Polymorphisms in PAH metabolising enzyme CYP1A1 in colorectal cancer and their clinicopathological correlations.

CYP1A1 enzyme is integral to the biotransformation of polycyclic aromatic hydrocarbons to carcinogenic compounds. This study aimed to screen mutations in exon 7 (ex7) of CYP1A1 and investigate its clinicopathological correlations in fresh tissue samples from 85 patients (42 women; 43 men) with colorectal carcinoma (CRC). Tumour tissues and matched non-neoplastic mucosa tissues were collected prospectively. Genomic DNA was extracted from all tissues, and subject to high-resolution melt curve analysis for CYP1A1-ex7. Sanger sequencing was employed to detect specific mutations. Three known single nucleotide polymorphisms (SNPs) were identified in both tumour and matched non-neoplastic tissue for the same individual. Of the 85 patients, one third (n = 28) harboured either rs1048943, rs1799814, or rs41279188. Patients who had a SNP at ex7 of CYP1A1 were significantly more likely to be over 65 years of age (p = 0.015). Furthermore, individuals harbouring a SNP at exon7 showed a low incidence of perineural cancer infiltration (p = 0.025) when compared to the wild-type population. Overall, polymorphisms at exon 7 of CYP1A1 are present in patients with CRC and associated with a few clinicopathological characteristics.

MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis.

The clinical picture of autoimmune hepatitis (AIH) varies markedly between patients, potentially due to genetic modifiers. The aim of this study was to evaluate genetic variants previously associated with fatty liver as potential modulators of the AIH phenotype. The study cohort comprised 313 non-transplanted adults with AIH. In all patients, the MARC1 (rs2642438), HSD17B13 (rs72613567), PNPLA3 (rs738409), TM6SF2 (rs58542926), and MBOAT7 (rs641738) variants were genotyped using TaqMan assays. Mitochondrial damage markers in serum were analyzed in relation to the MARC1 variant. Carriers of the protective MARC1 allele had lower ALT and AST (both P < 0.05). In patients treated for AIH for ≥ 6 months, MARC1 correlated with reduced AST, ALP, GGT (all P ≤ 0.01), and lower APRI (P = 0.02). Patients carrying the protective MARC1 genotype had higher total antioxidant activity (P < 0.01) and catalase levels (P = 0.02) in serum. The PNPLA3 risk variant was associated with higher MELD (P = 0.02) in treated patients, whereas MBOAT7 increased the odds for liver cancer (OR = 3.71). None of the variants modulated the risk of death or transplantation. In conclusion, the MARC1 polymorphism has protective effects in AIH. Genotyping of MARC1, PNPLA3, and MBOAT7 polymorphisms might help to stratify patients with AIH.

Assessment of morphological and molecular variability of some Solanum melongena L. cultivars and wild Solanum incanum L. in Saudi Arabia.

The genus Solanum exhibits a wide range of variability in morphology, flavor, and tolerance to biotic and abiotic stresses. Phenotypic and genetic variability using ISSR and RAPD markers of Solanum incanum distributed in Al-Baha province of the Kingdom of Saudi Arabia is assessed. Thirty samples are representing three different locations: Baljershy, Aqeeq, and Tohama, besides twenty-five samples representing five different commercial cultivars tested. Growth type, the number of leaves per plant, fruit size (phenotypic traits), crude protein, carbohydrates, digestive organic matter, and Mg, Ca, P were the principal contributors in the PCA. Molecular analysis showed that 114 ISSR and 80 RAPD alleles with a 100% polymorphism were recorded. The polymorphism information content (PIC) values ranged from 0.84 to 0.91 for ISSR and from 0.59 to 0.89 for RAPD data. Similarity values ranged from 0.16 to 1.00, with an average of 0.47 for ISSR and from 0.01 to 0.97, with an average of 0.36 for RAPD. It resulted in a positive and significant correlation between morphological, molecular, nutritional, and chemical analysis of fruits using Mantel analysis. UPGMA and PCA for morphological traits and molecular data discriminated commercial cultivars and wild relatives. Solanum incanum was more diverse than commercial varieties. This study revealed a wide genetic diversity among and within collected eggplant accessions and may use in breeding programs of eggplants. There is a need to increase the present eggplant collection to widen the genetic diversity of cultivated eggplant varieties in Saudi Arabia.

Genetic polymorphisms associated with obesity in the Arab world: a systematic review.

