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PubMed2006

Risk of HIV-1 transmission by breastfeeding among mothers infected with recombinant and non-recombinant HIV-1 genotypes.

BACKGROUND: Viral genotype and intersubtype recombination may influence the rate and/or timing of mother-to-child HIV-1 transmission. METHODS: We determined the HIV-1 subtype of the C2-C5 env and 5'LTR regions from milk and blood samples of 61 Tanzanian mothers who transmitted the virus through breastfeeding and their HIV-1 positive non-transmitting controls. Cases and controls were matched on infant's age at sample collection. All mothers resided in Dar es Salaam, Tanzania. RESULTS: Most infections among cases were due to recombinant viruses (41.0%), followed by HIV-1 subtype A (26.2%), subtype D (19.7%), and subtype C (13.1%). In multivariate analysis including maternal CD4+ cell counts, HIV disease stage, and proviral load in breast milk, the odds of breast milk transmission were 7.2 times higher if the mother carried an intersubtype recombinant genome in comparison to a subtype C virus (p=0.02). Viruses with recombinant LTRs were 4.9 times more likely to be transmitted through breastfeeding than viruses with non-recombinant LTRs of subtype A, C or D combined (p=0.01). CONCLUSIONS: This suggested that intersubtype recombinant genomes, and especially recombination within the LTR, might render HIV-1 more fit for transmission via breast milk in comparison with non-recombinant subtypes A, C, and D.

Adult↗
PubMed2000

Predictive power of individual genetic and environmental factor scores.

This study explores the use of an individual's genetic (IGFS) and environmental factor score (IEFS), constructed using genetic model fitting of a multivariate strength phenotype. Maximal isometric and dynamic strength measures, one maximal repetition load (1RM) and muscle cross-sectional area (MCSA) were measured in 25 monozygotic and 16 dizygotic twin pairs. The use of IGFS and IEFS in predicting the sensitivity to environmental stress was evaluated by the association of the scores with strength training gains after a 10-week high resistance strength training programme. Results show a high contribution of genetic factors to the covariation between maximal strength and muscle cross-sectional area (84-97%) at pre-training evaluation. Individual factor scores explained the largest part of the variation in IRM and other strength measures at pre-training and post-training evaluation respectively. Genes that are switched on due to training stress (gene-environment interaction) could explain the decrease in explained variation over time. A negative correlation was found between IGFS and strength training gains (-0.24 to -0.51, P < 0.05); individuals with a high IGFS tend to gain less strength than individuals with low IGFS. Individual environmental factor scores have lower differential power. The predictive value of the IGFS has potential utility in identifying an individual's susceptibility to environmental stress in a variety of multifactorial characteristics, eg diseases and impairments, and for selection of sib pairs for QTL analyses.

Adolescent↗
PubMed1990

Loading the lods.

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Chromosomes, Human, Pair 11↗
PubMed2006

The presence of IFNG 3/3 genotype in the recipient associates with increased risk for Epstein-Barr virus reactivation after allogeneic haematopoietic stem cell transplantation.

Recent studies have shown that interferon-gamma gene (IFNG) polymorphism constitutes a risk factor for acute and chronic graft-versus-host disease (GvHD) after allogeneic haematopoietic stem cell transplantation (HSCT). Patients with IFNG 3/3 have been found to be more prone to GvHD. This rather puzzling result, as 3/3 genotype is associated with a decreased IFN-gamma production, was investigated in the present study in the context of Epstein-Barr virus (EBV) reactivation. Microsatellite polymorphism (CA)n within the first intron of IFNG gene was assessed in 83 HSCT recipients and related to EBV load. Quantification of EBV copies was performed by a real-time polymerase chain reaction in peripheral blood cells taken from the patients 2-3 months after HSCT. It was found, that patients having IFNG 3/3 genotype presented with a high number of EBV copies (over 10/10(5) blood cells) when compared with the recipients with other IFNG genotypes (10/14 vs. 17/69, P < 0.001). This association was independent of recipient's age, underlying disease, conditioning regimen, type of donor, source of stem cells or pretransplant donor and recipient EBV serological status. Thus IFNG 3/3 genotype, known to be associated with a decreased IFN-gamma production, appeared as a factor significantly contributing to the risk of EBV reactivation after allogeneic HSCT.

