Contribution Of Genetic Variation Research Articles

Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease

Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes. We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics. We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD. We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.

Genetically Determined Severity of Anti-Myeloperoxidase Glomerulonephritis

Myeloperoxidase (MPO) is a target antigen for antineutrophil cytoplasmic autoantibodies (ANCA). There is evidence that MPO-ANCA cause necrotizing and crescentic glomerulonephritis (NCGN) and vasculitis. NCGN severity varies among patients with ANCA disease, and genetic factors influence disease severity. The role of genetics in MPO-ANCA NCGN severity was investigated using 13 inbred mouse strains, F1 and F2 hybrids, bone marrow chimeras, and neutrophil function assays. Mouse strains include founders of the Collaborative Cross. Intravenous injection of anti-MPO IgG induced glomerular crescents in >60% of glomeruli in 129S6/SvEv and CAST/EiJ mice, but <1% in A/J, DBA/1J, DBA/2J, NOD/LtJ, and PWK/PhJ mice. C57BL6J, 129S1/SvImJ, LP/J, WSB/EiJ, NZO/HILtJ, and C3H mice had intermediate severity. High-density genotypes at 542,190 single nucleotide polymorphisms were used to identify candidate loci for disease severity by identifying genomic regions that are different between 129S6/SvEv and 129S1/SvImJ mice, which are genetically similar but phenotypically distinct. C57BL/6 × 129S6 F2 mice were genotyped at 76 SNPs to capture quantitative trait loci for disease severity. The absence of a dominant quantitative trait locus suggests that differences in severity are the result of multiple gene interactions. Invivo studies using bone marrow chimeric mice and invitro studies of neutrophil activation by anti-MPO IgG indicated that severity of NCGN is mediated by genetically determined differences in the function of neutrophils.

Pharmacogenomics of Gemcitabine Metabolism: Functional Analysis of Genetic Variants in Cytidine Deaminase and Deoxycytidine Kinase

Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another.

Genetic and epigenetic interactions in adaptive thermogenesis pathways in association with obesity from a Public Health Genomics perspective

Background: studying and apprehending the pathways and mechanisms by which overweight and obesity trigger complex disease progression is of prime importance for the development of therapy and prevention measures of this major public health burden. This review describes Single Nucleotide Polymorphisms (SNPs) and epigenetic methylation as well as histone modification in genes with relevance in adaptive thermogenesis and their possible role in the development of obesity. Epigenetic marks are discussed as solid biomarkers for gene-environment interactions. Methods: a PubMed search on genetic and epigenetic variation of genes involved in adaptive thermogenesis was performed. The search included English publications between December 1996 and July 2010 reporting associations between SNPs and obesity in Caucasians. The search on epigenetic regulation was limited to DNA methylation and histone modifications. Genes that were found to be associated with the adaptive thermogenesis pathway included beta-3 adrenergic receptor (ADRB3), uncoupling protein 1 (UCP1), the transcription factors peroxisome proliferated activator receptor gamma (PPARγ), peroxisome proliferated activator receptor gamma co-activator 1 alpha (PGC1α), retinoid acid X receptor alpha (RXRα), CCAAT/enhancer-binding protein alpha (C/EBPα), fatty acid binding protein 4 (FABP4) and lipoprotein lipase (LPL). Results: epigenetic studies are mainly discovery orientated and do not test hypotheses. However, SNPs as well as epigenetic mechanisms seem to regulate obesity and adaptive thermogenesis whereas genetic association studies are inconsistent. Conclusions: the aim of this work was to confirm evidences on the contribution of genetic variations as well as epigenetic regulatory mechanisms of genes associated to obesity. The integration of epigenetic markers in epidemiologic research could help to unravel multi gene-environment interactions. With this article we show the importance to introduce aspects of the epigenetic regulation in the assessment of obesity: We also discuss the benefits of including epigenomics as an integrative way to account for an individual’s environmental impact in public health policies.