BACKGROUND: Obesity, one of the most common chronic health conditions worldwide, is a multifactorial disease caused by complex genetic and environmental interactions. Several association studies have revealed a considerable number of candidate loci for obesity; however, the genotype-phenotype correlations remain unclear. To date, no comprehensive systematic review has been conducted to investigate the genetic risk factors for obesity among Arabs. OBJECTIVES: This study aimed to systematically review the genetic polymorphisms that are significantly associated with obesity in Arabs. METHODS: We searched four literature databases (PubMed, Science Direct, Scopus, and Google Scholar) from inception until May 2020 to obtain all reported genetic data related to obesity in Arab populations. Quality assessment and data extraction were performed individually by three investigators. RESULTS: In total, 59 studies comprising a total of 15,488 cases and 9,760 controls were included in the systematic review. A total of 76 variants located within or near 49 genes were reported to be significantly associated with obesity. Among the 76 variants, two were described as unique to Arabs, as they have not been previously reported in other populations, and 19 were reported to be distinctively associated with obesity in Arabs but not in non-Arab populations. CONCLUSIONS: There appears to be a unique genetic and clinical susceptibility profile of obesity in Arab patients.

Cooperation, involuntary defection, and Polymorphic Evolutionary Games.

The subject of involuntary defection in the context of cycles of interaction approach to direct reciprocal cooperation was introduced some time ago (J. Theor. Biol., 242: 873-879). Current work is motivated by the subsequent accumulation of empirical evidence and the advances in the methodology of evolutionary games. In recent decades it become clear that individuals in many animal species vary consistently in their behavioral responses to specific challenges-animal personality. Moreover, these differences have a hereditary component. Finally, investigations into the effects of neuropeptides on behavior suggest that the variations in animal personalities involve polymorphisms based on non-Mendelian heritability within the neuropeptide signaling systems. The last observation suggests that animal personalities can be productively analyzed via Polymorphic Evolutionary Games, which allow us to add genetic model(s) to standard (phenotypic) evolutionary games. Such an analysis of reciprocal cooperation is the subject of the current paper. The results indicate that there is a marked difference between models that assume Mendelian vs. non-Mendelian inheritance of the pertinent traits. Monomorphic and polymorphic-Mendelian models predict pure-strategy (single phenotype) ESS, whereas the non-Mendelian genetic model predicts a mixed strategy ESS exhibiting all three phenotypes.

Functional variability of rhesus macaque (Macaca mulatta) NAT2 gene for drug-metabolising arylamine N-acetyltransferase 2.

Human NAT2 is a polymorphic pharmacogene encoding for N-acetyltransferase 2, a hepatic enzyme active towards arylamine and arylhydrazine drugs, including the anti-tubercular antibiotic isoniazid. The isoenzyme also modulates susceptibility to chemical carcinogenesis, particularly of the bladder. Human NAT2 represents an ideal model for anthropological investigations into the demographic adaptation of worldwide populations to their xenobiotic environment. Its sequence appears to be subject to positive selection pressures that are population-specific and may be attributed to gene-environment interactions directly associated with exogenous chemical challenges. However, recent evidence suggests that the same evolutionary pattern may not be observed in other primates. Here, we report NAT2 polymorphism in 25 rhesus macaques (Macaca mulatta) and compare the frequencies and functional characteristics of 12 variants. Seven non-synonymous single nucleotide variations (SNVs) were identified, including one nonsense mutation. The missense SNVs were demonstrated to affect enzymatic function in a substrate-dependent manner, albeit more moderately than certain NAT1 SNVs recently characterised in the same cohort. Haplotypic and functional variability of NAT2 was comparable to that previously observed for NAT1 in the same population sample, suggesting that the two paralogues may have evolved under similar selective pressures in the rhesus macaque. This is different to the population variability distribution pattern reported for humans and chimpanzees. Recorded SNVs were also different from those found in other primates. The study contributes to further understanding of NAT2 functional polymorphism in the rhesus macaque, a non-human primate model used in biomedicine and pharmacology, indicating variability in xenobiotic acetylation that could affect drug metabolism.

Role of Human Arylacetamide Deacetylase (AADAC) on Hydrolysis of Eslicarbazepine Acetate and Effects of AADAC Genetic Polymorphisms on Hydrolase Activity.

