Menopausal hormone therapy does not play a major role in left ventricular hypertrophy

Objectives

Left ventricular hypertrophy (LVH) is a precursor of morbidity and mortality in women. Use of menopausal hormone therapy (MHT) might be associated with decreased left ventricular mass (LVM) and lower risk of LVH, although results of previous observational and clinical studies are inconclusive. Therefore, we analyzed the association between MHT use and either LVM indexed to height^2.7 (LVMI) or LVH determined echocardiographically.

Methods

Data from women aged ≥ 45 years recruited for the population-based Study of Health in Pomerania were used for cross-sectional (n = 975) and longitudinal (n = 675; 361 women without LVH at baseline) analyses. Information on ever (past and current) and never use of MHT were obtained. Linear (LVMI) or logistic (LVH) regression analyses were performed while controlling for potential confounders.

Results

Crude and age-adjusted analyses suggested an association between ever use of MHT and lower odds for LVH. This association was no longer significant in fully adjusted models. Compared to women who never used MHT, the odds ratios of LVH for ever MHT users were 0.97 [95%-confidence interval (95%-CI) 0.71–1.30] in cross-sectional and 0.70 (95%-CI 0.44–1.11) in longitudinal fully adjusted analyses. Similarly, results with an alternative classification of MHT use (never, past, and current) indicated no significant associations with LVH after full adjustment.

Conclusions

This study provides little evidence of an association between MHT use and LVH. Differences in lifestyle or health-related factors between never and MHT users could provide an explanation, in part, for the presumptive protective benefit of MHT on LVH.     

Association analyses of the INSIG2 polymorphism in the obesity and cholesterol levels of Korean populations

Background  

While INSIG2 has been reported to be associated with BMI in many populations, conflicting results have prevented consensus over its role. In analyses of mice and cell cultures the gene has been found to be involved in the regulation of cholesterol synthesis; however, no relationship has been found with cholesterol metabolism in human epidemiological research. Therefore, this study attempts to assess the effect of rs7566605 near INSIG2 on both obesity- and cholesterol-related traits in Koreans.     

Phagocytosis does not play a major role in naturally acquired transmission-blocking immunity to Plasmodium falciparum malaria

Phagocytosis of Plasmodium falciparum sexual stages in vitro and within the mosquito midgut was assayed in order to assess its role in transmission-blocking immunity to malaria. Both monocytes/macrophages (MM) and polymorphonuclear neutrophils (PMN) phagocytosed malarial gametes in vitro, but levels of phagocytosis were low. Intraerythrocytic gametocytes were not susceptible to phagocytosis. In vitro phagocytosis was positively correlated with levels of antibodies against the gamete surface proteins Pfs230 and Pfs48/45. Immunoglobulin G (IgG) subclass analysis revealed that phagocytosis was correlated with levels of antigamete IgG1. In vivo membrane-feeding experiments were performed in the presence of both pooled and individual malaria immune sera. The phagocytic process proceeded less efficiently in vivo than in vitro, which may be related to the lower ambient temperature (26 degrees C, compared with 37 degrees C). Finally, although we found a correlation between the ability of a serum to promote phagocytosis in vitro and the presence of antibodies against transmission-blocking target antigens, we were unable to demonstrate a role for MM- or PMN-mediated phagocytosis in reduction of infectivity of the malarial parasite to mosquitoes.     

Complement does not play a role in promotingBabesia rodhaini infections in Balb/C mice

