Genética del TDAH en la práctica clínica / Genetics of ADHD in clinical practice

Resumen El trastorno por déficit de atención/hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo desde una perspectiva causal, clínica y pro nóstica. La investigación refleja su carácter multifactorial con un papel destacado de los factores genéticos. Los estudios poblacionales han señalado históricamente la implicación de numerosas variantes genéticas de escaso tamaño de efecto, las cuales por sí mismas apenas incre mentan el riesgo de TDAH y difícilmente justifican su ele vada heredabilidad. Muchas de ellas están presentes en más del 60% de la población general, lo que sugiere su pa pel modulador más que causal. No obstante, gracias a la irrupción de nuevas técnicas genéticas en los últimos 15 años, se están identificando un mayor número de casos con trastornos genéticos (muchos de ellos monogénicos), cuyas variantes genéticas explican por sí mismas la presencia del TDAH. El estudio detallado de los antecedentes personales y familiares, así como una exploración física completa, puede ayudar a identificar algunos de ellos. La identificación de la causa en este conjunto de casos tiene un valor crucial en el asesoramiento clínico, el consejo genético-familiar y la anticipación pronóstica, así como en la realización o evitación de estudios complementarios y en el diseño del plan terapéutico.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disor der from a causal, clinical and prognostic perspective. Research reflects its multifactorial nature with a promi nent role of genetic factors. Population studies have historically pointed to the involvement of numerous genetic variants of small effect size, which hardly by themselves increase the risk of presenting the disorder and hardly justify its high heritability. Many of them are present in more than 60% of the general population, suggesting their modulatory rather than causal role. However, after the irruption of new genetic techniques in the last 15 years, a greater number of cases are be ing identified with genetic disorders (many of them monogenic), whose genetic variants alone explain the presence of ADHD. A detailed study of the personal and family history, as well as a complete physical examination, can help to identify some of them. The identification of the cause in this group of cases has a crucial value in clinical counseling, genetic-familial counseling and prognostic anticipation, as well as in the performance or avoidance of complementary stud ies and in the design of the intervention plan.

Genetic variations among the isolates of Bipolaris Maydis based on phenotypic and molecular markers

Abstract Maydis leaf blight, caused by Bipolaris maydis, is an important disease of maize crop in Khyber Pakhtunkhwa (KP) Pakistan. Fifteen isolates of the pathogen, collected across KP, were studied for variability based on phenotypic and molecular markers. Significant variability among the isolates was observed when assessed using phenotypic traits such as radial growth, spore concentration, fungicide sensitivity and virulence. The isolates were classified into six culture groups based on colour, texture and margins of the colony. Conidial morphology was also variable. These were either straight or slightly curved and light to dark brown in colour. Fungicide test showed significant variation in the degree of sensitivity against Carbendazim. Isolate Bm8 exhibited maximum radial growth on carbendazim spiked plates. Conversely, isolate Bm15 showed the lowest radial growth. Variations in virulence pattern of the isolates were evident when a susceptible maize variety Azam was inoculated with spores of B. maydis. Genetic variability amongst the isolates was also estimated by RAPD as well as sequencing of ITS region. The RAPD dendrogram grouped all the isolates into two major clusters. Average genetic distance ranged from 0.6% to 100%, indicating a diverse genetic gap among the isolates. Maximum genetic distance was found between isolates Bm9 and Bm10 as well as Bm2 and Bm8. Conversely, isolates Bm13 and Bm15 were at minimum genetic distance. Phylogenetic dendrogram based on sequencing of ITS region grouped all the isolates into a single major cluster. The clusters in both the dendrogram neither correlate to the geographical distribution nor to the morphological characteristics.