Human arylacetamide deacetylase (AADAC) plays a role in the detoxification or activation of drugs and is sometimes involved in the incidence of toxicity by catalyzing hydrolysis reactions. AADAC prefers compounds with relatively small acyl groups, such as acetyl groups. Eslicarbazepine acetate, an antiepileptic drug, is a prodrug rapidly hydrolyzed to eslicarbazepine. We sought to clarify whether AADAC might be responsible for the hydrolysis of eslicarbazepine acetate. Eslicarbazepine acetate was efficiently hydrolyzed by human intestinal and liver microsomes and recombinant human AADAC. The hydrolase activities in human intestinal and liver microsomes were inhibited by epigallocatechin gallate, a specific inhibitor of AADAC, by 82% and 88% of the control, respectively. The hydrolase activities in liver microsomes from 25 human livers were significantly correlated (r = 0.87, P < 0.001) with AADAC protein levels, suggesting that the enzyme AADAC is responsible for the hydrolysis of eslicarbazepine acetate. The effects of genetic polymorphisms of AADAC on eslicarbazepine acetate hydrolysis were examined by using the constructed recombinant AADAC variants with T74A, V172I, R248S, V281I, N366K, or X400Q. AADAC variants with R248S or X400Q showed lower activity than wild type (5% or 21%, respectively), whereas those with V172I showed higher activity than wild type (174%). Similar tendencies were observed in the other four substrates of AADAC; that is, p-nitrophenyl acetate, ketoconazole, phenacetin, and rifampicin. Collectively, we found that eslicarbazepine acetate is specifically and efficiently hydrolyzed by human AADAC, and several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response. SIGNIFICANCE STATEMENT: This is the first study to clarify that arylacetamide deacetylase (AADAC) is responsible for the activation of eslicarbazepine acetate, an antiepileptic prodrug, to eslicarbazepine, an active form, in the human liver and intestines. In addition, we found that several AADAC polymorphic alleles would be a factor affecting the enzyme activity and drug response.

The signaling pathway and polymorphisms of Mrgprs.

Mas-related G protein-coupled receptors (Mrgprs) are a family of receptors implicated in a diverse array of human diseases. Since their discovery in 2001, great progress has been made in determining their relation to human disease. Vital for Mrgprs therapeutic efforts across all disease disciplines is a thorough understanding of Mrgprs signal transduction pathways and polymorphisms, as these offer insights into new drug candidates, existing discrepancies in drug response, and differences in disease susceptibility. In this review, we discuss the current state of knowledge regarding Mrgprs signaling pathways and polymorphisms.

Lessons Learned from CNV Analysis of Major Birth Defects.

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

Detention in Juvenile Correctional Facilities Is Associated with Higher Platelet Monoamine Oxidase B Activity in Males.

Juvenile delinquency is related to several biological factors, yet very few vulnerability biomarkers have been identified. Previous data suggest that the enzyme monoamine oxidase B (MAO-B) influences several personality traits linked to the propensity to engage in delinquent behavior. Building on this evidence, we assessed whether conduct disorder (CD), juvenile delinquency adjudications, or detention in a correctional facility were associated with either platelet MAO-B activity or the MAOB rs1799836 polymorphism. The study enrolled 289 medication-free male youths, including 182 individuals detained in a correctional facility (with or without a diagnosis of CD). Of the remaining 107 participants, 26 subjects had a diagnosis of CD, and 81 were mentally healthy controls. Platelet MAO-B activity was determined by spectrophotofluorometry, while MAOB rs1799836 was genotyped using qPCR. Platelet MAO-B activity, corrected for age and smoking, was significantly higher in juvenile detainees (p < 0.001), irrespective of CD diagnosis. MAOB rs1799836 was not associated with platelet MAO-B activity or with detention in a correctional facility, CD diagnosis, or delinquent behavior. These data suggest that detention in a juvenile correctional facility increases platelet MAO-B activity in male adolescents. Future studies are needed to determine the mechanisms and functional significance of MAO-B peripheral elevation in juvenile male detainees.

Polymorphism of Colias croceus from the Azores caused by differential pterin expression in the wing scales.

The pierid butterfly Colias croceus (Geoffroy in Fourcroy, 1785), established in the Azores archipelago, is polymorphic with six forms, C. croceus f. croceus ♂ and ♀, C. c. f. cremonae ♂ and ♀, C. c. f. helice ♀, and C. c. f. cremonaehelice ♀. We investigated the optical mechanisms underlying the wing colouration of the butterflies by performing spectrophotometry and imaging scatterometry of the variously coloured wing areas and scales. The scale colouration is primarily due to wavelength-selective absorption of incident light by pterins expressed in granular beads in the wing scales, but thin film reflections of the scales' lower lamina and scale stacking also contribute. Three forms (croceus ♂ and ♀ and helice ♀) are consistent with the patterns of the well-known 'alba' polymorphism. We postulate the coexistence of a second polymorphism, 'cremonae', to understand the three other forms (cremonae ♂ and ♀, and cremonaehelice ♀), which are characterized by the absence of red pigment, presumably due to the differential blocking of erythropterin expression.