A critical role of C3 and the C3b receptor for the erythrocyte invasion and the development of the parasitemia ofB. rodhaini in rats has been described recently (Jack and Ward 1980a). In the present study the influence of the C system onB. rodhaini infection in Balb/C mice is documented. Depletion of serum C3 to less than 5% of the normal level by treatment of mice with CoF, the C3 inactivator isolated from cobra venom, did not affect the course ofB. rodhaini parasitaemia. Treatment of mice with trypan blue, a reagent that inactivates the C3b receptor on human polymorphonuclear leukocytes, inhibited the development of parasitemia. However, whenB. rodhaini parasitized erythrocytes were incubated in vitro with trypan blue and subsequently tested for the in vivo and in vitro replication of the parasites, this old-fashioned therapy for babesiosis in cattle showed its babesiacidal activity. This indicates that the inhibition of parasite development by trypan blue is caused by its parasitotoxicity. These data suggest that the C system does not play an essential role in the development ofB. rodhaini infection of the Balb/C mouse.List of Abbreviations VSB veronal saline buffer, pH 7.4, containing 0.15 mM Ca²⁺ and 0.5 mM Mg²⁺ - EDTA-GVB veronal saline buffer, containing 1 g gelatin/l and 10 mM EDTA - EDTA ethylenediamine/tetraacetic/acid - C complement - CoF cobra venom factor - E₄₁₂ extinction at 412 nm - CH₅₀ units of total hemolytic complement activity in serum - RaRBC rabbit red blood cells - PBS phosphate buffered saline - EAC₁₄₂₃ sheep erythrocytes coated with rabbit amboceptor and human complement components C₁, C₄, C₂ and C₃ - S.D. standard deviation - SEM standard error of the mean - SRBC sheep red blood cells     

The vagal afferent pathway does not play a major role in the induction of satiety by intestinal fatty acid in rats

Intestinal infusion of long-chain fatty acids (LCFAs) strongly suppresses food intake and gut motility. Vagal afferents and cholecystokinin (CCK) signaling pathway are considered to play important roles in intestinal LCFA-induced satiety. Here, we first investigated the influence of vagus nerve on satiety following intestinal LCFA infusion in rats. Jejunal infusion of linoleic acid (LA) at 200 μL/h for 7 h suppressed food intake and the effect lasted for 24 h. The satiety induced by jejunal LA infusion occurred in a dose dependent manner. In contrast, the anorectic effect induced by octanoic acid, a medium-chain fatty acid, was weaker than that induced by LA. The reduction in food intake induced by jejunal LA infusion was not attenuated in rats treated with vagotomy, the ablation of bilateral subdiaphragmatic vagal trunks. Jejunal LA-induced satiety could also be observed in rats with bilateral midbrain transections, which ablates fibers between the hindbrain and hypothalamus. These findings suggest that the vagus nerve and fibers ascending from the hindbrain to the hypothalamus do not play a major role in intestinal LCFA-induced satiety. Jejunal LA infusion also reduced food intake in CCK-A receptor-deficient OLETF rats, suggesting that CCK signaling pathway is not critical for intestinal LCFA-induced anorexia. In conclusion, this study indicates that the vagus nerve and the CCK signaling pathway do not play major roles in conveying satiety signals induced by intestinal LCFA to the brain in rats.     

GIGYF2 has no major role in Parkinson genetic etiology in a Belgian population

Missense mutations were identified in the Grb10-Interacting GYF Protein-2 gene (GIGYF2), located in the chromosomal region 2q36-q37, in familial Parkinson disease (PD) patients of European descent. To determine the contribution of GIGYF2 mutations in an extended (N = 305) Belgian series of both familial and sporadic PD patients, we sequenced all 32 coding and non-coding exons of GIGYF2. In three sporadic PD patients we identified two novel heterozygous missense mutations (c.1907A>G, p.Tyr636Cys and c.2501G>A, p.Arg834Gln), that were absent from control individuals (N = 360). However, since we lack genetic as well as functional data supporting their pathogenic nature, we cannot exclude that these variants are benign polymorphisms. Together, our results do not support a role for GIGYF2 in the genetic etiology of Belgian PD.     

