Common Variation at 1q24.1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer

So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (P _combined =2.30x10^-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; P _combined =2.73x10^-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.     

Nutritional correlates of the “lean season”: Effects of seasonality and frugivory on the nutritional ecology of diademed sifakas

Primate field studies often identify “lean seasons,” when preferred foods are scarce, and lower‐quality, abundant foods (fallback foods) are consumed. Here, we quantify the nutritional implications of these terms for two diademed sifaka groups (Propithecus diadema) in Madagascar, using detailed feeding observations and chemical analyses of foods. In particular, we sought to understand 1) how macronutrient and energy intakes vary seasonally, including whether these intakes respond in similar or divergent ways; 2) how the amount of food ingested varies seasonally (including whether changes in amount eaten may compensate for altered food quality); and 3) correlations between these variables and the degree of frugivory. In the lean season, sifakas shifted to non‐fruit foods (leaves and flowers), which tended to be high in protein while low in other macronutrients and energy, but the average composition of the most used foods in each season was similar. They also showed dramatic decreases in feeding time, food ingested, and consequently, daily intake of macronutrients and energy. The degree of frugivory in the daily diet was a strong positive predictor of feeding time, amount ingested and all macronutrient and energy intakes, though season had an independent effect. These results suggest that factors restricting how much food can be eaten (e.g., handling time, availability, or intrinsic characteristics like fiber and plant secondary metabolites) can be more important than the nutritional composition of foods themselves in determining nutritional outcomes—a finding with relevance for understanding seasonal changes in behavior, life history strategies, competitive regimes, and conservation planning. Am J Phys Anthropol 153:78–91, 2014. © 2013 Wiley Periodicals, Inc.     

Cell death: hook, line and linker

The programmed death of particular cells in Caenorhabditis elegans and Drosophila has been shown to occur by non-apoptotic programs regulated by developmental timing. Such alternative programs may be used as a general mechanism to eliminate differentiated, functional cells.     

DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pK(i) (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q(2)=0.508, standard error of prediction=0.601, two components, r(2)=0.685, standard error of estimate=0.481, F value=39, percent steric contribution=65, and percent electrostatic contribution=35. A CoMFA contour map identified areas of the molecule that affect pK(i) (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules.     

Probes for narcotic receptor mediated phenomena. Part 42: synthesis and in vitro pharmacological characterization of the N-methyl and N-phenethyl analogues of the racemic ortho-c and para-c oxide-bridged phenylmorphans

A new synthesis of N-methyl and N-phenethyl substituted ortho-c and para-c oxide-bridged phenylmorphans, using N-benzyl- rather than N-methyl-substituted intermediates, was used and the pharmacological properties of these compounds were determined. The N-phenethyl substituted ortho-c oxide-bridged phenylmorphan(rac-(3R,6aS,11aS)-2-phenethyl-2,3,4,5,6,11a-hexahydro-1H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (12)) was found to have the highest μ-opioid receptor affinity (K(i)=1.1 nM) of all of the a- through f-oxide-bridged phenylmorphans. Functional data ([3?S]GTP-γ-S) showed that the racemate 12 was more than three times more potent than naloxone as an μ-opioid antagonist.     

Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption

We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4 × 10(-19)), near AHR, and 15q24 (P = 5.2 × 10(-14)), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2.     

Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk

Introduction

Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.

Methods

Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.

Results

The strongest associations with RCC risk were observed for SLC19A1 (P_min-P = 0.03) and MTHFR (P_min-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.

Conclusions

To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.     

Comprehensive analysis of 5-aminolevulinic acid dehydrogenase (ALAD) variants and renal cell carcinoma risk among individuals exposed to lead

Background

Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead.

Methods

The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.

Results

The adjusted risk associated with the ALAD variant rs8177796^CT/TT was increased (OR = 1.35, 95%CI = 1.05–1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles (^GGOR = 2.68, 95%CI = 1.17–6.12, p = 0.01; ^GAOR = 1.79, 95%CI = 1.06–3.04 with an interaction approaching significance (p_int = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435^(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results.

Conclusion

A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.     

Nutritional geometry: gorillas prioritize non-protein energy while consuming surplus protein

It is widely assumed that terrestrial food webs are built on a nitrogen-limited base and consequently herbivores must compensate through selection of high-protein foods and efficient nitrogen retention. Like many folivorous primates, gorillas' diet selection supports this assumption, as they apparently prefer protein-rich foods. Our study of mountain gorillas (Gorilla beringei) in Uganda revealed that, in some periods, carbohydrate-rich fruits displace a large portion of protein-rich leaves in their diet. We show that non-protein energy (NPE) intake was invariant throughout the year, whereas protein intake was substantially higher when leaves were the major portion of the diet. This pattern of macronutrient intake suggests that gorillas prioritize NPE and, to achieve this when leaves are the major dietary item, they over-eat protein. The concentrations of protein consumed in relation to energy when leaves were the major portion of the diet were close to the maximum recommended for humans and similar to high-protein human weight-loss diets. By contrast, the concentrations of protein in relation to energy when gorillas ate fruit-dominated diets were similar to those recommended for humans. Our results question the generality of nitrogen limitation in terrestrial herbivores and provide a fascinating contrast with human macronutrient intake.     

Altered gene expression in pulmonary tissue of tryptophan hydroxylase-1 knockout mice: implications for pulmonary arterial hypertension

The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (Tph1(-/-) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in Tph1(-/-) mice. We postulated that: 1) Tph1(-/-) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) Tph1(-/-) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female Tph1(-/-) mice. The expression of 51 distinct genes was significantly altered in the lungs of female Tph1(-/-) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female Tph1(-/-) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized.