off), carriers of the short–long haplotype were more prevalent in the extreme high group (30 vs. 10%: unadjusted odds ratio=3.8; 95% confidence interval=1.5–9.8; age-adjusted odds ratio=4.4; 95% confidence interval=1.6–12; P<0.004). Conclusion Our findings suggest that the androgen receptor CAG and GGN polymorphisms might influence impulsive-disinhibited personality traits.

Impulsive-disinhibited personality and serotonin transporter gene polymorphisms: Association study in an inmate’s sample

The association between different impulsive-disinhibited personality traits with 5-HTTLPR and 5-HTTVNTR genetic polymorphisms was examined in an imprisoned male sample. Higher scores of the impulsive-disinhibited personality traits tended to be associated with carrying one or two copies of the 5-HTTPLR S allele (S/S homozygous and S/L heterozygous), and carrying two copies of the 5-HTTVNTR 12 allele (12/12 homozygous). Genotype, allele, haplotype and extended genotype distribution between low and high impulsive-disinhibited groups confirmed this association. Allele S and genotypes S/S+S/L at the 5-HTTLPR locus and allele 12 and genotype 12/12 at the 5-HTTVNTR locus were overrepresented in the high scoring group. Accordingly, allele S and allele 12 conferred a trend for risk to be in the high scoring group with an odds ratio (OR) of 1.8 (p < 0.035) and 1.7 (p < 0.014), respectively. In addition, extended genotype distribution shows that those S allele carriers (S/S homozygote and S/L heterozygote) that were also 12/12 homozygote, were overrepresented in the high scoring group (OR = 3.2; p < 0.004). The main risk of being in the high scoring group was assigned to those carrying two copies of the S-12 haplotype (OR = 5.7; p < 0.0007). We discuss the possible relationship between the two genetic serotonin polymorphisms and the personality impulsive-disinhibited traits investigated.

Association between AIDS disease progression rates and the Fok-I polymorphism of the VDR gene in a cohort of HIV-1 seropositive patients☆

In addition to its role in mineral metabolism, 1,25-dihydroxivitamin D3 (1,25(OH)2D3) also has immunomodulatory effects. Vitamin D receptor (VDR) mediates genomic actions of 1,25(OH)2D3, by acting as a transcription factor that modulates the expression of several 1,25(OH)2D3 response genes. Variations at the VDR locus have been associated with susceptibility and progression to several immune diseases. We investigated the association between rates of progression to acquired immunodeficiency syndrome (AIDS) and the Fok-I polymorphism, which is located at the initiation codon of the VDR gene. The study was performed with a cohort of 185 patients infected with human immunodeficiency virus type 1 (HIV-1): all belonged to the intravenous drug abuse risk group. Progression to AIDS was according to the Centers for Disease Control 1993 criterion (CDC-1993). In addition, a first drop in CD4 cell count to below 200 microL(-1) was considered as outcome. Patients who reached outcomes during follow-up were considered progressors. Non-progressors were those patients remaining outcome-free after a minimum follow-up of 8 years. Heterozygous at the Fok-I polymorphism were over-represented in the group of patients that progressed to AIDS CDC-1993 (50% of progressors versus 36% of non-progressors, P=0.061; risk ratio (RR)=1.38 (95% confidence interval (CI): 0.98-1.96)) and in the group of patients that showed a drop in CD4 cell count to below 200 microL(-1) (52% of progressors versus 36% of non-progressors, P=0.037; RR=1.44 (95% CI: 1.02-2.03)). Mean time to AIDS CDC-1993 was shorter for those with Ff genotype than for those with FF and ff genotypes (non-Ff genotype patients), (log rank test P=0.035; Cox hazard ratio (HR) for Ff versus non-Ff=1.53 (95% CI: 1.0-2.33), P=0.047). In addition the drop in CD4 cell count to below 200 microL(-1) was reached faster in Ff carriers than in non-Ff patients (log rank test P=0.015; HR for Ff versus non-Ff=1.77 (95% CI: 1.12-2.8), P=0.014). According to these results, HIV-1 seropositive patients carrying the Ff genotype could be considered prone to a faster progression to AIDS.

Analysis of meiotic recombination in 22q11.2, a region that frequently undergoes deletions and duplications

BackgroundThe 22q11.2 deletion syndrome is the most frequent genomic disorder with an estimated frequency of 1/4000 live births. The majority of patients (90%) have the same deletion of 3 Mb (Typically Deleted Region, TDR) that results from aberrant recombination at meiosis between region specific low-copy repeats (LCRs).MethodsAs a first step towards the characterization of recombination rates and breakpoints within the 22q11.2 region we have constructed a high resolution recombination breakpoint map based on pedigree analysis and a population-based historical recombination map based on LD analysis.ResultsOur pedigree map allows the location of recombination breakpoints with a high resolution (potential recombination hotspots), and this approach has led to the identification of 5 breakpoint segments of 50 kb or less (8.6 kb the smallest), that coincide with historical hotspots. It has been suggested that aberrant recombination leading to deletion (and duplication) is caused by low rates of Allelic Homologous Recombination (AHR) within the affected region. However, recombination rate estimates for 22q11.2 region show that neither average recombination rates in the 22q11.2 region or within LCR22-2 (the LCR implicated in most deletions and duplications), are significantly below chromosome 22 averages. Furthermore, LCR22-2, the repeat most frequently implicated in rearrangements, is also the LCR22 with the highest levels of AHR. In addition, we find recombination events in the 22q11.2 region to cluster within families. Within this context, the same chromosome recombines twice in one family; first by AHR and in the next generation by NAHR resulting in an individual affected with the del22q11.2 syndrome.ConclusionWe show in the context of a first high resolution pedigree map of the 22q11.2 region that NAHR within LCR22 leading to duplications and deletions cannot be explained exclusively under a hypothesis of low AHR rates. In addition, we find that AHR recombination events cluster within families. If normal and aberrant recombination are mechanistically related, the fact that LCR22s undergo frequent AHR and that we find familial differences in recombination rates within the 22q11.2 region would have obvious health-related implications.