Testosterone decrease does not play a major role in the suppression of hippocampal cell proliferation following social defeat stress in rats

Stress of social defeat in rodents is known to have a strong and long-lasting effect on brain, physiology and behavior, which bears similarities with certain human stress related psychopathologies. Previous experiments in this lab showed that social defeat stress suppresses testosterone secretion and causes a lasting desensitization of the serotonergic 5-HT_1A receptors. Testosterone supplementation in socially stressed tree shrews prevented a decrease in hippocampal 5-HT_1A receptor binding. These receptors are hypothesized to play an important role in neurogenesis in this brain structure. We designed the present experiment to test if social defeat reduces hippocampal cell proliferation and neurogenesis in rats and if testosterone supplementation can prevent this reduction. The results indicate that repeated social defeat stress on 5 successive days induces a significant drop in plasma testosterone levels in male rats and suppresses hippocampal cell proliferation 24 h and 3 weeks after the end of the stress period. Testosterone supplementation prevented the social stress induced drop in plasma testosterone levels. The hormone supplementation also reduced the negative effect of stress on hippocampal BrdU labeling at 3 weeks post-defeat. This effect was, however, rather weak and was caused by the tendency of the hormone in itself to suppress proliferation and the failure to fully recover the proliferation rate. Survival of dentate gyrus cells that either proliferated prior to the stress period or 24 h after the last defeat was not affected by the social defeats. Thus the stress-induced lowering of hippocampal cell proliferation is not likely to be caused by transient inhibition of testosterone secretion during social stress.     

The MMP2 rs243865-T allele is not a major genetic factor for rheumatoid arthritis in the French Caucasian population

The MMP2 rs243865-T allele was recently suggested to be associated with rheumatoid arthritis (RA) in a case-control study. MMP2 is a positional RA candidate gene. Our aim was to test rs243865 in a French family based study. No significant result was shown. The MMP2 rs243865-T allele is not a major rheumatoid arthritis genetic factor in this population.     

Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies

Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n = 436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples.     

RIT2 variant is not associated with Parkinson's disease in a Taiwanese population

Recent genome-wide association studies of Parkinson's disease (PD) have identified the rs12456492 variant of the novel susceptibility loci, RIT2, as being associated with disease risk in a large white population. Studies among Asians are scarce. We genotyped RIT2 rs12456492 variant in a total of 1000 participants, comprising 500 patients with PD and 500 control subjects in a Taiwanese population. The frequency of GA/AA genotype was slightly higher in PD patients compared with controls, but was without statistical significance (odds ratio = 1.03, 95% confidence interval = 0.73–1.46, p = 0.86). We failed to replicate the RIT2 rs12456492 variant as a genetic risk factor for PD in our population.     

C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism

Background  

Research indicates that the etiology of autism has a strong genetic component, yet so far the search for genes that contribute to the disorder, including several whole genome scans, has led to few consistent findings. However, three studies indicate that the complement C4B gene null allele (i.e. the missing or nonfunctional C4B gene) is significantly more frequent in individuals with autism. Due to the close proximity of the CYP21A2 gene to the C4B locus (3 kb) it was decided to examine samples from autistic subjects, including many with known C4B null alleles for common CYP21A2 mutations.     

PLCL1 rs7595412 variation is not associated with hip bone size variation in postmenopausal Danish women

Background  

Bone size (BS) variation is under strong genetic control and plays an important role in determining bone strength and fracture risk. Recently, a genome-wide association study identified polymorphisms associated with hip BS variation in the PLCL1 (phospholipase c-like 1) locus. Carriers of the major A allele of the most significant polymorphism, rs7595412, have around 17% larger hip BS than non-carriers. We therefore hypothesized that this polymorphism may also influence postmenopausal complications.     