Adolescent↗
PubMed1998

Obesity-independent hyperinsulinemia in nondiabetic first-degree relatives of individuals with type 2 diabetes.

A close association between obesity and hyperinsulinemia is well recognized, but it is not known whether this relationship is affected by the genetic susceptibility to type 2 diabetes. Insulin response to a 75-g oral glucose load was evaluated in healthy nondiabetic Caucasians with first-degree family history of diabetes (relatives, n = 55) and those without family history (nonrelatives, n = 33). A significant correlation between the BMI and insulin response (area under the curve [AUC] during the 2-h period) was seen in nonrelatives (r = 0.68, P < 0.0001) but not in the relatives (r = 0.12, P = 0.37). Multivariate analysis revealed that obesity (BMI) was the primary determinant of insulin response in nonrelatives (P < 0.001), whereas among the relatives, BMI had no significant impact (P = 0.28). Thus, these distinctions between the relatives and nonrelatives remained after adjusting for glucose level, age, and gender. Among first-degree relatives, the commonly observed association between BMI and insulin response is lost, and hyperinsulinemia is present even in the absence of obesity. First-degree family history of diabetes may confer insulin resistance that is independent of obesity. Alternatively, this could suggest a pathological regulation of an obesity-insulin feedback loop, e.g., a defective recognition of adiposity.

Adult↗
PubMed2002

The impact of message mutation on the fitness of a genetic code.

The Standard Genetic Code is organized such that similar codons encode similar amino acids. One explanation suggested that the Standard Code is the result of natural selection to reduce the fitness "load" that derives from the mutation and mistranslation of protein-coding genes. We review the arguments against the mutational load-minimizing hypothesis and argue that they need to be reassessed. We review recent analyses of the organization of the Standard Code and conclude that under cautious interpretation they support the mutational load-minimizing hypothesis. We then present a deterministic asexual model with which we study the mode of selection for load minimization. In this model, individual fitness is determined by a protein phenotype resulting from the translation of a mutable set of protein-coding genes. We show that an equilibrium fitness may be associated with a population with the same genetic code and that genetic codes that assign similar codons to similar amino acids have a higher fitness. We also show that the number of mutant codons in each individual at equilibrium, which determines the strength of selection for load minimization, reflects a long-term evolutionary balance between mutations in messages and selection on proteins, rather than the number of mutations that occur in a single generation, as has been assumed by previous authors. We thereby establish that selection for mutational load minimization acts at the level of an individual in a single generation. We conclude with comments on the shortcomings and advantages of load minimization over other hypotheses for the origin of the Standard Code.

Amino Acids↗
PubMed2006

Virologic and host characteristics of human immunodeficiency virus type 1-infected pediatric long term survivors.

BACKGROUND: There are limited data concerning determinants of varying clinical progression rates in human immunodeficiency virus type 1 (HIV-1)-infected children. Therefore, we sought to determine whether viral or host factors associated with nonprogressive HIV-1 infection in adults play a role in limiting progression of infection in 5 vertically infected youths, ages 12-18 years, who have displayed no signs of advanced HIV-1 disease or acquired immunodeficiency syndrome despite having received minimal treatment with antiretroviral drugs. RESULTS: The 5 individuals, whom we characterize as long term survivors, have maintained low loads of HIV-1 RNA in plasma when compared to many of their peers, and have also maintained normal and stable CD4 T-lymphocyte numbers and percentages throughout their lives. Determination of their predominant HIV-1 sequences revealed that 4 of 5 patients harbor virus with markers of resistance to their therapy (one was never treated). Furthermore 2 harbored viral isolates that contained insertions in Gag or Vif that inhibit HIV-1 replication. Moreover, 2 were found to be heterozygous for the CCR2 polymorphism 64I, a genotype associated with slower progression to acquired immunodeficiency syndrome in adults. All 5 expressed the histocompatibility leukocyte antigen DQ1 and 2 had unusual DR/DQ1 phenotypes. CONCLUSIONS: We believe that the limited antiretroviral therapy received by the long term survivors cannot solely account for their benign clinical status. Therefore, we conclude that other factors, including gene polymorphisms that affect viral replicative capacity, account for the long term survival in some, and deduce that, as in adults, no single factor (virologic or host) can account for this clinical phenotype in all cases.

