Candidate Gene Polymorphisms Research Articles

Single nucleotide polymorphism of candidate genes in non-descript local goats of Sri Lanka

In the present study, genetic polymorphism in exon 4 of kappa casein (k-CSN3), exon 2–3 of alpha lactalbumin (LALBA) and exon 1 of gonadotropin releasing hormone receptor (GnRHR) genes were analyzed as candidate genes for milk production, milk quality and prolificacy aiming to provide information for future studies on genetic improvements in non-descriptive local goats in Sri Lanka. Altogether eleven, thirteen and three single nucleotide polymorphisms (SNPs) were identified in k-CSN3, LALBA and GnRHR gene fragments respectively utilizing the DNA sequencing technique in Sri Lanka. Seven polymorphic sites out of eleven in k-CSN3 gene fragment and the recorded polymorphic site in exon 3 of LALBA gene fragment were homozygous while all three polymorphic sites in GnRHR gene fragment were heterozygous. Two of the SNPs recorded in the present study are found to unique for Sri Lankan non-descript goat population at G203T and A730G in k-CSN3 and GnRHR genes respectively. The study records another two SNPs in GnRHR gene which are already known to be correlated with higher fecundity in goats (G757A and G891T). Results of the present study will be extremely important in future attempts to indicate markers to improve the milk production, composition of milk and litter size of non-descript local goats in Sri Lanka.

Editor's Highlight: Genetic Targets of Acute Toluene Inhalation in Drosophila melanogaster.

Interpretation and use of data from high-throughput assays for chemical toxicity require links between effects at molecular targets and adverse outcomes in whole animals. The well-characterized genome of Drosophila melanogaster provides a potential model system by which phenotypic responses to chemicals can be mapped to genes associated with those responses, which may in turn suggest adverse outcome pathways associated with those genes. To determine the utility of this approach, we used the Drosophila Genetics Reference Panel (DGRP), a collection of ∼200 homozygous lines of fruit flies whose genomes have been sequenced. We quantified toluene-induced suppression of motor activity in 123 lines of these flies during exposure to toluene, a volatile organic compound known to induce narcosis in mammals via its effects on neuronal ion channels. We then applied genome-wide association analyses on this effect of toluene using the DGRP web portal (http://dgrp2.gnets.ncsu.edu), which identified polymorphisms in candidate genes associated with the variation in response to toluene exposure. We tested ∼2 million variants and found 82 polymorphisms located in or near 66 candidate genes that were associated with phenotypic variation for sensitivity to toluene at P < 5 × 10-5, and human orthologs for 52 of these candidate Drosophila genes. None of these orthologs are known to be involved in canonical pathways for mammalian neuronal ion channels, including GABA, glutamate, dopamine, glycine, serotonin, and voltage sensitive calcium channels. Thus this analysis did not reveal a genetic signature consistent with processes previously shown to be involved in toluene-induced narcosis in mammals. The list of the human orthologs included Gene Ontology terms associated with signaling, nervous system development and embryonic morphogenesis; these orthologs may provide insight into potential new pathways that could mediate the narcotic effects of toluene.

Germline Genetic Variations in Methotrexate Candidate Genes Are Associated with Pharmacokinetics and Outcome in Pediatric Acute Lymphoblastic Leukemia in China