Respuesta de creatina quinasa a un ejercicio anaerobio supramáximo en genotipos de ACTN3 / Response of Creatine Kinase to an Anaerobic Supramaximal Exercise in ACTN3 Genotypes

El objetivo del presente estudio fue investigar las diferencias en la actividad de la enzima Creatina Quinasa (CK) en pre y post ejercicio anaerobio supramáximo (EASM) en portadores de los genotipos del gen de la alfa-actinina-3 (ACTN3). Se reclutaron 39 hombres sanos físicamente activos (18-35 años) y se sometieron a un EASM de 30 s (Wingate). El gen ACTN3 se determinó a partir del ADN de glóbulos blancos en sangre periférica y se evaluó la actividad de la CK en muestras sanguíneas en condiciones basales, a las 24 y 48 h post EASM. Los portadores del genotipo XX vs RR presentaron 1,4 veces menor actividad de CK en condiciones basales (p < 0,05) y una mayor actividad de CK a las 24 h post ejercicio (p < 0,05). Una serie de EASM fue capaz de causar un incremento significativo de la actividad de CK a las 24 h en los portadores del genotipo XX

The aim of the present study was to investigate the differences in the activity of the enzyme Creatine Kinase (CK) in pre and post anaerobic supramaximal exercise (ASME) on carriers of the genotypes of the alpha-actinin-3 gene (ACTN3). 39 healthy physically active men (18-35 years) were enrolled and underwent an ASME of 30 s (Wingate). The ACTN3 gene was determined from the DNA of white blood cells in peripheral blood and the CK activity was evaluated in blood samples in basal conditions, at 24 and 48 h after of ASME. The carriers of genotype XX vs RR had 1.4 times lower CK activity in basal conditions (p < 0.05) and higher CK activity at 24 h after exercise (p < 0.05). A series of ASME was capable of causing a significant increase in CK activity at 24 h in the XX genotype carriers

Underlying Susceptibility to Eating Disorders and Drug Abuse: Genetic and Pharmacological Aspects of Dopamine D4 Receptors.

The dopamine D4 receptor (DRD4) has a predominant expression in the prefrontal cortex (PFC), brain area strictly involved in the modulation of reward processes related to both food and drug consumption. Additionally, the human DRD4 gene is characterized by a variable number of tandem repeats (VNTR) in the exon 3 and, among the polymorphic variants, the 7-repeat (7R) allele appears as a contributing factor in the neurobiological mechanisms underlying drug abuse, aberrant eating behaviors and related comorbidities. The 7R variant encodes for a receptor with a blunted intracellular response to dopamine, and carriers of this polymorphism might be more tempted to enhance dopamine levels in the brain, through the overconsumption of drugs of abuse or palatable food, considering their reinforcing properties. Moreover, the presence of this polymorphism seems to increase the susceptibility of individuals to engage maladaptive eating patterns in response to negative environmental stimuli. This review is focused on the role of DRD4 and DRD4 genetic polymorphism in these neuropsychiatric disorders in both clinical and preclinical studies. However, further research is needed to better clarify the complex DRD4 role, by using validated preclinical models and novel compounds more selective for DRD4.

Genetic Color Polymorphism of the Whitelined Sphinx Moth larva (Lepidoptera: Sphingidae).

For a trait to be considered polymorphic, it must fulfill both genetic and ecological criteria. Genetically, a polymorphic trait must have multiple heritable variants, potentially from the same female, in high-enough frequency as to not be due to mutation. Ecologically, in a single wild population, these variants must co-occur, and be capable of interbreeding. Polymorphism is frequently considered in the context of either geographical cause or genetic consequence. However, the incorporation of both in a single study can facilitate our understanding of the role that polymorphism may play in speciation. Here, we ask if the two color morphs (green and yellow) exhibited by larvae of the whitelined sphinx moth, Hyles lineata (Fabricius), co-occur in wild populations, in what frequencies, and whether they are genetically determined. Upon confirmation from field surveys that the two color morphs do co-occur in wild populations, we determined heritability. We conducted a series of outcrosses, intercrosses and backcrosses using individuals that had exhibited yellow or green as laboratory-reared larvae. Ratios of yellow:green color distribution from each familial cross were then compared with ratios one would expect from a single gene, yellow-recessive model using a two-sided binomial exact test. The offspring from several crosses indicate that the yellow and green coloration is a genetic polymorphism, primarily controlled by one gene in a single-locus, two-allele Mendelian-inheritance pattern. Results further suggest that while one gene primarily controls color, there may be several modifier genes interacting with it.