Adolescent↗
PubMed2006

Genetic influences on the response to warfarin.

PURPOSE OF REVIEW: Warfarin has a narrow therapeutic index and there is wide interindividual variability in the drug dose requirement. Uncertainty of response renders currently used loading regimens inaccurate as they fail to take into account individual patient factors that have a major influence on anticoagulation response. This review focuses on recent research findings demonstrating the impact of genetics on warfarin sensitivity and dose requirement and the issues concerning the clinical utility of individualized therapy. RECENT FINDINGS: Single-nucleotide polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase have been shown to make significant contributions to the variability in warfarin dose requirements. Polymorphisms in other genes that mediate the actions of warfarin make little or no contribution to the variability. Racial and cultural differences influence dose requirements, which can be explained at least in part by genetic and dietary factors. SUMMARY: Individualization of therapy based on genetic and environmental factors has the potential to reduce the adverse effects associated with the commencement of warfarin therapy. Prospective studies that incorporate both CYP2C9 and VKORC1 genes and environmental factors in warfarin dose calculation will be required to demonstrate the safety, cost-effectiveness, and feasibility of individualized dosing regimens.

Anticoagulants↗
PubMed2004

Association between exercise and pubertal BMD is modulated by estrogen receptor alpha genotype.

UNLABELLED: Genetic and environmental factors contribute to bone mass, but the ways they interact remain poorly understood. This study of 245 pre- and early pubertal girls found that the PvuII polymorphism in the ER-alpha gene modulates the effect of exercise on BMD at loaded bone sites. INTRODUCTION: Impaired achievement of bone mass at puberty is an important risk factor for the development of osteoporosis in later life. Genetic, as well as environmental, factors contribute to bone mass, but the ways they interact with each other remain poorly understood. MATERIALS AND METHODS: We investigated the interaction between a PvuII polymorphism at the ER-alpha gene and physical activity (PA) on the modulation of bone mass and geometry in 245 10- to 13-year-old pre- and early pubertal Finnish girls. Level of PA was assessed using a questionnaire. Bone properties were measured using DXA and pQCT. The analyses were controlled for the effects of Tanner stage and body size index. RESULTS: Girls with heterozygote ER-alpha genotype (Pp) and high PA had significantly higher bone mass and BMD, as well as thicker cortex, at loaded bone sites than their low-PA counterparts. No differences were found in bone properties of the distal radius, which is not a weight-bearing bone. Bone properties did not differ in either homozygote groups (PP and pp) regardless of the PA level. CONCLUSIONS: These findings suggest that the PvuII polymorphism in the ER-alpha gene may modulate the effect of exercise on BMD at loaded bone sites. The heterozygotes may benefit most from the effect of exercise, whereas neither of the homozygote groups received any significant improvement from high PA. Furthermore, high PA may hide the genetic influence on bone. Indeed, it seems that one may compensate one's less favorable Pp genotype by increasing leisure PA at early puberty.

Adolescent↗
PubMed1996

[Safer trials of vaccine and gene therapy against HIV].

HIV, the etiological agent of AIDS, induces depletion of CD4+T cells. Upon primary infection, there is an initial viremia that is followed rapidly by a cell-mediated immune response and apparent viral clearance. Thereafter, the persistence of low levels of HIV in the blood for years before the onset of the disease is facilitated by the ability of the virus to establish persistent and latent infection. Notwithstanding the latent form in most population, the clinical stage of disease is significantly associated with all measures of virus load levels. This may be mainly due to the function of HIV to induce apoptosis in a patients' uninfected CD4+T cells, as a bystander effect. Thus, the mechanisms that latently infect in the cells after HIV infection and stimulate active replication of HIV from the latency are essential for an understanding of the pathogenicity of the disease. Therefore, prophylactic and therapeutic trials should be focused to their effect to reduce the HIV load level.

AIDS Vaccines↗
PubMed2002

High genetic diversity revealed by the study of TLMV infection in French hemodialysis patients.