Genetic determinants and early carotid atherosclerosis: is there a role for the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP-1) K121Q polymorphism? Preliminary results in non diabetic individuals

Carotid intima-media thickness (CIMT) is an intermediate phenotype for early atherosclerosis and a strong predictor of myocardial infarction and ischemic stroke [1]. Several studies have described the effects of candidate genes on CIMT, being unclear, however, the relative contribution of genetic variation to the development of the early stages of atherosclerosis [2]. The ectoenzyme pyrophosphatase phosphodiesterase 1 (ENPP-1) inhibits insulin receptor signaling [3]. A non synonymous polymorphism (K121Q, rs1044498) of the ENPP-1 gene is responsible for a gain of function of the protein [3], resulting in an increased ability to inhibit insulin receptor signaling. This variant has been associated with insulin resistance and type 2 diabetes in most studies [4, 5]. In agreement with the link between insulin resistance and cardiovascular disease (CVD), the Q121 variant has been shown to modulate susceptibility to premature myocardial infarction [6] and ischemic stroke [7] and to increase pulse pressure, a marker of arterial stiffness [8]. Some of these associations have been shown to be stronger in obese subjects, suggesting a gene-byobesity interaction in facilitating insulin resistance and atherogenic process [4, 9]. Up to date no results on ENPP-1 function on CIMT are available. Thus, we tested whether the ENPP-1 Q121 variant exerts an effect on CIMT measured at the common carotid artery (CCA) and at bulb and interacts with overweight–obesity in modulating CIMT.

Contribution of genetic variation within SuprMam1 and SuprMam2 to breast cancer susceptibility

Two recessive mammary tumour susceptibility loci, SuprMam1 (for suppressor of mammary tumours) on chromosome 7 (110-140 Mb) and SuprMam2 on chromosome 2 (120-140MB) have been identified in the BALB/c mouse strain in the Trp53+/- mouse model of spontaneous breast cancer [1]. We studied mammary gland morphology and expression levels of potential candidate genes in SM09 congenic mice (BALB/c SuprMam loci in C57BL/6 background) in comparison to parental strains, to identify the genes within the SuprMam loci that might be responsible for higher cancer susceptibility in BALB/c mice. We analysed mammary gland wholemounts for differences in their basic morphology. The average of ductal branch count per 4x field of view was, BALB/c (diestrus) =171, BALB/c (estrus) =173, C57BL/6 (diestrus) =43, C57BL/6 (estrus) =38, SM09 (diestrus) =29 and SM09 (estrus) =23. According to these results, even though there is a significant difference between the numbers of ductal branches between the two parental strains BALB/c and C57BL/6 (estrus:p=0.002, diestrus:p=0.027), there is no significant difference between congenic (SM09) and control (C57BL/6) mice during either estrus (p=0.164) or diestrus (p=0.299) stages at 12 months of age. A similar pattern was observed for total epithelial area. This suggests that BALB/c SuprMam alleles alone do not contribute significantly to the morphological differences of the parental strains. The tumour suppressor DMBT1 (deleted in malignant brain tumors) has previously been identified as a candidate modifier gene within SuprMam1 (1). Using semi-quantitative RT-PCR, Dmbt1 mRNA was found to be significantly lower in mammary glands of susceptible BALB/c mice when compared to C57BL/6, while SM09 congenic mice had similar levels to the control C57BL/6 mice. This indicates that the lower level of Dmbt1 expression in BALB/c mice must be due to transcriptional factor differences outside the region, which is not present in SM09 congenics. Using Affymetrix data comparing T cell gene expression across 5 different mouse strains, Cyp2r1, a major vitamin D hydroxylase, was identified as another potential candidate gene in SuprMam1. Plasma 25(OH)D levels were measured in SM09 and control mice to detect the effect of the different Cyp2r1 alleles. The plasma levels of 25(OH)D were 20% higher in SM09 mice compared to control mice (control= 49.71 nM/L, SM09= 59.44 nM/L). Surprisingly, however, this is the opposite of what is expected based on the association of CYP2R1 expression and cancer susceptibility in human populations. With these results, we are able to rule out two important candidate genes, DMBT1 and CYP2R1, from being responsible for the higher susceptibility of SuprMam loci. In order to confirm these results, and also to identify the possible involvement of other selected candidate genes, we aim to carry out transcriptional profiling on mammary glands of SM09 congenic and control mice.