CD62L is required for the priming of encephalitogenic T cells but does not play a major role in the effector phase of experimental autoimmune encephalomyelitis

CD62L (l ‐selectin, mel 14) regulates naïve T cell homing into lymph nodes and the migration of leucocytes to sites of inflammation. The requirement of CD62L in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, has been demonstrated previously. However, it remains controversial as to whether CD62L is required for the induction or the effector phase of EAE. It is also unclear whether other non‐T effector cells need CD62L to enter the central nervous system (CNS) parenchyma and exert their damaging effects on myelin. We report that mice with a targeted mutation of CD62L are resistant to Myelin oligodendrocyte glycoprotein peptide‐induced EAE. CD62L‐deficient mice had no peptide‐specific T cell responses in the draining lymph nodes and had lower levels of peptide‐specific T cell responses in spleens at a later time point. Adoptive transfer studies showed that CD62L‐deficient mice were fully susceptible to adoptive transfer EAE induced by either wildtype or CD62L‐deficient T cells. Moreover, CD62L‐deficient, F4/80⁺ macrophages can be efficiently recruited into the CNS parenchyma. These data suggest that CD62L is required for the induction of encephalitogenic T cells during EAE development, but is not required by T and non‐T effector cells to attack the CNS parenchyma.     

Characterisation of CYP2C8, CYP2C9 and CYP2C19 polymorphisms in a Ghanaian population

Background  

Genetic influences on drug efficacy and tolerability are now widely known. Pharmacogenetics has thus become an expanding field with great potential for improving drug efficacy and reducing toxicity. Many pharmacologically-relevant polymorphisms do show variability among different populations. Knowledge of allelic frequency distribution within specified populations can be useful in explaining therapeutic failures, identifying potential risk groups for adverse drug reactions (ADRs) and optimising doses for therapeutic efficacy. We sought to determine the prevalence of clinically relevant Cytochrome P450 (CYP) 2C8, CYP2C9, and CYP2C19 variants in Ghanaians. We compared the data with other ethnic groups and further investigated intra country differences within the Ghanaian population to determine its value to pharmacogenetics studies.     

Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis

Rheumatoid arthritis (RA) is a common, systemic autoimmune disease which leads to destruction of the joint architecture and consequent disability. Although the aetiology of RA remains unknown, accumulating studies have established a strong association between RA and periodontitis (PD).Recently, anti-cyclic citrullinated peptide (anti-CCP) autoantibody and citrullinated peptide have been realized to be involved in the breaking of self-tolerance and development of autoimmune in RA. The citrullinated peptide is generated by post-translational modification (citrullination) of protein-bound arginine by peptidylarginine deiminase (PAD). Porphyromonas gingivalis (P. gingivalis), the major aetiological agent of PD and the only bacterium known to express a PAD enzyme, has been reported to be significantly associated with RA. The antibody titers to P. gingivalis are significantly increased in patients with RA and P. gingivalis antibody titers are significantly correlated with anti-CCP antibody isotypes that are specific to RA. Recent study indicates that the major synovial targets of the RA-specific anti-CCP autoantibodies are deiminated forms of the α- and β- chains of fibrin. Meanwhile, it is also confirmed that bacterial PAD produced by P. gingivalis has the capacity of deiminating arginine in fibrin found in the periodontal lesion. Whatsmore, it has been demonstrated that citrullination of HLA binding peptide causes a 100-fold increase in peptide-MHC affinity and leads to the activation CD4⁺T cells in HLA DRB1 0401 transgenic mice. Therefore, we postulate that P. gingivalis may play a crucial role in the pathogenesis of periodontitis-associated RA. P. gingivalis, which colonizes in the oral cavity, produces PAD enzyme continuously that leads to the citrullination of RA autoantigen such as fibrin in synovium joint. These PAD engendered antigens, presented in association with major histocompatibility complex (MHC) molecules by antigen-presenting cells (APC), ultimately lead to production of the anti-CCP antibody. The anti-CCP antibodies form immune complexes with citrullinated proteins, which can be bound by inflammatory cells via their Fc receptors. The roles of these immune complexes and inflammatory cells are mediated by a complex cascade involving complement activation. These mechanisms result in a release of mediators of inflammation and joint destruction ultimately leading to the onset of RA. This hypothesis reveals that oral bacterial infection may play a role in peptide citrullination which might be involved in loss of self-tolerance and development of autoimmune in RA.     

