Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia. Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared. Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant. Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

Download Full-text

Abstract 13640: Dapagliflozin Lowers HbA1c, Systolic Blood Pressure and Serum Uric Acid in Patients With Type 2 Diabetes and Hypertension, Regardless of Class of Concomitant Antihypertensive Therapy

Circulation ◽

10.1161/circ.130.suppl_2.13640 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Michael A Weber ◽

Traci A Mansfield ◽

Nayyar Iqbal ◽

Shamik J Parikh ◽

Agata Ptaszynska

Keyword(s):

Type 2 Diabetes ◽

Uric Acid ◽

Serum Uric Acid ◽

Small Sample Size ◽

Small Sample ◽

Channel Blockers ◽

Ca Channel ◽

Urinary Glucose ◽

Β Blockers

Hypertension (HTN) in Type 2 diabetes (T2D) is often treated with an ACEi/ARB + additional antihypertensives agents (AHTs). Dapagliflozin (DAPA) is an inhibitor of sodium glucose co-transporter 2, reducing hyperglycemia in T2D by increasing urinary glucose excretion. This is associated with weight reduction, osmotic diuresis and serum uric acid reduction, all of which may contribute to BP lowering. This Phase 3 study assessed 12 weeks of DAPA 10 mg (N=225) or placebo (PBO; N=224) in T2D patients (HbA1c 7.0-10.5%) with HTN (seated SBP / DBP 140 - <165 / 85 - <105 mmHg) receiving glucose-lowering drugs, an ACEi/ARB, + an additional AHT: β-blockers (27%), Ca-channel blockers (CCBs; 27%), thiazide/thiazide-like diuretics (diuretics; 44%) or α-adrenergic antagonists (α-AAs; 1%). Main results were presented previously. Here we describe treatment effects according to the additional AHT (α-AA group not analyzed due to small sample size). Patients were randomized to DAPA 10 mg or PBO, stratified by insulin use and diuretics vs CCBs/β-blockers/α-AA. Baseline characteristics were similar for DAPA vs PBO. Reduction in HbA1c and mean 24-hour ambulatory SBP was greater with DAPA vs PBO overall, and appeared greater with DAPA vs PBO in all AHT sub-groups (Fig). Reduction in seated SBP was greater with DAPA overall (diff vs PBO; –4.28 [95% CI: –6.54, –2.02] mmHg) and also appeared greater with DAPA in sub-groups (diff vs PBO: β-blockers –5.76 [–10.28, –1.23]; CCB –5.13 [–9.47, –0.79]; diuretics –2.38 [–6.16, 1.40] mmHg). Serum uric acid decreased more with DAPA overall (diff vs PBO; –0.40 [95% CI: –0.57, –0.23]), and was observed to decrease more with DAPA in sub-groups (diff vs PBO: β-blockers –0.62 [–0.95, –0.29]; CCBs –0.33 [–0.65, –0.01]; diuretics –0.22 [–0.49, 0.05] mg/dL). DAPA was well tolerated; AEs were similar for DAPA (44%) vs PBO (42%). In summary, regardless of the concomitant AHT, DAPA reduced HbA1c, SBP and serum uric acid vs PBO in patients with uncontrolled T2D and HTN.

Download Full-text

A new allele of the kappa-casein gene in local zebu cattle breeds

Journal of Dairy Research ◽

10.1017/s0022029917000656 ◽

2017 ◽

Vol 85 (1) ◽

pp. 3-6

Author(s):

Tauseef Ahmad ◽

Ashwin Atkulwar ◽

Sameera Farah ◽

Vijendra Singh ◽

Mumtaz Baig

Keyword(s):