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction for prescription medication, or a natural source of food to fight various infections and diseases. Genetics has played a role in identifying various interactions between existing drugs and side effects. In addition, various food allergies have been identified with children in recent years, suggesting genetic associations between certain populations carrying specific genetic alleles. The recent availability of genomic data and our increased understanding of the effects of genetic variations permit a quantitative examination of the contribution of genetic variation to efficacy or toxicity of compounds derived from natural sources. The identification of target molecules relevant for diseases allows screening for natural products capable of inhibiting targets which can lead to the development of rational treatment of various diseases including neurobiological disorders, cancer, osteoporosis, and cardiovascular diseases. This allows for more opportunities to predict the response of individual patients. Identification of genetic variations that arose as a consequence of naturally occurring compounds will help identify gene alleles, or protein ligands that can affect the pharmacodynamic and pharmacokinetics of the natural products in question. In addition, diet modification and precautions to food products can be identified to help consumers limit or increase certain food intake. Understanding the molecular mechanisms underlying these interactions and their modification by genetic variation is expected to result in the development of new drugs that optimize individual health. We expect that strategies for individualized therapies will lead to improved results for patients.

Influence of COMT val158met and ADRA2B deletion polymorphisms on recollection and familiarity components of human emotional memory

Emotional enhancement of memory is a widely accepted phenomenon that, in addition to its adaptive role, may play a role in the evolution of psychiatric disorders. Hence a comprehensive understanding of its neurobiological basis is imperative. Whilst the pharmacological and neural mechanisms are well known, the contribution of genetic variation is not. Research suggests that two qualitatively different processes (recollection and familiarity) contribute to recognition memory. In this study, we examined the relative contribution of two common genetic polymorphisms, the deletion variant of the ADRA2B gene that codes the α2b adrenergic receptor and the val158met polymorphism of the COMT gene that codes the catechol-O-methyltransferase enzyme, to emotional enhancement of these two memory processes in 97 healthy male volunteers. There was a significant interaction between COMT genotype and emotional arousal in relation to recollection, but not familiarity, with the former being significantly elevated for emotionally arousing versus neutral pictures in carriers of the val158 allele compared with met158 carriers. There were no main effects or interactions in relation to ADRA2B genotype.

Genetic variant of HTR2A associates with risk of impulse control and repetitive behaviors in Parkinson’s disease

Objectives To determine the role of a serotonin 2A receptor gene (= HTR2A) variant in the development of impulse control and repetitive behaviors in Parkinson’s disease. Methods We performed a genetic association analysis to a cohort of 404 Korean patients with Parkinson’s disease who had been enrolled in a previous study. Presence of impulse control and repetitive behaviors was screened using modified version of Minnesota Impulsive Disorders Interview and genotyping for HTR2A c.102T > C was performed using the TaqMan assay. Results The T allele, which is presumably linked to higher receptor expression, was marginally associated with impulse control and repetitive behaviors in Parkinson’s disease; the genetic influence was significantly enhanced in the lower levodopa-equivalent-dose group, increasing the risk by 2.8 and 6.9 times in CT and TT carriers, respectively ( p-trend = 0.011). There was no significant interaction between the c.102T > C variant and clinical risk variables such as sex, age at onset, total daily levodopa-equivalent-dose, use of dopamine agonist and daily dose of dopamine agonist. Conclusion Our data support a possible contribution of genetic variation in the HTR2A to the susceptibility to impulse control and repetitive behaviors in Parkinson’s disease.