Homozygous deletion of CDKN2A (p16, p14) and CDKN2B (p15) genes is a poor prognostic factor in adult but not in childhood B-lineage acute lymphoblastic leukemia: a comparative deletion and hypermethylation study

The biological behavior of childhood B-lineage acute lymphoblastic leukemia (B-ALL) is different from that of adults. We performed a comprehensive analysis of the deletion and the methylation profile of CDKN2A (hereafter identified separately as p16 and p14, for the different proteins encoded) and CDKN2B (hereafter p15) in 91 newly diagnosed B-ALL patients (61 children, 30 adults). The prognostic significance of the profiles of these genes and the association between alterations in these genes and known cytogenetic prognostic factors (BCR/ABL; ETV6/RUNX1, formerly TEL/AML1; MLL rearrangement; and ploidy changes of chromosomes) were also assessed. The prevalence of homozygous deletion, hemizygous deletion, and no deletion of the 9p21 region was 11.5%, 16.4%, and 72.1%, respectively, in children and 30.0%, 20.0%, and 50.0%, respectively, in adults; the higher incidence of homozygous deletion in adults was significant (P=0.029). Homozygous deletion was associated with poor overall survival in adults (P=0.019), but not in children. The incidence of promoter methylation of p16, p14, and p15 was 34.4%, 14.8%, and 34.4%, respectively, in children and 26.7%, 10.0%, and 40.0%, respectively, in adults, with no significant difference between the two groups. No significant association was observed between deletion and methylation or with known cytogenetic prognostic factors. The difference in incidence, distribution, and prognostic effect of homozygous deletion in children and adults may explain the prognostic disparity.     

No association of the LRRK2 genetic variants with Alzheimer's disease in Han Chinese individuals

The leucine-rich repeat kinase–2 (LRRK2) gene has been regarded as 1 of the most common genetic causes of Parkinson's disease (PD). We hypothesized that LRRK2-susceptible allele(s) for PD might pose a risk for Alzheimer's disease (AD). In this study, we screened 12 LRRK2 gene variants in 2 independent cohorts from southwestern China (341 AD patients and 435 normal individuals) and eastern China (297 AD patients and 384 normal individuals), to discern the potential association between this gene and AD. No variant was identified to be associated with AD in either case-control sample. As both of the cohorts were of Han Chinese origin, we combined the LRRK2 variant data for the 2 sample sets together (a total of 638 AD patients and 819 normal individuals) and still found no association between the LRRK2 gene and AD, suggesting that LRRK2 gene variants may not affect the development of AD in Han Chinese individuals.     

Common genetic variations in TPH1/TPH2 genes are not associated with schizophrenia in Japanese population

Alteration of serotonin transmission in the brain of patients with schizophrenia has been reported in postmortem brain studies, cerebrospinal fluid studies, and pharmacological challenges. Although a genetic association of tryptophan hydroxylase isoform 1 (TPH1), the rate-limiting enzyme in serotonin synthesis, with schizophrenia has been suggested by recent systematic meta-analyses, the newly identified neuronal isoform TPH2 is more relevant to the central nervous system and the association of TPH2 gene with schizophrenia has been much less explored. We, therefore, explored the association of TPH2 gene with schizophrenia using a case–control study of 720 Japanese populations and also tried to replicate the association of the TPH1 rs1800532 (A218C) single nucleotide polymorphism (SNP) with schizophrenia. We selected 15 tagging SNPs in the TPH2 gene. We found no significant differences in genotypic distributions (uncorrected P = 0.18–0.98) or allelic frequencies (uncorrected P = 0.18–0.98) of the 15 SNPs between the schizophrenia and control groups. Haplotypes constructed with these SNPs were also not associated with schizophrenia (uncorrected P = 0.12–0.97). The genotypic and allelic distribution of the TPH1 rs1800532 SNP was also not different between the case and control groups in our samples. In addition, a subsequent meta-analysis including our results did not showed a significant association with schizophrenia in Asian populations. Our findings suggest that neither common genetic variations of TPH1 nor TPH2 are likely to contribute to the genetic susceptibility to schizophrenia in Japanese population.