Resumo A ferrugem das folhas de maydis, causada por Bipolaris maydis, é uma doença importante da cultura do milho em Khyber Pakhtunkhwa (KP), Paquistão. Quinze isolados do patógeno, coletados em KP, foram estudados quanto à variabilidade com base em marcadores fenotípicos e moleculares. Variabilidade significativa entre os isolados foi observada quando avaliada por meio de características fenotípicas, como crescimento radial, concentração de esporos, sensibilidade a fungicida e virulência. Os isolados foram classificados em seis grupos de cultura com base na cor, textura e margens da colônia. A morfologia dos conídios também foi variável. Estes eram retos ou ligeiramente curvos e de cor marrom-claro a escuro. O teste de fungicida mostrou variação significativa no grau de sensibilidade ao carbendazim. O isolado Bm8 exibiu crescimento radial máximo em placas com adição de carbendazim. Por outro lado, o isolado Bm15 apresentou o menor crescimento radial. As variações no padrão de virulência dos isolados foram evidentes quando uma variedade de milho suscetível Azam foi inoculada com esporos de B. maydis. A variabilidade genética entre os isolados também foi estimada por RAPD, bem como sequenciamento da região ITS. O dendrograma RAPD agrupou todos os isolados em dois grupos principais. A distância genética média variou de 0,6% a 100%, indicando uma lacuna genética diversa entre os isolados. A distância genética máxima foi encontrada entre os isolados Bm9 e Bm10 e também entre Bm2 e Bm8. Por outro lado, os isolados Bm13 e Bm15 estavam a uma distância genética mínima. O dendrograma filogenético baseado no sequenciamento da região ITS agrupou todos os isolados em um único aglomerado principal. Os agrupamentos em ambos os dendrogramas não se correlacionam com a distribuição geográfica nem com as características morfológicas.

THE ATP-BINDING CASSETTE TRANSPORTER A1 GENE POLYMORPHISMS AND TYPE 2 DIABETES MELLITUS.

Insulin resistance (IR), secretion of insulin, and abnormalities of lipid metabolism are all markers of type 2 diabetes (T2DM), which is a progressive and complex metabolic disorder. Major risk factors for the development of T2DM were identified as genetic, environmental, and lifestyle factors. Several studies found that many genes contribute to T2DM susceptibility after glucose tolerance. Adenosine Binding Cassette Transporter Proteins 1 is a member of the ABC gene superfamily that is involved in cholesterol transport and HDL cholesterol (HDL-C) biosynthesis. Abnormal cholesterol metabolism, particularly high-density lipoprotein, has been related to genetic variations in the ABCA1 gene (HDL-C). Previous research suggested that ABCA1 gene polymorphisms may a hereditary risk factor for type 2 diabetes, along with lower HDL levels in various populations.

Genetic Diversity and Molecular Surveillance of Antimalarial Drug Resistance of Plasmodium falciparum among Hospitals Patients in Benue State Nigeria

Introduction: Malaria is a febrile illness caused by parasites of the genus Plasmodium and transmitted by female Anopheles mosquitoes. The genetic diversity and antimalarial drug resistance of Plasmodium falciparum are some of the major challenges of malaria control programme in Nigeria. Aim: This study was aimed at determining the genetic diversity, and molecular surveillance of antimalarial drug resistance among patients attending Government hospitals in Benue State, Nigeria. Methodology: Plasmodium falciparum deoxyribonucleic acid was extracted from dried blood spots of 60 positive malariacases among the patients. The diversity of Plasmodium falciparum was done by genotyping 3D7 and FC27 families of merozoite surface protein- 2 alleles. The Plasmodium falciparum multidrug resistance 1 and Plasmodium falciparum kelch13 genes of Plasmodium falciparum were also amplified and assessed by restriction fragment length polymorphism (RFLP) to survey molecular resistance to antimalarial drugs. Results: The results showed that the frequency of 3D7 allele 37(61.7%) was higher than FC27 allele 18(30.0%). The frequency of merozoite surface protein- 2 infections with both allelic types was 5(8.3%). There was a significant difference in the distribution of the merozoite surface protein two alleles (?2=25.9,df=2 P<.0.001). Both the Plasmodium falciparum multidrug resistance 1 Asparagine 86Tyrosine (N86Y) and Aspartic acid 1246Tyrosine (D1246Y), had 100 % mutant while the 100% while the Plasmodium falciparum kelch13 G449A had 100% wild type allele. Conclusion: The current study underscores the need for frequent monitoring of indicators of antimalaria drug resistance in Nigeria.

Bovine TMEM95 gene: Polymorphisms detecting in five Chinese indigenous cattle breeds and their association with growth traits

BACKGROUND: Transmembrane protein 95 (TMEM95) plays a role in male fertility. Previous studies showed that genes with a significant impact on reproductive traits can also affect the growth traits of livestock. Thus, we speculated that the genetic variation of TMEM95 gene may have effects on growth traits of cattle. RESULTS: Two SNPs were genotyped. The rs136174626 and rs41904693 were in the intron 4 and 30 -untranslated region, respectively. The linkage disequilibrium analysis illustrated that these two loci were not linked. The rs136174626 was associated with six growth traits of Nanyang cattle, four traits of Luxi cattle, and three traits of Ji'an cattle. For rs41904693 locus, the GG individuals had greater body height and abdominal girth in Ji' an cattle than TT and TG individuals. In Jinnan cattle, GG and TT individuals had greater body height, height at hip cross, body length, and heart girth than TG individuals. The potential splice site prediction results suggest that the rs136174626 may influence the splicing efficiency of TMEM95, and the miRNA binding site prediction results showed that the rs41904693 may influence the expression of TMEM95 by affecting the binding efficiency of Bta-miR-1584 and TMEM95 30 -UTR. CONCLUSIONS: The findings of the study suggested that the two SNPs in TMEM95 could be a reliable basis for molecular breeding in cattle.

Insights of window-bsed mechanism approach to visualize composite bioData point in feature spaces

In this paper, we propose a window-based mechanism visualization approach as an alternative way to measure the seriousness of the difference among data-insights extracted from a composite biodata point. The approach is based on two components: undirected graph and Mosaab-metric space. The significant application of this approach is to visualize the segmented genome of a virus. We use Influenza and Ebola viruses as examples to demonstrate the robustness of this approach and to conduct comparisons. This approach can provide researchers with deep insights about information structures extracted from a segmented genome as a composite biodata point, and consequently, to capture the segmented genetic variations and diversity (variants) in composite data points.

Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis / 华中科技大学学报（医学）（英德文版）

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood,with a high heritability about 60％ to 90％.Serotonin is a monoamine neurotransmitter.Numerous studies have reported the association between the serotonin receptor family (5-HTR) gene polymorphisms and ADHD,but the results are still controversial.In this study,we conducted a meta-analysis of the association between 5-HTR1B,5-HTR2A,and 5-HTR2C genetic variants and ADHD.The results showed that the 861G allele of 5-HTR1B SNP rs6296 could significantly increase the risk of ADHD (OR=1.09,95％ CI:1.01-1.18);the 5-HTR2C gene rs518147 (OR=1.69,95％ CI:1.38-2.07) and rs3813929 (OR =1.57,95％ CI:1.25-1.97) were all associated with the risk of ADHD.In addition,we also carried on a casecontrol study to explore the relevance between potential candidate genes 5-HTR 1 A,5-HTR1E,5-HTR3A and ADHD.The results indicated that 5-HTR1A rs6295 genotype (CC+CG vs.GG OR=2.00,95％ CI:1.23-3.27) and allele (OR=1.77,95％ CI:1.16-2.72) models were statistically significantly different between case group and control group.This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD,and it also provides more evidence for the etiology of ADHD.

Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis / 华中科技大学学报（医学）（英德文版）

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood,with a high heritability about 60％ to 90％.Serotonin is a monoamine neurotransmitter.Numerous studies have reported the association between the serotonin receptor family (5-HTR) gene polymorphisms and ADHD,but the results are still controversial.In this study,we conducted a meta-analysis of the association between 5-HTR1B,5-HTR2A,and 5-HTR2C genetic variants and ADHD.The results showed that the 861G allele of 5-HTR1B SNP rs6296 could significantly increase the risk of ADHD (OR=1.09,95％ CI:1.01-1.18);the 5-HTR2C gene rs518147 (OR=1.69,95％ CI:1.38-2.07) and rs3813929 (OR =1.57,95％ CI:1.25-1.97) were all associated with the risk of ADHD.In addition,we also carried on a casecontrol study to explore the relevance between potential candidate genes 5-HTR 1 A,5-HTR1E,5-HTR3A and ADHD.The results indicated that 5-HTR1A rs6295 genotype (CC+CG vs.GG OR=2.00,95％ CI:1.23-3.27) and allele (OR=1.77,95％ CI:1.16-2.72) models were statistically significantly different between case group and control group.This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD,and it also provides more evidence for the etiology of ADHD.

Complete genome sequence of two genotype III Japanese encephalitis virus isolates from West Bengal, India.

Background & objectives: Japanese encephalitis (JE), caused by a mosquito-borne virus JE virus (JEV), is a serious health problem in West Bengal, India. In this study, we report the complete genome sequence of two JEV isolates from West Bengal. The amino acid and nucleotide sequence homology was compared with other Indian strains. Methods: two JEV isolates (IND-WB-JE1 and IND-WB-JE2) obtained in 2008 and 2010, respectively, from two districts of the state of West Bengal, respectively were analyzed for genetic variations by sequencing the 10934 bp whole genome of the virus. Of these two districts, one was covered under JE vaccination programme in 2007. Results: Phylogenetic analysis showed that both the isolates belonged to the genotype III. A total of 16 mutations were identified in the two isolates studied with respect to Vellore P20778 strain. One unique mutation A3215S was only found in IND-WB-JE2 isolate, but not in the isolate IND-WB-JE1. These two isolates showed maximum homology with P20778 strain of India. Interpretation & conclusions: This study reports on complete gene based phylogenetic analysis of JEV isolates from the State of West Bengal. it was evident from the results that JEV was still under circulation in both vaccine covered and not covered districts of West Bengal.

Genetic variability & chemotoxicity of 5-fluorouracil & cisplatin in head & neck cancer patients: a preliminary study.

Background & objectives: The efficacy and toxicity of a given chemotherapy regimen varies widely among patients due to the inherited variability of genes that are involved in drug metabolism. There are several crucial enzymes identified involving metabolism of 5-fluorouracil (5-FU) and cisplatin, which are polymorphic. We studied head and neck cancer patients (n=23) on 5-FU and cisplatin combination therapy attending a tertiary care cancer research institute in Gujarat, India, to understand the effect of a particular genotype on toxicity. Methods: The patients were genotyped for dihydropyrimidine (DPYD) (85T>C, IVS14+1G>A, 2846A>T, 2194G>A), thymidylate synthase (TYMS) [28bp tandem repeat in the promoter enhancer region (TSER)], methylenetetrahydrofolate reductase (MTHFR) (677C>T, 1298A>C), glutathione S-transferase P1(GSTP1) (Ile105Val), glutathione S-transferase T1 (GSTT1) (null allele) and glutathione S-transferase M1 (GSTM1) (null allele) by multiplex allele-specific PCR and long range PCR. Results: Of the 23 (19 males 4 females, age range 18-16 yr) patients, two had grade 3 and 4 toxicity while the remaining 21 had 0 to 2 grade toxicity after treatment with 5-FU and cisplatin combination therapy. An association between the genotype of GSTM1 (+/- and -/-) and the toxicity of cisplatin (P=0.043) was observed. Interpretation & conclusions: The findings of this preliminary study suggested an association between the variants of GSTM1 and toxicity observed due to cisplatin. Well planned studies on a large sample of head and neck cancer patients need to be conducted to understand the effects of these genetic variants on toxicity and efficacy of anticancer drugs.