BackgroundMethotrexate (MTX) is a key chemotherapeutic agent in the treatment of pediatric acute lymphoblastic leukemia (ALL). Nevertheless, MTX can cause severe adverse effects and toxicities. The aim of the present study was to identify genetic polymorphisms in candidate genes of the MTX pathway associated with MTX pharmacokinetics, toxicity, and outcome in ALL in China.MethodsThree hundred and twenty-two Chinese children with ALL in the standard-risk and medium-risk treatment branches from the Beijing Children's Hospital-2003 and Chinese Childhood Leukemia Group-2008 protocols were enrolled in this study. Sequenom MassARRAY was used to genotype 12 single nucleotide polymorphisms (SNPs) in 4 candidate genes of the MTX/folate pathway. A total of 1268 high-dose MTX (HD-MTX) courses were analyzed. The plasma MTX levels were evaluated at 48 h after the first dose of HD-MTX infusion. Oral mucositis during the consolidation therapy period was recorded.Results No polymorphism was associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. Long-term outcome was better in SLCO1B1 rs4149056 T and TC allele carriers than patients with C allele (5-year RFS 92.3±1.6% vs. 27.8±23.2%,P<0.0001), in ABCB1 rs1128503 T and TC allele carriers than patients with C allele (92.7±1.6% vs. 78.2±6.9%, P=0.020), and in SCL19A1 rs2838958 AG and G allele carries than patients with A allele (93.9±1.6% vs. 83.0±4.2%, P =0.010). Multiple Cox regression analyses revealed an association of MRD at day 33 (hazard ratio 3.356; P=0.018), MRD at day 78 (hazard ratio 2.843; P=0.034), and SLCO1B1 rs4149056 (hazard ratio 8.073; P=0.002) with RFS in the study population.As to MTX pharmacokinetics, ABCB1 rs1128503 showed a significant association with serum MTX levels (P=0.004). SNPs (rs3788200, rs1131596, rs1051266) of the SLC19A1 gene were also associated with the plasma levels of MTX (P=0.003, 0.004, and 0.003, respectively). No association was found between oral mucositis with any polymorphism.Conclusions Genetic variations substantially influence the kinetics and response to HD-MTX therapy in childhood ALL. DisclosuresNo relevant conflicts of interest to declare.

Role of GNB3, NET, KCNJ11, TCF7L2 and GRL genes single nucleotide polymorphism in the risk prediction of type 2 diabetes mellitus.

Type 2 diabetes (T2DM) is a polygenic metabolic disorder characterized by hyperglycemia occurring as a result of impaired insulin secretion or insulin resistance. Various environmental and genetic factors interact and increase the risk of T2DM and its complications. Among the various genetic factors associated with T2DM, single nucleotide polymorphism in different candidate genes have been studied intensively and the resulting genetic variants have been found to have either positive or negative association with T2DM thereby increasing or decreasing the risk of T2DM, respectively. In this review, we will focus on Guanine nucleotide-binding protein subunit beta 3 (GNB3), Norepinephrine Transporter (NET), Potassium Channel gene (KCNJ11), Transcription Factor 7-Like 2 (TCF7L2) and Glucocorticoid receptor (GRL) genes and their association with T2DM studied in different ethnic groups. The products of these genes are involved in the biochemical pathway leading to T2DM. Polymorphisms in these genes have been intensively studied in individuals of different ethnic origins. Results show that genetic variants of TCF7L2 and KCNJ11 genes have potential to emerge as a risk biomarker for T2DM whereas results of GNB3, GRL and NET genes have been controversial when studied in individuals of different ethnicities. We have tried to summarize the results generated globally in context to the selected genes which could possibly help researchers working in this field and would eventually help in understanding the mechanistic pathways of T2DM leading early diagnosis and prevention.

Association study of arcuate nucleus neuropeptide Y neuron receptor gene variation and serum NPY levels in clozapine treated patients with schizophrenia

BackgroundAntipsychotic-induced weight gain (AIWG) leads to metabolic consequences and comorbidity, social stigmatization and nonadherence in patients with schizophrenia. Neuropeptide Y (NPY) has an important role in appetite and body weight regulation. Associations between AIWG and serum NPY levels, and genetic polymorphisms (SNPs) associated with its serum levels have been little studied in these patients. Subjects and methodsAssociations between serum NPY concentration and other metabolic and inflammatory markers, and 215 SNPs in 21 genes (NPY gene, NPY receptor genes and genes encoding arcuate nucleus NPY neuron receptors) were studied in 180 patients with schizophrenia on clozapine treatment. ResultsThe serum levels of NPY correlated with levels of resistin (r=0.31, P<0.001) and age (r=0.22, P=0.003). In the general linear univariate model the best-fitting model with explanatory factors age, serum resistin level, serum insulin level, BMI and gender explained 18.0% (P<0.001) of the variance of serum NPY. Genetic risk score (GRSNPY) analysis found twelve significant (P<0.05) serum NPY concentration related SNPs among α7 nicotinic acetylcholine receptor gene CHRNA7, insulin receptor gene INSR, leptin receptor gene LEPR, glucocorticoid receptor (GR) gene NR3C1, and NPY gene. However, after permutation test of gene score the predictive value of GRSNPY remained non-significant (P=0.078). ConclusionsSerum NPY level does not seem to be a feasible biomarker of AIWG. Serum NPY level alterations are not significantly associated with the candidate gene polymorphisms studied.