TT virus-like minivirus (TLMV) was recently discovered as a human circovirus. Little is known about its natural history and molecular epidemiology. A study of TLMV infection is described in a population of French hemodialysis patients. TLMV DNA was tested by seminested PCR system located in the noncoding region in 81 patients divided into seven groups according to the origin of their renal disease. Quantitation of TLMV DNA in serum was carried out. Sequences from 28 patients were compared with 40 sequences retrieved from databases and 53 TLMV sequences cloned from the serum of a single patient. The prevalence of TLMV DNA in hemodialysis patients was 95.1%. In this study, 24 samples (29.6%) presented viral loads of > 125 equivalents of plasmid (Ep)/ml, and only 6 (7.8%) had viral loads of > 125 x 10(2) Ep/ml. A significant correlation (P < 0.029) was found between viral loads of > 125 x 10(2) Ep/ml and the neoplastic origin of end-stage renal disease. Analysis of 53 sequences cloned from a single individual demonstrated high sequence variability, as shown by the genetic distance of 40.2%. This genetic distance is comparable to that between the most divergent sequences of TLMV reported to date (43.5%). These data suggest that TLMV viral load is possibly related to the level of immunocompetence of hemodialysis patients; the genetic diversity of TLMV is extremely high; and co-infection by different strains is possible.

Adult↗
PubMed2005

A note on ENDOG: a computer program for analysing pedigree information.

The aim of this note is to describe the program ENDOG (v.3.0). The program handles pedigree information to conduct several demographic and genetic analyses including: (a) the individual inbreeding and average relatedness coefficients; (b) effective population size; (c) parameters characterizing the concentration of both gene and individuals origin such as the effective number of founders and ancestors, the effective number of founder herds; (d) F statistics and paired genetic distances for each subpopulation under study; (e) descriptors of the genetic importance of the herds in a population and (f) generation intervals. The program will help breeders and researchers to monitor the changes in genetic variability and population structure with limited costs of preparing datasets. The program, user's guide and example file can be down-loaded free of charge from the World Wide Web at http://www.ucm.es/ info/prodanim/Endog30.zip.

Animals↗
PubMed2006

Association of core promoter mutations with viral breakthrough in chronic hepatitis B patients on long-term lamivudine therapy.

BACKGROUND AND AIM: Virologic breakthrough (VBTH) during long-term lamivudine therapy is believed to be due to the emergence of rtYM204I/VDD mutants. We observed VBTH in 17 of 67 patients receiving long-term lamivudine therapy. The YMDD mutant at the onset of VBTH and/or subsequently was seen in eight (47%) of 17 such patients. We investigated other potential loci in the viral genome contributing to VBTH. METHODS: Chronic hepatitis B (CHB) patients (n=17) on long-term (>or=12 months) lamivudine therapy who had at least one episode of VBTH were selected (group I). Age, sex, serology and baseline viral load matched patients on long-term lamivudine without VBTH (n=12) served as controls (group II). Hepatitis B virus (HBV) DNA sequences were analyzed for pre-S, surface, polymerase, core promoter, precore and core regions and were compared with sequences of respective genotypes. RESULTS: Group I patients with VBTH (n=17) either had rtYM204I/VDD mutations (n=8, group Ia YMDD) or no rtYM204I/VDD mutations (n=9, group Ib non-YMDD). Group Ia patients had median baseline HBV DNA of 2794 pg/mL (range 3-9166 pg/mL) and a mean alanine aminotransferase (ALT) level of 86+/-33 IU/L. In group Ib, the median baseline viral DNA was 916 pg/mL (range 8.3-5787 pg/mL) and the mean ALT was 61+/-38 IU/L. The first VBTH in group Ia and Ib patients was noted at 21+/-9 months and 15.2+/-5.9 months, respectively, with a rise in HBV DNA levels from undetectable limits to 952 pg/mL (range 4.3-4875 pg/mL) and 571 pg/mL (range 1.2-1970 pg/mL), respectively. Core promoter mutations were seen in five of eight (62.5%) and in six of nine (66.6%); classic double mutations (A1762T/G1764A) of core promoter region were detected in two and three patients and novel double mutations of core promoter (G1764T/C1766G) in one patient each of group Ia and Ib patients, respectively. Compared to 11 (68%) of 17 group I patients, only three (25%) of 12 patients in group II had core promoter mutations (P<0.05). No patient in group II had double mutations of the core promoter region. No significant difference in viral mutations was seen in any other region of the viral genome between group I and group II patients. In group I, none of the 15 patients (two died of hepatocellular carcinoma), but five (42%) group II patients achieved hepatitis B e antigen (HBeAg) seroconversion and sustained response by month 24 (P<0.05). CONCLUSION: Both core promoter and YMDD motif mutation(s) are associated with VBTH in patients on long-term lamivudine therapy. Whether or not these promoter mutations in the absence of YMDD mutations confer drug resistance needs to be studied in an in vitro cell culture system, as they could create novel and stronger binding sites for hepatocyte nuclear factors.