Heritability of bipolar affective disorder: Family study

Bipolar affective disorder is mental disorder with polygenic type of heredity. Heritability--relation between genetic and environmental variance is used to estimate the level of influence of genetic variance to phenotype variance. Study results show decreasing trend in the value of heritability of bipolar affective disorder, thus indicating that this disorder is a complex behavioral threshold characteristic. Therefore, the aim of this study was to estimate the contribution of genetic variance to phenotype variance of bipolar affective disorder, i.e. to estimate heritability of this disorder. By the use of a questionnaire, 80 patients with over crossed threshold for bipolar affective disorder were asked for functional information about the members of their families belonging to the first degree of relation (fathers, mothers and full-sibs). By using "Applet for calculating heritability for threshold traits (disease)", and regression analysis, heritability of bipolar affective disorder as well as its statistical significance, were estimated (chi2 test). Heritability and relationship of genetic and environmental variance of bipolar affective disorder is 0.2 with statistically significant difference from zero (p < 0.001). The estimated contribution of genetic variance to phenotype variance of bipolar affective disorder is low being 20%, while the contribution of environmental variance is 80%. This result contributes to the understanding of bipolar affective disorder as a complex behavioral threshold trait.

REVIEW: Cognitive effects of nicotine: genetic moderators

Cigarette smoking is the main preventable cause of death in developed countries, and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive enhancement. Based on knockout mice studies, beta2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. alpha7nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine-induced improvement in spatial working memory. Less is known about the contribution of genetic variation in DA transporter and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine.

Desensitization of vascular response in vivo: contribution of genetic variation in the α2B-adrenergic receptor subtype

Vascular alpha2B-adrenergic receptors (alpha2B-ARs) mediate vasoconstriction and contribute to peripheral regulation of vascular tone. In vitro, a common 301-303 deletion in the alpha2B-AR gene, ADRA2B, results in loss of alpha2B-AR desensitization. We examined the hypothesis that ADRA2B del301-303 or other common ADRA2B variants alter vascular desensitization in vivo. We measured sensitivity to a highly selective alpha2-AR agonist, dexmedetomidine, (0.01-1000 ng/min) in the dorsal hand vein in 41 healthy individuals. To induce desensitization a dose of dexmedetomidine that resulted in submaximal constriction was infused for 180 min and dorsal hand vein responses measured. Desensitization was defined as the ratio between the area-under-the-effect curve for each individual's response and the hypothetical area-under-the-effect curve assuming that the initial response had been maintained for 180 min (ratio below 1 reflecting desensitization). The relationship between six ADRA2B variants (one promoter, three coding, and two in the 3' untranslated region ) with an allele frequency of more than 5% and desensitization was determined. Forty-one individuals (22 men, 21 whites, age 18-45 years) were studied. The ADRA2B 301-303 deletion allele (ins/del and del/del, n = 18) was associated with resistance to desensitization [1.01 (interquartile range 0.90-1.06)] as compared with ins/ins homozygous individuals (n = 23) [0.91 (interquartile range 0.73-0.99)], P = 0.026. In addition, the -98 GG, 1182 CC, and 1776 CC genotypes were associated with significantly less desensitization than GC or CC, and CA or AA genotypes, respectively. Common ADRA2B variants contribute to the interindividual variability in vascular desensitization to an alpha2-AR agonist in vivo.

The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis

The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals.

Genetic basis of thrombosis

Venous thrombosis (VT) represents a common and serious disorder that occurs as the result of clotting of the blood in the venous system and venous obstruction. Environmental risk factors and genetic predisposition play an important role in the development of thrombosis. It is therefore seen as a classic example of a complex common disease. We have focused on the role of genetic risk factors, primarily related to the hemostatic system, in triggering thrombotic events. Since the identification of antithrombin deficiency in 1965, major efforts have been made during the past 15 years to identify other genetic entities that lead to increased thrombotic risk. Results of early genetic studies demonstrated that two types of genetic defects cause VT: loss of function mutations in the natural anticoagulants antithrombin, protein C and protein S and gain of function mutations in procoagulant factors V (FV Leiden) and II (prothrombin G20210A). The high incidence of these mutations in Caucasians induced a shift from family studies to case-control association studies. Several investigations have been performed on the role of other candidate genetic risk factors predisposing to VT, including such variants in FXIII, FIX and fibrinogen genes. Moreover, the contribution of genetic variation in genes encoding less-well studied proteins that are part of the anticoagulant pathways has been evaluated. Recently, different genome-wide association studies have been performed in which several single nucleotide polymorphisms were investigated and related to the risk of VT. However, further studies are needed to identify additional genetic causes of thrombosis and to assess functional molecular mechanisms.