Genome-wide Association Study of Parental Life Span

Having longer lived parents has been shown to be an important predictor of health trajectories and life span. As such, parental life span is an important phenotype that may uncover genes that affect longevity. A genome-wide association study of parental life span in participants of European and African ancestry from the Health and Retirement Study was conducted. A genome-wide significant association was observed for rs35715456 (log10BF = 6.3) on chromosome 18 for the dichotomous trait of having at least one long-lived parent versus not having any long-lived parent. This association was not replicated in an independent sample from the InCHIANTI and Framingham Heart Study. The most significant association among single nucleotide polymorphisms in longevity candidate genes (APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1) was observed in the EBF1 gene region (rs17056207, p = .0002). A promising genetic signal for parental life span was identified but was not replicated in independent samples.

Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8× 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5× 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for Tcell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.

ADH1B and CDH1 polymorphisms predict prognosis in male patients with non-metastatic laryngeal cancer.

In this study, we assessed the association between single nucleotide polymorphisms (SNPs) in candidate genes and the prognosis of laryngeal cancer (LC) patients. Thirty-seven SNPs in 26 genes were genotyped in 170 male Han Chinese patients with LC. The effects of the candidate genes on the prognosis of LC patients were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. The GA genotype of rs1229984 (hazard ratio [HR], 0.537; 95% confidence interval [CI], 0.340–0.848; p = 0.008) in alcohol dehydrogenase 1B (ADH1B), and the AA genotype of rs9929218 (HR, 6.074; 95% CI, 1.426–25.870; p = 0.015) in CDH1 were associated with overall survival. Our data suggest that polymorphisms in ADH1B and CDH1 may be prognostic indicators in LC.

Ethnogenetic aspects of obesity and disorders of carbohydrate metabolism as a risk factor of arterial hypertension

Objective - to explore the association of candidate genes of arterial hypertension ACE, ADRA2B, ADRB1, MTHFR and eNOS with obesity and impaired glucose metabolism based on ethnicity. Materials and methods. Clinical and epidemiological study of compactly living population in the remote areas of the Mountain Shoria (Orton, Ust-Kabyrza, Sheregesh settlements, Kemerovo region). 1178 residents of these settlements were surveyed with the help of continuous sampling method; the sample consisted of adults (18 years and older). Results. In the group of respondents of the indigenous nationality averages Quetelet index, waist circumference and fasting blood glucose, depending on the polymorphism of candidate genes of arterial hypertension ACE, ADRA2B, ADRB1, MTHFR and eNOS were lower than in non-indigenous ethnic group surveyed. In a population of Shor was found a statistically significant relationship with the body mass index of ACE gene genotypes in a population of non-indigenous representatives - with genotypes of ADRA2B gene. In the group of indigenous ethnic group revealed the relationship from ACE gene polymorphism. Regardless of nationality, found associative connection of the indicator polymorphism of ADRA2B gene. The level of plasma glucose levels in a population of non-indigenous ethnic group was correlated with genotypes of ADRA2B gene. Conclusion. Metabolic abnormalities were detected less frequently in indigenous ethnic group compared with the non-indigenous. In Shor group ACE DD genotype and ADRA2B genes associated with obesity, the genotype 4a/4a eNOS gene - with abdominal obesity. In the group of non-indigenous ethnic group CC genotype of the MTHFR gene was associated with abdominal obesity, II genotype of ACE gene and DD ADRA2B gene - with impaired carbohydrate metabolism.

Association of candidate gene polymorphisms for autoimmune thyroid diseases in patients with familial diffuse toxic goiter and autoimmune thyroiditis