Incremental effect for antisocial personality disorder genetic risk combining 5-HTTLPR and 5-HTTVNTR polymorphisms

As the serotonin transporter gene (SLC6A4 or 5-HTT) is a key regulator of central serotonergic activity, several association studies between Antisocial Personality Disorder (APD) and the SLC6A4 polymorphisms have been conducted in the last decade. In the present study, the role of both 5-HTTLPR and 5-HTTVNTR polymorphisms of the SLC6A4 gene in APD is investigated. A sample of 147 male inmates was analyzed. APD was assessed by Alujas Antisocial Personality Disorder Scale, a measure that correlates 0.73 with the dimensional score of DSM-IV APD and 0.62 with factor II of the Psychopathy Checklist-Revised. Inmates presenting both 5-HTTLPR S/S+S/L and 5-HTTVNTR 12/12 had a higher risk of being classified in the APD group (Odds ratio=3.48). The results also showed that the genotype and haplotype distribution was more dissimilar when extreme groups were compared with odds ratios up to 6.50. Our results supported that, in addition to the widely investigated 5-HTTLPR polymorphism, the 5-HTTVNTR polymorphism might be an interesting candidate for association studies with APD. Results also suggested that previous failures to replicate the association between serotonin transporter gene polymorphisms and APD, or similar phenotypes, could have been due to an under-representation of extremely high APD subjects in the samples analyzed.

Immunophenotype of Vitamin D Receptor Polymorphism Associated to Risk of HIV-1 Infection and Rate of Disease Progression

Vitamin-D-receptor (VDR) mediates immunomodulatory effects of vitamin-D₃ (VD₃). The VDR-rs1544410_GG polymorphism has been associated with delayed progression rates to AIDS and resistance to HIV-1 infection. The aim of the present study was to investigate differences in VD₃ mediated effects on rs1544410 genotyped dendritic cells (DCs) and macrophages (MDM), key cells involved in HIV-1 infection. Immature DCs exhibited lower b-actin-normalized VDR mRNA expression in rs1544410_GG compared to cells with a rs1544410_AA genotype. VD₃ response on cell differentiation markers (CD14 inhibition and CD209 induction) was two-fold higher in rs1544410_AA (CD209, p=0.012; CD14, p=0.02). HIV-1-LTR reporter gene activity in MDM was boosted by VD₃; however, the effect was up to 50% higher in rs1544410_AA. We conclude that the rs1544410_AA association with progression to AIDS and resistance to HIV-1 appears to be linked to an enhanced response to VD₃.

Interactions among impulsiveness, testosterone, sex hormone binding globulin and androgen receptor gene CAG repeat length.

Impulsive personality phenotype has been extensively related with genetic and hormonal factors. This study has two objectives: a) to analyse the interactions between testosterone levels and CAG repeat length polymorphism as a modulator of androgen receptor (AR) sensitivity with regard to impulsiveness traits, and b) to evaluate the contribution of other biological variables as Luteinising Hormone, Follicle Stimulating Hormone, Sex Hormone Binding Globulin (LF, FSH, SHBG) and albumin in the relationship between testosterone levels and AR CAG length polymorphism with impulsiveness. A sample of 105 healthy males (mean age 26.71±9.68 SEM) was analysed resulting in three groups of subjects according to CAG repeat lengths. Impulsiveness was measured through the Barratts Impulsiveness Personality Scale, including three components: Motor Impulsiveness, Cognitive Impulsiveness and Non-Planning Impulsiveness. A series of ANOVAS and linear regression models predicting impulsiveness scales were conducted. Age, hormones, CAG repeat length and hormone×CAG repeat interactions were included in the regression models as independent variables. Results show that subjects with short or medium CAG repeat length tended to show higher impulsiveness phenotypes compared to long CAG repeat. The interaction between Free Testosterone and CAG, and between SHBG and CAG accounted for differences on impulsiveness (R: .47, R(2): .22 and R: .43; R(2): .18, respectively).This pattern was especially observed for the short CAG repeat group and Motor Impulsiveness.

IFNL4 rs368234815 polymorphism is associated with innate resistance to HIV-1 infection.

The interferon (IFN)L4 polymorphism rs368234815 is associated with hepatitis C virus (HCV) spontaneous clearance and response to IFN-based treatments. The role of this polymorphism in HIV-1 infection is controversial. We investigated whether genetic variation at IFNL4 is associated to HIV-1 acquisition. The HCV protective allele TT was associated with decreased likelihood of HIV-1 infection in male intravenous drug users [odds ratio (OR): 0.3; P = 0.006], and this association was not modified by the genotype of CCR5. These results suggest that genetic susceptibility to HCV and HIV-1 infection shares common molecular pathways.