Genetic testing in other GI diseases

Gastrointestinal development is a complex process comprising folding of the endodermal layer to form the primitive gut tube, cell differentiation along its anteroposterior axis, the budding of the various organ primordia and development of derivative organs like the liver and pancreas and the colonisation of the gut with neuronal precursors. Genetic factors are increasingly recognised as playing a significant role in the disturbance of this developmental process which underlies congenital malformations and gastrointestinal disorders. Furthermore, genetic variation and its interaction with environmental influences play an important role in the pathogenesis of functional gastrointestinal disorders. In this review, we discuss the contribution of genetic variants, ranging from highly penetrant mutations and chromosomal abnormalities to genetic polymorphisms, to the pathogenesis of a number of structural and functional gastrointestinal disorders.

Relative importance of tree genetics and microhabitat on macrofungal biodiversity on coarse woody debris

Understanding the contribution of genetic variation within foundation species to community-level pattern and diversity represents the cornerstone of the developing field of community genetics. We assessed the relative importance of intraspecific genetic variation, spatial variation within a forest and microhabitat variation on a macrofungal decay community developing on logs of the Australian forest tree, Eucalyptus globulus. Uniform logs were harvested from trees from eight geographic races of E. globulus growing in a 15-year-old genetic trial. Logs were placed as designed grids within a native E. globulus forest and after 3 years of natural colonisation the presence of 62 macrofungal taxa were recorded from eight microhabitats on each log. The key factor found to drive macrofungal distribution and biodiversity on structurally uniform coarse woody debris was log-microhabitat, explaining 42% of the total variation in richness. Differences between log-microhabitats appeared to be due to variation in aspect, substrate (bark vs wood) and area/time of exposure to colonisation. This findings demonstrates the importance of considering fine-scale (within substrate) variation in the conservation and management of macrofungal biodiversity, an area that has received little previous attention. While a number of recent studies have demonstrated that the genetics of foundation tree species can influence dependent communities, this was not found to be the case for the early log decay community associated with E. globulus. Despite genetic variation in wood and bark properties existing within this species, there was no significant effect of tree genetics on macrofungal community richness or composition. This finding highlights the variation that may exist among guilds of organisms in their response to genetic variation within foundation species, an important consideration in a promising new area of research.

Morphological and physiological variation among seagrass (Zostera marina) genotypes

Intraspecific variation in habitat-forming species can have important ecological consequences at the population, community, and ecosystem level. However, the contribution of genetic variation among individuals to these effects is seldom documented. We quantified morphological and physiological variation among genotypes of a marine foundation species, the seagrass Zostera marina. We grew replicate shoots of eight genetically distinct Zostera individuals collected from Bodega Bay, California, in a common garden environment and then quantified shoot production and morphology, nutrient uptake, and key photosynthetic parameters. We found that genotypes differed in shoot production, biomass, and both root and shoot nutrient uptake rates, even when corrected for genotype-specific biomass differences. In addition, the rank order of uptake ability differed for ammonium and nitrate, indicating that genotypes may exhibit resource partitioning of different forms of nutrients. Our results suggest that both niche complementarity among genotypes and the sampling/selection effect could contribute to previously observed positive effects of seagrass clonal diversity on resource utilization and biomass production. Further, they highlight that genotypic variation in key traits of habitat-forming species could have measurable effects on community structure and function.