Small Sample Size ◽

Genetic Erosion ◽

Agricultural Practices ◽

Small Sample ◽

Zebu Cattle ◽

Full Potential ◽

Nucleotide Polymorphisms ◽

Nonsynonymous Mutation ◽

Cattle Breeds ◽

Farmer Suicides

Local zebu cattle breeds in Indian villages are crossbred with exotic breeds at an unprecedented rate without utilising the full potential of genomic technologies. In addition to agriculture produce, livestock, particularly cattle, constitute a vital source of livelihood for farmers in India. Age-old agricultural practices, errant monsoon, and frequent crop failures have resulted in Maharashtra having the highest number of farmer suicides in the country. Local cattle breeds are considered low-yield breeds and thus are primarily used as beasts of burden. Information on functional gene variants in Indian cattle breeds is scant and limited to PCR-RFLP study in few breeds. In this study, 32 samples from 8 cattle breeds were obtained from remote villages of Maharashtra state. By using the re-sequencing technology, we sequenced 403 bp of the exon IV CSN3 allele and inferred its haplotypes. From 32 samples, 14 genotypes (G1–G14) defined by 7 single-nucleotide polymorphisms (SNP's) were identified. From these 14 genotypes, we reconstructed 3 haplotypes (H01, H02, and H03) and estimated their frequencies. Of the 3 haplotypes, two (H01 and H03) corresponded to CSN3*B4 and CSN3*B and CSN3*H and CSN3*G alleles, respectively. The third haplotype H02 was identified as a new allele and differed from CSN3*B4 and CSN3*B and CSN3*H and CSN3*G alleles by one nonsynonymous mutation at the position C5306T-Ile100Thr. The neighbour-joining tree reconstruction revealed haplotype sharing or hybridisation between B. t. indicus and B. t. taurus because the 3 haplotypes originated in this study clustered with A1, B2, B4, B, G, and H alleles, which were reported previously in both the subspecies of B. taurus. The occurrence of one new allele in a small sample size highlights the urgency to screen local zebu cattle breeds by using genomic tools for circumventing genetic erosion that is widespread in Indian villages in India.

Download Full-text

Impact of malnutrition on systemic immune and metabolic profiles in type 2 diabetes

BMC Endocrine Disorders ◽

10.1186/s12902-020-00649-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Anuradha Rajamanickam ◽

Saravanan Munisankar ◽

Chandra Kumar Dolla ◽

Kannan Thiruvengadam ◽

Subash Babu

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Small Sample Size ◽

Normal Weight ◽

Small Sample ◽

Metabolic Profiles ◽

Immunological Parameters

Abstract Background While obesity and overweight status are firmly established risk factors for Type 2 diabetes mellitus (T2DM), a substantial proportion of diabetic individuals, especially in Africa and Asia, are often underweight or normal weight. However, very little is known about the immunological and metabolic profiles of these individuals. Methods This study aimed to assess the relationship between malnutrition and Type 2 diabetes mellitus (T2DM). We examined a variety of analytes associated with the immunological and metabolic profiles of T2DM individuals with low (< 18.5 kg/m2) or normal (18.5–24.9 kg/m2) body mass index (BMI). To this end, we measured plasma levels of HbA1c, glucose, insulin, glucagon, adipocytokines and Type 1, Type 2, Type 17, pro-inflammatory and regulatory cytokines in T2DM individuals with low BMI (LBMI) or normal BMI (NBMI) with small sample size n = 44 in each group. Results LBMI individuals exhibited significantly higher levels of HbA1c, random blood glucose, insulin and glucagon compared to NBMI individuals. Similarly, LBMI individuals exhibited significantly higher levels of adiponectin and adipsin and significantly lower levels of leptin in comparison to NBMI individuals. LBMI individuals also exhibited significantly lower levels of the Type 1, Type 2, Type 17, pro-inflammatory and regulatory cytokines in comparison to NBMI individuals. Finally, while the metabolic parameters exhibited a significant negative correlation with BMI, the immunological parameters exhibited a significant positive correlation with BMI. Conclusions Malnutrition is associated with a significant modulation of glycemic, hormonal and cytokine parameters in T2DM. Hence, the biochemical and immunological profiles of T2DM is significantly influenced by BMI.

Download Full-text

Gene variants of monocyte chemoattractant protein 1 and components of metabolic syndrome in KORA S4, Augsburg

Acta Endocrinologica ◽

10.1530/eje.1.02345 ◽

2007 ◽

Vol 156 (3) ◽

pp. 377-385 ◽

Cited By ~ 9

Author(s):

Eva-Maria Sedlmeier ◽

Harald Grallert ◽

Cornelia Huth ◽

Hannelore Löwel ◽

Christian Herder ◽

...

Keyword(s):

Metabolic Syndrome ◽

Uric Acid ◽

Multiple Testing ◽

Population Based ◽

Nucleotide Polymorphisms ◽

Monocyte Chemoattractant Protein 1 ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

New Finding

Objective: Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the development of several components of metabolic syndrome (MetS). The present study investigated the association of nine MCP-1 single nucleotide polymorphisms (SNPs) with MetS, type 2 diabetes mellitus and metabolic risk factors. Subjects and methods: The population-based study sample comprised 1630 subjects aged 55–74 years from KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4). Genotyping was carried out by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis of allele-dependent primer extension products. Results: The MCP-1 SNP c.-3813C>T exhibited trends for differences between the genotype groups in triglycerides, 2-h glucose and uric acid (P = 0.0084, 0.014, 0.027). Other trends were observed for c.-928G>C associated with height and fasting glucose (P = 0.0024, 0.033), for c.105T>C with height and leukocytes (P = 0.0095, 0.047), for c.*65C>T and c.*3879C>T with MCP-1 levels (both P = 0.012) and for c.-2138A>T with interleukin-6 levels. After correction for multiple testing, none of the analysed SNPs, except c.-928G>C in men showed a significant association with MetS, T2DM or other analysed parameters. Haplotype MCP-1*1 and c.-928G>C in men (P = 0.0002, 0.0004) were significantly associated with an increase in height. Conclusions: This is the first study to investigate the associations of MCP-1 SNPs with MetS. We found trends for several components of MetS. These parameters were hyperlipidaemia, fasting and 2-h glucose, and uric acid. A new finding is that MCP-1*1 haplotype is associated with height. Further investigation in larger populations is needed to clarify the involvement of MCP-1 in MetS.

Download Full-text

Patients’ Preferences for Insulin Injection Devices

Journal of Diabetes Science and Technology ◽

10.1177/1932296816688014 ◽

2017 ◽

Vol 11 (2) ◽

pp. 270-271 ◽

Cited By ~ 1

Author(s):

Andreas Pfützner

Keyword(s):

Type 2 Diabetes ◽

Treatment Satisfaction ◽

Human Factor ◽

Small Sample Size ◽

Insulin Injection ◽

Small Sample ◽

Ease Of Use ◽

Regulatory Agencies ◽

Assessment Study

In this issue, Pohlmeier et al report on a device assessment study in insulin-naïve patients with type 2 diabetes, to investigate the ease of use/learning and patient preference of the new prefilled U300 insulin glargine injection pen. Human factor studies are required by regulatory agencies and should ensure the proper use of the device in the context of the provided instructions. The patients found the device easy to learn/use and had a stable treatment satisfaction despite introduction of injection treatment. The lack of a control arm, the short duration, and the small sample size make it difficult to translate these results into clinical practice. It is encouraging to know, however, that the new pen is accepted by one of the intended patient populations.

Download Full-text

Rare and Potentially Pathogenic Variants in Hydroxycarboxylic Acid Receptor Genes Identified in Breast Cancer Cases.

10.21203/rs.3.rs-61768/v1 ◽

2020 ◽

Author(s):

Cierla McGuire Sams ◽

Kasey Shepp ◽

Jada Pugh ◽

Madison R. Bishop ◽

Nancy D. Merner

Keyword(s):

Breast Cancer ◽

Genetic Variants ◽

Small Sample Size ◽

Treatment Strategies ◽

Missense Variant ◽

Small Sample ◽

Acid Oxidation ◽

Cancer Proliferation ◽

Hydroxycarboxylic Acid ◽

Pathogenic Variants

Abstract BackgroundThree genes, clustered together on chromosome 12, comprise a group of Hydroxycarboxylic Acid Receptors (HCARs), HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors that are responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor, and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify genetic variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer. MethodsDue to the extreme homology between HCAR1, HCAR2, and HCAR3, primers were carefully designed to amplify each gene separately through nested PCRs followed by Sanger sequencing. Forty-six unrelated breast cancer cases were screened for rare, non-synonymous coding variants. ResultsUpon screening, a total of four variants were identified in four different cases, each with estrogen receptor-positive (ER+) breast cancer. The variants were identified exclusively in HCAR1 and HCAR3. In HCAR1, two highly conserved and potentially damaging missense variants were identified, c.58C>G;p.Pro20Ala and c.721C>T;p.Leu241Phe. Statistical analyses revealed that c.58C>G;p.Pro20Ala was in significantly more cases than controls. In HCAR3, in addition to the breast cancer-associated missense variant c.560G>A;p.Arg187Gln, a frameshift mutation, c.1117delC;p.Gln373Lysfs*82, was detected that greatly extends the C-terminus and changes the secondary and tertiary protein structure. ConclusionsDue to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation, as well as their consequences on treatment strategies. Due to the small sample size, additional and larger studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.

Download Full-text

Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population

Bioscience Reports ◽

10.1042/bsr20190078 ◽

2019 ◽

Vol 39 (10) ◽

Author(s):

Tae-Joon Park ◽

Heun-Sik Lee ◽

Young Jin Kim ◽

Bong-Jo Kim

Keyword(s):

Type 2 Diabetes ◽

Genetic Variants ◽

Multiple Testing ◽

Association Studies ◽

Linear Regression Analysis ◽

Genetic Regulation ◽

Genome Wide Association Studies ◽

Functional Variants ◽

Genome Wide

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.

Download Full-text

Comparative genome analysis of 12 Shigella sonnei strains: virulence, resistance, and their interactions

10.1101/544387 ◽

2019 ◽

Author(s):

Zuobin Zhu ◽

Liang Wang ◽

Feng Gu ◽

Ying Li ◽

Heng Zhang ◽

...