Aim : to study the relation polymorphism of some genes of the immune response with familial autoimmune thyroid disease. Materials and methods. 100 patients from 49 families were examined. At least 2 first-degree affected relatives with autoimmune thyroiditis or diffuse toxic goiter were included from each family. 76 persons were included to control group without thyroid pathology and negative history of any thyroid disease in families. Clinical, hormonal, ultra-sound data was collected for each subject. Genotyping ofCTLA4 A49G and PTPN22 C1858T polymorphisms was performed for 70 patients (35 families) with familial autoimmune thyroid disease and for all subjects from the control group. Results. Autoimmune thyroid disease was observed among one generation (siblings) in 11 families (22.5%) and among two generations (parent-child) in 38 families (75.5%). Patients with chronic autoimmune thyroiditis with hypothyroidism in the outcome were dominated – 66%, 34% experienced diffuse toxic goiter. Autoimmune thyroiditis was observed in parent and offspring from 21 families (55%). In the group of siblings autoimmune thyroiditis was diagnosed for both relatives in 6 families (54%). Frequency of genotypes of CTLA4 A49G polymorphism is not differ between patients with familial autoimmune thyroid disease and control group. Carriage of T allele of PTPN22 C1858T polymorphism is associated with the risk of autoimmune thyroid disease developing in a group of female offspring: OR = 3.175; 95% CI 1,423–7,262. These results allow us to recommend to test this polymorphism to identify patients with the risk of autoimmune thyroid diseases in families. Conclusion. Taking into account that DNA testing is one of the most important part of personalized approach in medicine, the current results of molecular genetic study for familial cases of autoimmune thyroid disease creates prerequisites for optimizing the diagnostic pathway of these patients.

Candidate gene polymorphisms related to lipid and carbohydrate metabolism show an association with risk factor components of the metabolic syndrome in Asian Indians

Candidate gene polymorphisms related to lipid and carbohydrate metabolism show an association with risk factor components of the metabolic syndrome in Asian Indians

Metabolic indicators in cattle breeding

Potential associations among glucose tolerance test (GTT) as ability to metabolize glucose, estimated breeding values (EBVs) for milk traits and selected candidate gene polymorphisms were evaluated. German Holstein sires, born in 1993 and between years 1999 and 2003, were analysed. A few significant negative correlations between milk and protein yield and GTT were found in sires born in 1993. Only a few significant correlations were found for protein yield, protein percentage and for fat percentage and yield (sires born in different years). Any linkage of DGAT1, GH1, GHR, FASN and OLR1 to GTT was found. Keywords: milk, glucose, correlation, breeding values References Deepa, P.M . et al. (2015) Alteration in clinico-biochemical profile and oxidative stress indices associated with hyperglycaemia with special reference to diabetes in cattle-a pilot study. Trop. Anim. Health Prod. , Vol. 47, no. 1, pp. 103-109. DOI:10.1007/s11250-014-0691-5 Di Stasio, L. et al. (2005) Polymorphism of the GHR gene in cattle and relationships with meat production and quality. Anim. Genet. , Vol. 36, pp. 138–140. Grisart, B. et al. (2002) Positional candidate cloning of a QTL in dairy cattle: Identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition. Genome Res., Vol. 12, pp. 222-231. Kneeskern, S. G . et al. (2016) Effects of chromium supplementation to feedlot steers on growth performance, insulin sensitivity, and carcass characteristics. J. Anim. Sci. , Vol. 94, no. 1, pp. 217-226. DOI: 10.2527/jas2015-9517 Khatib, H. et al. (2006) Association of the OLR1 Gene with Milk Composition in Holstein Dairy Cattle. J. Dairy Sci. , Vol. 89, pp. 1753–1760. Morris, C. A. (2007) Fatty acid synthase effects on bovine adipose fat and milk fat. Mamm. Genome , Vol. 18, pp. 64–74. Panicke, L. et al. (2000) Relationships between parameters of the glucose tolerance test by young sires and estimated their breeding values. Arch. Tierz. , Vol. 43, pp. 231-239.

Significant interactions between maternal PAH exposure and single nucleotide polymorphisms in candidate genes on B[ a ]P-DNA adducts in a cohort of non-smoking Polish mothers and newborns.