DNA repair polymorphisms and the risk of stomach adenocarcinoma and severe chronic gastritis in the EPIC-EURGAST study

The contribution of genetic variation in DNA repair genes to gastric cancer (GC) risk remains essentially unknown. The aim of this study was to explore the relative contribution of DNA repair gene polymorphisms to GC risk and severe chronic atrophic gastritis (SCAG). Method A nested case control study within the EPIC cohort was performed including 246 gastric adenocarcinomas and 1175 matched controls. Controls with SCAG (n = 91), as defined by low pepsinogen A (PGA) levels, and controls with no SCAG (n = 1061) were also compared. Twelve polymorphisms at DNA repair genes (MSH2, MLH1, XRCC1, OGG1 and ERCC2) and TP53 gene were analysed. Antibodies against Helicobacter pylori were measured. No association was observed for any of these polymorphisms with stomach cancer risk. However, ERCC2 K751Q polymorphism was associated with an increased risk for non-cardial neoplasm [odds ratio (OR) = 1.78; 95% confidence interval (CI) 1.02-3.12], being ERCC2 K751Q and D312N polymorphisms associated with the diffuse type. ERCC2 D312N (OR = 2.0; 95% CI 1.09-3.65) and K751Q alleles (OR = 1.82; 95% CI 1.01-3.30) and XRCC1 R399Q (OR = 1.69; 95% CI 1.02-2.79) allele were associated with an increased risk for SCAG. Our study supports a role of ERCC2 in non-cardial GC but not in cardial cancer. A concordant result was observed for subjects with low PGA levels. XRCC1 allele was associated also with SCAG. This is the first prospective study suggesting that individual variation in DNA repair may be relevant for gastric carcinogenesis, a finding that will require further confirmation validation in larger independent studies.

ORIGINAL ARTICLE: Genetic Predisposition to Idiopathic Recurrent Spontaneous Abortion: Contribution of Genetic Variations in IGF‐2 and H19 Imprinted Genes

Problem Recurrent spontaneous abortion (RSA) is a common clinical problem with a complex etiology of genetic and non‐genetic causes, which remains to be fully determined. IGF‐2 stimulates trophoblast invasion, proliferation and maturation of placenta, while H19 RNA suppresses growth. As genomic imprinting plays a critical role in the development of placenta and embryo, our aim was to evaluate the possible role of variations in IGF‐2 and H19 imprinted genes as factors of predisposition for RSA.Method of study A case–control study was conducted to determine the association between IGF‐2 and H19 gene polymorphisms and the susceptibility to RSA in 113 couples with RSA and 226 controls. PCR/RFLP were performed to analyze IGF‐2 ApaI and H19 HhaI polymorphisms.Results We found a statistically significant difference in the genotype frequency distribution of IGF‐2 ApaI polymorphism between males from couples with RSA and healthy males (χ2(2) = 45.12; P &lt; 0.0001). There were no differences in the genotype and allele distribution of H19 polymorphism frequencies, or for the IGF‐2 ApaI polymorphism between female groups.Conclusion The presence of IGF‐2 ApaI polymorphism in partners of RSA women could affect IGF‐2 level of expression in placenta and embryo and represent a risk factor for RSA susceptibility.

Pharmacogenetics in epilepsy treatment: sense or nonsense?

Epilepsy is the most common serious chronic neurological disorder. Treatment consists mainly of antiepileptic drugs (AEDs), with more than 15different molecules available. However, AED treatment is often problematic because of unpredictability of drug response, adverse drug reactions and optimal dosing in individual patients. Moreover, up to one in three patients with epilepsy are refractory to currently available AEDs. Pharmacogenetic studies explore the contribution of genetic variants to interindividual differences in drug response. An increasing number of pharmacogenetic association studies in epilepsy are being reported. Nevertheless, at present only one association is firmly established, namely that of the HLA-B*1502 allele with severe cutaneous adverse drug reactions on carbamazepine therapy in the Han Chinese population. It is likely that large collaborations looking at multiple genes encoding entire drug pathways, or even the entire human genome, together with new pharmacogenetic strategies will result in the discovery of other genetic variants involved in AED response. Although several challenges remain, it is hoped that, ultimately, these findings will lead to the development of predictive tests, resulting in a more efficacious and safer AED treatment, and to the development of new AEDs with novel mechanisms of action, particularly aimed at patients with drug-refractory epilepsy.