Adult↗
PubMed2005

Transcriptional diversity and expression of NEDD4L gene in distal nephron.

The ubiquitin ligase NEDD4L participates in plasma volume and blood pressure regulation by controlling expression of the epithelial sodium channel (ENaC). Genetic impairment of EnaC-Nedd4L-Proteasome system caused a rare mendelian hereditary human hypertension, Liddle syndrome. This finding suggested that Nedd4L is playing an important role in pathogenesis for hypertensive disorders. This prompted us to test a possible involvement of NEDD4L for the development of sodium-sensitive hypertension in Dahl salt-sensitive (DS) rats and its normotensive littermate Dahl salt-resistant (DR) rats. First, we analyzed the transcriptional diversity of rat Nedd4L gene and observed several isoforms with and without calcium-dependent membrane binding (C2) domain at the N-terminal of the protein as we found in human and mouse before. Then, we analyzed the expression of rat NEDD4L in the kidney of both DS and DR under high and low sodium regimens. NEDD4L expression examined by quantitative PCR technique revealed lower expression of NEDD4L transcripts in DS rats under either diet compared to DR animals; additionally, NEDD4L expression was significantly increased with sodium loading. Using in situ hybridization experiments, rat NEDD4L was predominantly expressed in distal nephron in a manner dependent on both sodium regimen and genetic background. A similar histological distribution pattern was observed in human kidney. The expression of NEDD4L in distal nephron and its response to chronic sodium loading suggest that it participates in the functioning of this segment in sodium reabsorption. This response was impaired in genetically sodium-sensitive animals. These findings suggested that Nedd4L gene products were involved in the development of salt-sensitive hypertension.

Adrenal Glands↗
PubMed2005

Is fetal gender a risk factor for severe congenital cytomegalovirus infection?

Cytomegalovirus is the main cause of congenital viral infection and amniotic fluid viral load appears to be the single nonclinical prognostic factor. However, as in other infectious diseases, host genetics may influence the severity of the disease. To test this hypothesis, we looked retrospectively at the fetal gender in cases of severe congenital cytomegalovirus infection in our database. We also analyzed the international English literature covering this subject between 1985 and 2003. The proportion of females with brain abnormalities was statistically different from that of males (62/258: 24% vs 30/251: 12%, p = 0.004). The risk of abnormal brain development in infected fetuses was twice as high in females than in males (Chi(2) = 8.7; OR = 2, IC [1.26-3.21]). In our cases, amniotic fluid CMV DNA load was not significantly higher in males than in females (p = 0.06) and was also similar in severely and non-severely infected fetuses (p = 0.09).

Adult↗
PubMed2003

A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks.

Homologous recombination repair (HRR) is required for both the repair of DNA double strand breaks (DSBs) and the maintenance of the integrity of DNA replication forks. To determine the effect of a mutant allele of the RAD51 paralog XRCC2 (342delT) found in an HRR-defective tumour cell line, 342delT was introduced into HRR proficient cells containing a recombination reporter substrate. In one set of transfectants, expression of 342delT conferred sensitivity to thymidine and mitomycin C and suppressed HRR induced at the recombination reporter by thymidine but not by DSBs. In a second set of transfectants, the expression of 342delT was accompanied by a decreased level of the full-length XRCC2. These cells were defective in the induction of HRR by either thymidine or DSBs. Thus 342delT suppresses recombination induced by thymidine in a dominant negative manner while recombination induced by DSBs appears to depend upon the level of XRCC2 as well as the expression of the mutant XRCC2 allele. These results suggest that HRR pathways responding to stalled replication forks or DSBs are genetically distinguishable. They further suggest a critical role for XRCC2 in HRR at replication forks, possibly in the loading of RAD51 onto gapped DNA.

Base Pair Mismatch↗