Gene Polymorphisms and Circulating Levels of MMP-2 and MMP-9: A Review of Their Role in Breast Cancer Risk.

MMP-2 and MMP-9 genes have been suggested to play a role in breast cancer. Their functions have been associated with invasion and metastasis of breast cancer; however, their involvement in the development of the disease is not well-established. Herein, we reviewed the literature investigating the association between circulating levels and polymorphisms of MMP-2 and MMP-9 and breast cancer risk. Various studies report conflicting results regarding the relationship of polymorphisms in MMP-2 and MMP-9 and breast cancer risk. Nevertheless, it appears that the T allele in rs243865 and rs2285053 in MMP-2 are associated with reduced risk of breast cancer. In addition, high levels of latent form and low levels of active form of MMP-2 were observed in breast cancer patients compared to controls. For MMP-9, high latent levels and low total levels were found in breast cancer patients compared to controls. Additional studies are needed to comprehend the role of these genes in breast carcinogenesis.

The impact of genetic polymorphisms on weight regain after successful weight loss.

Obesity is associated with an increased risk of various diseases and mortality. Although nearly 50 % of adults have been reported trying to lose weight, the prevalence of obesity has increased. One factor that hinders weight loss-induced decrease in obesity prevalence is weight regain. Although behavioural, psychological and physiological factors associated with weight regain have been reviewed, the information regarding the relationship between weight regain and genetics has not been previously summarised. In this paper, we comprehensively review the association between genetic polymorphisms and weight regain in adults and children with obesity after weight loss. Based on this information, identification of genetic polymorphism in patients who undergo weight loss intervention might be used to estimate their risks of weight regain. Additionally, the genetic-based risk estimation may be used as a guide for physicians and dietitians to provide each of their patients with the most appropriate strategies for weight loss and weight maintenance.

Polimorfismos asociados con la susceptibilidad para pie diabético: una revisión integrafiva / Polymorphism associated with diabetic foot susceptibility: a integrative review

INTRODUCCIÓN: La presencia del pie diabético es una complicación frecuente en la persona que vive con diabetes. En su etiopatogenia confluyen factores conductuales, ambientales y el control de la enfermedad; no obstante, se reconoce la influencia de factores genéticos en su desarrollo y evolución. OBJETIVO: Sistematizar la asociación de los polimorfismos genéticos como riesgo para el desarrollo de pie diabético a través de la producción científica indexada. METODOLOGÍA: Revisión bibliográfica de los años 2010 a 2018; se realizó mediante la búsqueda sistemática en las bases de datos PubMed, Scopus, CONRICYT y WOS. Los descriptores fueron tres: "polymorphism" AND "diabetic foot" OR "foot ulcer diabetic". Se incluyeron artículos a texto completo en inglés con metodología de casos y controles, y que midieran estadísticamente factores de riesgo mediante la odds ratio y los riesgos relativos. Se utilizó la plataforma FLC 2.0 para evaluar la calidad del estudio. RESULTADOS: 13 artículos cumplieron con los criterios de inclusión; se identificaron 9 polimorfismos como factores para la aparición de pie diabético: HIF-1α, MCP-1-2518A/G, TLR9-1237 T/C, MAPK14 rs80028505, LOX G473A, gen FokI del receptor VDR, MMPs-1562C>T, TCF7L2, HIF-1α p582s y 4 como factores protectores: VEGF rs699947, VEGF-634G/C, eNOS Glu298Asp y VEGF 2578 C/A. CONCLUSIÓN: La susceptibilidad, gravedad y aparición del pie diabético está asociado con factores genéticos implicados en distintos mecanismos fisiopatológicos

INTRODUCTION: Diabetic foot is a frequent complication in patients with diabetes. The risk factors associated with its development and evolution are related to the behavioral, environmental and disease control characteristics, however, the influence of genetic factors in the development of this complication has been recognized. OBJECTIVE: To analyze the available evidence on the association of genetic polymorphisms in the risk of presenting diabetic foot. METHODOLOGY: Articles were reviewed in English, not older than 10 years, with a methodology of cases and controls that statistically measure risk factors through odds ratio and relative risk. Therefore the search was performed in databases such as PubMed, Scopus, CONRICYT and WOS with maximum date until January 31, 2018. Controlled descriptors "polymorphism" AND "diabetic foot" OR "foot ulcer diabetic" were applied. The FLC 2.0 platform was used to evaluate the quality of the study. RESULTS: Thirteen articles were selected, there being 9 polymorphisms with risk factors such as HIF-1α, MCP-1-2518A/G, TLR9-1237 T/C, MAPK14 rs80028505, LOX G473A, FokI gene of the VDR receptor, MMPs-1562C>T, TCF7L2, HIF-1α p582s and 4 protective factors such as VEGF rs699947, VEGF-634G/C, eNOS Glu298Asp and VEGF 2578 C/A. CONCLUSION: The susceptibility, severity and appearance of diabetic foot they are associated with genetic factors that are involved in different physiopathological mechanisms

The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function.

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

Associations of Plasma BACE1 Level and BACE1 C786G Gene Polymorphism with Cognitive Functions in Patients with Type 2 Diabetes: A Cross- Sectional Study.

BACKGROUND: ß-Site APP-cleaving enzyme 1 (BACE1) is a key enzyme involved in the pathophysiology of Type 2 Diabetes Mellitus (T2DM) and Mild Cognitive Impairment (MCI). We aimed to investigate the potential associations of plasma BACE1 levels and BACE1 gene polymorphism with different cognitive performances in T2DM patients with MCI. METHODS: The recruited 186 T2DM subjects were divided into 92 MCI group and 94 healthy-cognition controls, according to the Montreal Cognitive Assessment (MoCA) scores. Sociodemographic characteristics, clinical parameters and neuropsychological tests were assessed. BACE1 C786G gene polymorphism and plasma BACE1 level were determined. RESULTS: Compared to controls, MCI patients exhibited higher plasma BACE1 levels. Plasma BACE1 levels were negatively associated with MoCA, Clock Drawing Test and Logical Memory Test scores, whereas positively associated with Trail Making Test-B time in the MCI group (all p<0.05), after adjusting fasting blood glucose, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance by C-peptide. Multivariable logistic regression analysis showed a significant trend towards increased MCI risk with high plasma BACE1 level in T2DM patients (OR = 1.492, p = 0.027). The plasma BACE1 levels of GG and GC genotypes were obviously higher than that of CC genotype in T2DM-MCI patients (p = 0.035; p = 0.026, respectively). CONCLUSION: Increased plasma BACE1 levels were associated with poor overall cognition functions, especially visuospatial abilities, visual/logical memory and executive functions in T2DM-MCI patients. Additionally, elevated plasma BACE1 level was a risk factor for MCI in T2DM patients, and might be influenced by BACE1 C786G gene mutations.

Genome-wide analysis of polymorphisms identified domestication-associated long low-diversity region carrying important rice grain size/weight quantitative trait loci.

Rice grain size and weight are major determinants of grain quality and yield and so have been under rigorous selection since domestication. However, the genetic basis for contrasting grain size/weight trait among Indian germplasms and their association with domestication-driven evolution is not well understood. In this study, two long (LGG) and two short grain (SGG) genotypes were resequenced. LGG (LGR and PB 1121) differentiated from SGG (Sonasal and Bindli) by 504 439 single nucleotide polymorphisms (SNPs) and 78 166 insertion-and-deletion polymorphisms. The LRK gene cluster was different and a truncation mutation in the LRK8 kinase domain was associated with LGG. Phylogeny with 3000 diverse rice accessions revealed that the four sequenced genotypes belonged to the japonica group and were at the edge of the clades indicating them to be the potential source of genetic diversity available in Indian rice germplasm. Six SNPs were significantly associated with grain size/weight and the top four of these could be validated in mapping a population, suggesting this study as a valuable resource for high-throughput genotyping. A contiguous long low-diversity region (LDR) of approximately 6 Mb carrying a major grain weight quantitative trait loci (harbouring OsTOR gene) was identified on Chromosome 5. This LDR was identified as an evolutionary important site with significant positive selection and multiple selection sweeps, and showed association with many domestication-related traits, including grain size/weight. The aus population retained more allelic variations in the LDR than the japonica and indica populations, suggesting it to be one of the divergence loci. All the data and analyses can be accessed from the RiceSzWtBase database.