Polycyclic aromatic hydrocarbons (PAH) are a class of chemicals common in the environment. Certain PAH are carcinogenic, although the degree to which genetic variation influences susceptibility to carcinogenic PAH remains unclear. Also unknown is the influence of genetic variation on the procarcinogenic effect of in utero exposures to PAH. Benzo[ a ]pyrene (B[ a ]P) is a well-studied PAH that is classified as a known human carcinogen. Within our Polish cohort, we explored interactions between maternal exposure to airborne PAH during pregnancy and maternal and newborn single nucleotide polymorphisms (SNPs) in plausible B[ a ]P metabolism genes on B[ a ]P-DNA adducts in paired cord blood samples. The study subjects included non-smoking women ( n = 368) with available data on maternal PAH exposure, paired cord adducts, and genetic data who resided in Krakow, Poland. We selected eight common variants in maternal and newborn candidate genes related to B[ a ]P metabolism, detoxification, and repair for our analyses: CYP1A1 , CYP1A2 , CYP1B1 , GSTM1 , GSTT2 , NQO1 , and XRCC1 . We observed significant interactions between maternal PAH exposure and SNPs on cord B[ a ]P-DNA adducts in the following genes: maternal CYP1A1 and GSTT2 , and newborn CYP1A1 and CYP1B1 . These novel findings highlight differences in maternal and newborn genetic contributions to B[ a ]P-DNA adduct formation and have the potential to identify at-risk subpopulations who are susceptible to the carcinogenic potential of B[ a ]P.

Genes and patent ductus arteriosus

The genetics of cardiovascular disease has been a confusing area, in part because our classification of cardiac morphology has not mapped well to genetic influences on cardiac development, but also because cardiac development is a very complex process involving many genes and environmental influences. In this volume of The Journal, Patel et al evaluate single nucleotide polymorphisms in candidate genes potentially associated with patent ductus arteriosus (PDA) in term infants. The candidate gene approach can be troublesome because it is often difficult to know which genes to pick. When results are negative, it is not always clear whether the wrong genes were chosen, the power was inadequate, or if there were other issues. When the results are positive, it is not always clear whether there is a causal relationship or whether significance (if not corrected) resulted from multiple statistical tests. In this case, Patel et al chose 17 genes, some of which were associated with syndromes with increased prevalence of PDA. Others were thought to be related to the physiology of PDA closure. They used two populations and accepted only results that were positive in both. They corrected for multiple comparisons. They found a gene in the transforming growth factor-beta pathway that met their criteria. Identification of this pathway may result in new approaches to prevent or treat PDA in term infants. Article page 57 ▶ Genetic Modifiers of Patent Ductus Arteriosus in Term InfantsThe Journal of PediatricsVol. 176PreviewTo identify single-nucleotide polymorphisms (SNPs) in specific candidate genes associated with patent ductus arteriosus in term infants. Full-Text PDF

The genetic background of climacteric symptoms in women during menopause

The subject of the study is the evaluation of the correlation between the polymorphism of candidate genes in the etiology of depression and the occurrence of the symptoms of the climacteric syndrome in women during menopause. The group subjected to the study comprised of 203 women aged between 42-65 years: 71 of them still menstruated (premenopausal group) and 132 at least one year after the last period (postmenopausal group), admitted to the Department of Gynecological Endocrinology at the University of Medical Sciences in Poznan with symptoms of the climacteric syndrome. All the examined women were evaluated according to the degree of severity of the climacteric syndrome symptoms using the Kupperman index and the concentration of FSH, LH hormones, 17&#x03B2;-estradiol, PRL, total testosterone, and DHEAS in peripheral blood serum. Among the candidate genes in the aetiology of depression the following were selected for the research: the serotonergic system receptor genes: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, and MAO-A; the genes of noradrenergic and dopaminergic systems (COMT, NET), the genes of the GABAergic (GABRB1) system, a gene of the estrogen receptor (ESR1), and the genes of the enzymes crucial in the methyl cycle (MTHRF, MTR, and MTHFD1). With regards to the correlation between the examined polymorphisms and the occurrence of the symptoms of the climacteric syndrome, the associations analysis indicated a connection between GABRB1.TaqI polymorphism and the occurrence of vertigo in premenopausal women (0.0198; after correction: 0.0497 CC to CA). The correlation was also found regarding the examined polymorphisms and the concentration of the examined hormones in blood serum: TPH1.MaeI polymorphism and the LH concentration in the postmenopausal group (0.004; after correction: 0.014 CC to CA), NET.Eco147I polymorphism, and the 17&#x03B2;-estradiol concentration in the postmenopausal group (0.0208; after correction: 0.048 GG to GA) and HTR2AMspI polymorphism and PRL concentration in all examined women (0.03; after correction: 0.038 TT to CT).

Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy: Replication of the Reported Candidate Susceptibility Loci.

The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a significance level p value <0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.

