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Several studies have provided evidence for associations of polymorphisms located in and near dopamine-related genes and nicotine dependence and other smoking-related phenotypes, including pharmacogenetic interactions. Aim: The purpose of the present work was to examine the association of SNPs in the DOPA decarboxylase (DDC), dopamine receptor D2 (DRD2) and dopamine transporter (SLC6A3) genes with smoking cessation in a large retrospective study featuring approximately 900 cessation events. Materials & methods: Data originated from the enrollment questionnaire of the epidemiological ESTHER study of community-dwelling adults aged 50–74 years, conducted in the German state of Saarland between July 2000 and December 2002. Restricting the analyses to subjects who reported to have regularly smoked >20 cigarettes per day at some point in their life, we used survival analysis methods to model the time from initiation of regular smoking to cessation (defined as quitting with abstinence lasting until enrollment) and its relation with eight polymorphisms in the aforementioned genes (five in DDC, two in DRD2 and one in SLC6A3) in 1446 participants. Results: Neither individual variants nor DDC haplotypes were associated with the probability of overcoming nicotine dependence in this cohort. Conclusion: The repeated suggestion of associations between the variants examined and nicotine dependence in previous reports seems to contrast the negative results in the present study. This would appear consistent with the hypothesis that the establishment of regular heavy smoking might abolish associations between genetic determinants of nicotine dependence and nicotine dependence-related phenotypes, in particular the probability of successful smoking cessation. Original submitted 15 February 2011; Revision submitted 2 May 2011

Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression. © 2010 Wiley-Liss, Inc.

Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5′ untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerstrom index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically. © 2009 Wiley-Liss, Inc.

The terrestrial slug Limax sarnensis Heim & Nitz new species is described from morphological and molecular characters, based on 298 specimens from 64 localities. Detailed descriptions of coloration, reproductive anatomy, distribution and ecology are provided. The new species differs from all other sympatric congeners by a diagnostic combination of characters: variable coloration of body with unicoloured mantle; outer fields of tripartite sole light grey to nearly black, fading from posterior to anterior and from outer edges to unpigmented middle field; penis dimension in preserved specimens about one-third to half of body length; penis interior with small transverse riblets, one longitudinal interior crest, a transverse penial crest and one longitudinal interior cord; copulates on a slime thread. It is restricted to inner alpine habitats in Switzerland and northern Italy. Phylogenetic analysis of 47 Limax specimens and outgroups using 1317 nucleotides of the cytochrome c oxidase subunit I gene supports the recognition of L. sarnensis as a new species. Limax alpinus Ferussac, 1822, becomes a junior synonym of Limax cinereoniger Wolf, 1803, by the designation of a neotype. Genotypic and phenotypic data are concordant with copulation (behavioural observations). The combination of morphological, genetic, ecological and behavioural data should set a new standard in slug species

Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the gastric inhibitory polypeptide (GIP) receptor (GIPR) prevents high-fat diet (HFD)–induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or HFD during pregnancy (intrauterine [IU]) and lactation (L). Male wild-type (WT) and Gipr−/− offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr−/− offspring of mice exposed to HFD during IU/L became insulin resistant and obese and exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being reintroduced to HFD, similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared with Gipr−/− mice on control diet during IU/L. DNA methylation analysis revealed increased methylation of CpG dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in the muscle of Gipr−/− offspring on HFD during IU/L, which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming.

Genome-wide studies have identified single nucleotide polymorphisms associated with smoking behaviour and nicotine dependence. Less is known about genetic determinants of smoking cessation, but rs4680 in COMT has recently been shown to explain a substantial proportion of the variation in cessation in the general population. We attempted to replicate the reported, clinically relevant effect in a population-based retrospective cohort analysis of 1443 ever-heavy smokers, of whom 925 had reached abstinence. In Cox regression models, neither rs4680 nor two polymorphisms nearby were associated with smoking cessation. The adjusted relative cessation rate (95% confidence interval) in rs4680 methionine carriers in reference to valine homozygotes was 0.97 (0.83-1.12). The absence of a significant effect of rs4680 in this statistically well-powered study - the 95% confidence interval even excluding the previously reported effect - highlights the need for rigorous replication efforts and suggests that rs4680 genotype should not yet be considered informative for smoking patient care.

Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 x 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 x 10(-5)) and CPD (P=9.3 x 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

Contains fulltext : 89305.pdf (Publisher’s version ) (Closed access) Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006). 01 mei 2010

Slugs of the genus Limax (Gastropoda: Stylommatophora) show a highly complicated genital system and reproductive behaviour probably triggering radiation and speciation. Pre-studies have revealed two so far largely undescribed species groups of Limax in Corsica. In order to clear up the phylogeny and evolutionary history of these radiations, we used a combination of molecular techniques and morphological characters. The two independent species groups of Corsican Limax species are monophyletic, and consist of six to ten species each, most of them new to science. The first species group, the endemic Wolterstorffi-group, can be differentiated by COI-Sequences, whereas COI-sequences fail to discriminate species of the Corsicus-group, which also has representatives in the Apennine Peninsula. This pattern suggests a much younger radiation of the Corsicus-group. Two hitherto unrecognized species on the adjacent islands of Elba and Capraia are described in an appendix.

Background Teleost fishes of the Coregonidae are good model systems for studying postglacial evolution, adaptive radiation and ecological speciation. Of particular interest is whether the repeated occurrence of sympatric species pairs results from in-situ divergence from a single lineage or from multiple invasions of one or more different lineages. Here, we analysed the genetic structure of Baltic ciscoes (Coregonus albula complex), examining 271 individuals from 8 lakes in northern Germany using 1244 polymorphic AFLP loci. Six lakes had only one population of C. albula while the remaining two lakes had C. albula as well as a sympatric species (C. lucinensis or C. fontanae). Results AFLP demonstrated a significant population structure (Bayesian θB = 0.22). Lower differentiation between allopatric (θB = 0.028) than sympatric (0.063-0.083) populations contradicts the hypothesis of a sympatric origin of taxa, and there was little evidence for stocking or ongoing hybridization. Genome scans found only three loci that appeared to be under selection in both sympatric population pairs, suggesting a low probability of similar mechanisms of ecological segregation. However, removal of all non-neutral loci decreased the genetic distance between sympatric pairs, suggesting recent adaptive divergence at a few loci. Sympatric pairs in the two lakes were genetically distinct from the six other C. albula populations, suggesting introgression from another lineage may have influenced these two lakes. This was supported by an analysis of isolation-by-distance, where the drift-gene flow equilibrium observed among allopatric populations was disrupted when the sympatric pairs were included. Conclusions While the population genetic data alone can not unambiguously uncover the mode of speciation, our data indicate that multiple lineages may be responsible for the complex patterns typically observed in Coregonus. Relative differences within and among lakes raises the possibility that multiple lineages may be present in northern Germany, thus understanding the postglacial evolution and speciation in the C. albula complex requires a large-scale phylogenetic analysis of several potential founder lineages., BMC Evolutionary Biology, 10, ISSN:1471-2148