Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.

The association between cigarettes smoking, cannabis use and alcohol consumption in a population of young men: results of a population-based survey.

BACKGROUND: Cigarette smoking is often initiated at a young age as well as other risky behaviors such as alcohol drinking, cannabis and other illicit drugs use. Some studies suggest that cigarette smoking may have an influence on other risky behaviors but little is known about the chronology of occurrence of those different habits. The aim of this study was to assess, by young men, what were the other risky behaviors associated with cigarette smoking and the joint prevalence and chronology of occurrence of those risky behaviors. METHODS: Cross-sectional analyses of a population-based census of 3526 young men attending the recruitment for the Swiss army, aged between 17 and 25 years old (mean age: 19 years old), who filled a self reported questionnaire about their alcohol, cigarettes, cannabis and other illicit drugs habits. Actual smoking was defined as either regular smoking (¡Ý1 cigarette/day, on every day) or occasional smoking, binge drinking as six or more drinks at least twice a month, at risk drinking as 21 drinks or more per week, recent cannabis use as cannabis consumption at least once during the last month, and use of illicit drugs as consumption once or more of illicit drugs other than cannabis. Age at begin was defined as age at first use of cannabis or cigarette smoking. RESULTS: In this population of young men, the prevalence of actual smoking was 51.2% (36.5% regular smoking, 14.6% occasionnal smoking). Two third of participamnts (60.1%) declared that they ever used cannabis, 25.2% reported a recent use of cannabis. 53.8% of participants had a risky alcohol consumption considered as either binge or at risk drinking. Cigarette smoking was significantly associated with recent cannabis use (Odds Ratio (OR): 3.85, 95% Confidence Interval (CI): 3.10- 4.77), binge drinking (OR: 3.48, 95% CI: 3.03-4.00), at risk alcohol drinking (OR: 4.04, 95% CI: 3.12-5.24), and ever use of illicit drugs (OR: 4.34, 95% CI: 3.54-5.31). In a multivariate logistic regression, odds ratios for smoking were increased for cannabis users (OR 3.10,, 95% CI: 2.48-3.88), binge drinkers (OR: 1.77, 95% CI: 1.44-2.17), at risk alcohol drinkers (OR 2.26, 95% CI: 1.52-3.36) and ever users of illicit drugs (OR: 1.56, 95% CI: 1.20-2.03). The majority of young men (57.3%) initiated smoking before cannabis and mean age at onset was 13.4 years old, whereas only 11.1% began to use cannabis before smoking cigarettes and mean age at onset was slightly older (14.4 years old). 31.6% started both cannabis and tobacco at the same age (15 years old). About a third of participants (30.5%) did have a cluster of risky behaviours (smoking, at risk drinking, cannabis use) and 11.0% did cumulate smoking, drinking, cannabis and ever use of illegal drugs. More than half of the smokers (59.6%) did cumulate cannabis use and at risk alcohol drinking whereas only 18.5% of non-smokers did. CONCLUSIONS: The majority of young smokers initiated their risky behaviors by first smoking and then by other psychoactive drugs. Smokers have an increased risk to present other risky behaviors such as cannabis use, at risk alcohol consumtion and illicit drug use compared to nonsmokers. Prevention by young male adults should focus on smoking and also integrate interventions on other risky behaviors.

Page County Landfill Association, Independent Auditor's Reports, Basic Financial Statements and Required Supplementary Information, Schedule of Findings, June 30, 2004

Other Audit Reports - 28E Organizations

Genome-wide association study of co-occurring anxiety in major depression.

OBJECTIVES: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype. METHODS: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD. RESULTS: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10⁻⁶. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait. CONCLUSIONS: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.

Association with coregulators is the major determinant governing peroxisome proliferator-activated receptor mobility in living cells.

The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 × 10−4) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 × 10−5) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

Association between GIS-based exposure to urban air pollution during pregnancy and birth weight in the INMA Sabadell Cohort

Background: There is growing evidence that traffic-related air pollution reduces birth weight. Improving exposure assessment is a key issue to advance in this research area.Objective: We investigated the effect of prenatal exposure to traffic-related air pollution via geographic information system (GIS) models on birth weight in 570 newborns from the INMA (Environment and Childhood) Sabadell cohort.Methods: We estimated pregnancy and trimester-specific exposures to nitrogen dioxide and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] by using temporally adjusted land-use regression (LUR) models. We built models for NO2 and BTEX using four and three 1-week measurement campaigns, respectively, at 57 locations. We assessed the relationship between prenatal air pollution exposure and birth weight with linear regression models. We performed sensitivity analyses considering time spent at home and time spent in nonresidential outdoor environments during pregnancy.Results: In the overall cohort, neither NO2 nor BTEX exposure was significantly associated with birth weight in any of the exposure periods. When considering only women who spent < 2 hr/day in nonresidential outdoor environments, the estimated reductions in birth weight associated with an interquartile range increase in BTEX exposure levels were 77 g [95% confidence interval (CI), 7–146 g] and 102 g (95% CI, 28–176 g) for exposures during the whole pregnancy and the second trimester, respectively. The effects of NO2 exposure were less clear in this subset.Conclusions: The association of BTEX with reduced birth weight underscores the negative role of vehicle exhaust pollutants in reproductive health. Time–activity patterns during pregnancy complement GIS-based models in exposure assessment.

Design and evaluation of a panel os single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease

MicroRNAs (miRNA) are recognized posttranscriptional gene repressors involved in the control of almost every biological process. Allelic variants in these regions may be an important source of phenotypic diversity and contribute to disease susceptibility. We analyzed the genomic organization of 325 human miRNAs (release 7.1, miRBase) to construct a panel of 768 single-nucleotide polymorphisms (SNPs) covering approximately 1 Mb of genomic DNA, including 131 isolated miRNAs (40%) and 194 miRNAs arranged in 48 miRNA clusters, as well as their 5-kb flanking regions. Of these miRNAs, 37% were inside known protein-coding genes, which were significantly associated with biological functions regarding neurological, psychological or nutritional disorders. SNP coverage analysis revealed a lower SNP density in miRNAs compared with the average of the genome, with only 24 SNPs located in the 325 miRNAs studied. Further genotyping of 340 unrelated Spanish individuals showed that more than half of the SNPs in miRNAs were either rare or monomorphic, in agreement with the reported selective constraint on human miRNAs. A comparison of the minor allele frequencies between Spanish and HapMap population samples confirmed the applicability of this SNP panel to the study of complex disorders among the Spanish population, and revealed two miRNA regions, hsa-mir-26a-2 in the CTDSP2 gene and hsa-mir-128-1 in the R3HDM1 gene, showing geographical allelic frequency variation among the four HapMap populations, probably because of differences in natural selection. The designed miRNA SNP panel could help to identify still hidden links between miRNAs and human disease.

Association between weight perception and socioeconomic status among adults in the Seychelles.

BACKGROUND: Few studies have examined the association between weight perception and socioeconomic status (SES) in sub-Saharan Africa, and none made this association based on education, occupation and income simultaneously. METHODS: Based on a population-based survey (n = 1255) in the Seychelles, weight and height were measured and self-perception of one's own body weight, education, occupation, and income were assessed by a questionnaire. Individuals were considered to have appropriate weight perception when their self-perceived weight matched their actual body weight. RESULTS: The prevalence of overweight and obesity was 35% and 28%, respectively. Multivariate analysis among overweight/obese persons showed that appropriate weight perception was directly associated with actual weight, education, occupation and income, and that it was more frequent among women than among men. In a model using all three SES indicators together, only education (OR = 2.5; 95% CI: 1.3-4.8) and occupation (OR = 2.3; 95% CI: 1.2-4.5) were independently associated with appropriate perception of being overweight. The OR reached 6.9 [95% CI: 3.4-14.1] when comparing the highest vs. lowest categories of SES based on a score including all SES indicators and 6.1 [95% CI: 3.0-12.1] for a score based on education and occupation. CONCLUSIONS: Appropriately perceiving one's weight as too high was associated with different SES indicators, female sex and being actually overweight. These findings suggest means and targets for clinical and population-based interventions for weight control. Further studies should examine whether these differences in weight perception underlie differences in cognitive skills, healthy weight norms, or body size ideals.

A targeted association study of immunity genes and networks suggests novel associations with placental malaria infection

A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactionson a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single geneanalysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.