Sequence-Based Introgression Mapping Identifies Candidate White Mold Tolerance Genes in Common Bean.

White mold, caused by the necrotrophic fungus (Lib.) de Bary, is a major disease of common bean ( L.). WM7.1 and WM8.3 are two quantitative trait loci (QTL) with major effects on tolerance to the pathogen. Advanced backcross populations segregating individually for either of the two QTL, and a recombinant inbred (RI) population segregating for both QTL were used to fine map and confirm the genetic location of the QTL. The QTL intervals were physically mapped using the reference common bean genome sequence, and the physical intervals for each QTL were further confirmed by sequence-based introgression mapping. Using whole-genome sequence data from susceptible and tolerant DNA pools, introgressed regions were identified as those with significantly higher numbers of single-nucleotide polymorphisms (SNPs) relative to the whole genome. By combining the QTL and SNP data, WM7.1 was located to a 660-kb region that contained 41 gene models on the proximal end of chromosome Pv07, while the WM8.3 introgression was narrowed to a 1.36-Mb region containing 70 gene models. The most polymorphic candidate gene in the WM7.1 region encodes a BEACH-domain protein associated with apoptosis. Within the WM8.3 interval, a receptor-like protein with the potential to recognize pathogen effectors was the most polymorphic gene. The use of gene and sequence-based mapping identified two candidate genes whose putative functions are consistent with the current model of pathogenicity.

Inherited genetic variants associated with childhood acute lymphoblastic leukemia risk.

Numerous efforts have been made to elucidate the roles of individual genetic background factors in the risk of childhood acute lymphoblastic leukemia. Most have taken the form of case-control studies focusing on specific candidate gene polymorphisms. Recently, a more rigorous and comprehensive approach referred to as a genome-wide association study (GWAS) has been widely utilized and has achieved success. Case-control studies evaluating candidate gene associations have shown cumulative evidence of a role for folate metabolism and xenobiotic metabolism/transport pathway genetic variants. In addition, single nucleotide polymorphism (SNP)s identified by GWAS appear to indicate a strong role for genes encoding transcription factors involved in cellular differentiation. Further studies are needed to clarify the accumulating evidence obtained from both candidate gene and genome-wide investigations.

Genetic Modifiers of Patent Ductus Arteriosus in Term Infants

To identify single-nucleotide polymorphisms (SNPs) in specific candidate genes associated with patent ductus arteriosus in term infants. We conducted an initial family-based, candidate gene study to analyze genotype data from DNA samples obtained from 171 term infants and their parents enrolled in the National Birth Defects Prevention Study (NBDPS). We performed transmission disequilibrium testing (TDT) using a panel of 55 SNPs in 17 genes. Replication of SNPs with P<.1 in the NBDPS trios was performed with a case-control strategy in an independent population. TDT analysis of the NBDPS trios resulted in 6 SNPs reaching the predetermined cutoff (P<.1) to be included in the replication study. These 6 SNPs were genotyped in the independent case-control population. A SNP in TGFBR2 was found to be associated with term patent ductus arteriosus in both populations after we corrected for multiple comparisons. (rs934328, TDT P=2×10(-4), case-control P=6.6×10(-5)). These findings confirm the importance of the transforming growth factor-beta pathway in the closure of the term ductus arteriosus and may suggest new therapeutic targets.

Novel single nucleotide polymorphisms in candidate genes for growth in tilapia ( Oreochromis niloticus )

The objective of the present work was to identify and validate single nucleotide variations located in candidate genes to growth traits in tilapia (Oreochromis niloticus). Two transitions were identified in the promoter region of the growth hormone gene (GH); eight nucleotide changes were identified in introns and promoter region of the IGF-I gene; and a transition (T/C) was identified in the Myogenin gene (MyoG). The highest genotypic frequency (0.8) for GHpA1 and MyoG was found in the GG and TT homozygous individuals, while the highest frequency (0.9) for GHpB1 was observed in the CT heterozygous fish. There was no genotypic frequency in the CC homozygous tilapia for the GHpB1 and MyoG markers. Based on their allelic frequencies, validation as novel single nucleotide polymorphisms (SNP) of those variations located at O. niloticus GH and MyoG genes was possible. These new markers will allow their association with growth traits in tilapia to be exploited in order to determine their potential use as assisted-selection markers.