Keyword(s):

Antibiotic Resistance ◽

Virulence Factors ◽

Small Sample Size ◽

Small Sample ◽

Phylogenomic Analysis ◽

Industrialized Countries ◽

Resistant Strains ◽

Prevalent Species ◽

Experimental And Theoretical Studies

AbstractShigellosis is a highly infectious disease that are mainly transmitted via faecal-oral contact of the bacteria Shigella. Four species have been identified in Shigella genus, among which S. flexneri is used to be the most prevalent species globally and commonly isolated from developing countries. However, it is being replaced by S. sonnei that is currently the main causative agent for dysentery pandemic in many emerging industrialized countries such as Asia and the Middle East with unclear reasons. For a better understanding of S. sonnei virulence and antibiotic resistance, we sequenced 12 clinical S. sonnei strains with varied antibiotic-resistance profiles collected from four cities in Jiangsu Province, China. Phylogenomic analysis clustered antibiotic sensitive and resistant S. sonnei into two distinct groups while pangenome analysis reveals the presence and absence of featured genes in each group. Screening of 31 classes of virulence factors found out that type 2 secretion system is doubled in resistant strains. Further principle component analysis based on the interactions between virulence and resistance indicated that abundant virulence factors are associated with higher resistant phenotypes. The result present here is based on statistical analysis of a small sample size and serves basically as a guidance for further experimental and theoretical studies.

Download Full-text

Abstract P113: Lipid-related Genetic Variants and Lipid Outcomes in a Cohort of Chilean Children

Circulation ◽

10.1161/circ.135.suppl_1.p113 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Ann Von Holle ◽

Anne Justice ◽

Kari E North ◽

Bárbara Angel ◽

Estela Blanco ◽

...

Keyword(s):

Genetic Variants ◽

Genetic Model ◽

Small Sample Size ◽

A Priori ◽

Density Lipoprotein ◽

The United States ◽

Small Sample ◽

Lipoprotein Cholesterol ◽

Risk Scores ◽

Lipid Levels

Dyslipidemia is an important risk factor for chronic cardiometabolic diseases. Lipid traits are highly heritable and there are currently >185 established loci influencing lipid levels in adults. Recent studies have confirmed that variants associated with lipids influence lipid levels across the lifecourse, and in ancestrally diverse populations. Given that Hispanic/Latinos (HL) shoulder much of the cardiometabolic burden in the United States, it is important to identify genetic variants that contribute the greatest risk for elevated lipid levels across life stages. Thus, our primary aim is to examine the association of known lipid variants with lipid traits identified in large study of adult participants from a Chilean infancy cohort of primarily European-descent. The sample assessed from 2008 to 2013 (n=546) had genotyping and well-measured lipid phenotypes (median age: 16.8 years, interquartile range: 16.6, 16.9). We assessed single variant associations using linear regression for high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), assuming an additive genetic model, adjusted for sex. Additionally, we regressed phenotypes onto weighted trait-specific polygenic risk scores (PRS). Only six variants from the Chilean sample met the a priori threshold of power > 0.8. We found statistically significant effect sizes (mmol/l (se)) for four of the six variants: rs3764261 (0.16 (0.04)) and rs1532085 (0.05 (0.04)) for HDL and rs1260326 (0.34 (0.15)) and rs964184 (0.33 (0.15)) for TG. For each significant variant, direction of effect matched the multiethnic adult GWAS from which SNPs were selected. We compared our findings to a previous study in Finnish children at age 18 years (n=1,216) and found an opposite direction of effect for our significant HDL variants. Likewise, when comparing coefficients for the PRS between the Chilean and Finnish youth sample we found the association to be stronger in the Chilean sample for every trait and gender group with the exception of LDL for males. The lipid loci explained the least amount of total variance for LDL (males=4% and females=5%) and the most amount of variance for HDL (males=20% and females=14%). In conclusion, there is evidence that lipid loci from a HL sample of adolescents contain similar associations as those from European children and adults. Despite the small sample size and possibility for bias with different ancestral groups we found meaningful and statistically significant associations relating lipid loci in a HL cohort of Chilean adolescents with those found in European ancestral groups. These associations emphasize the importance of adolescence as a time for disease prevention given studies demonstrating both the persistence of associations between PRS and lipids over the life course and the increasing role PRS plays in predicting disease.

Download Full-text

Genetic Analysis of the Atrial Natriuretic Peptide Gene Polymorphisms among Essential Hypertensive Patients in Malaysia

BioMed Research International ◽

10.1155/2016/6712529 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8

Author(s):

Nooshin Ghodsian ◽

Patimah Ismail ◽

Salma Ahmadloo ◽

Narges Eskandarian ◽

Ali Etemad

Keyword(s):

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Gene Polymorphisms ◽

Small Sample Size ◽

Sociodemographic Factors ◽

Small Sample ◽

Sequence Variations ◽

Peptide Gene ◽

Atrial Natriuretic

Background. Atrial natriuretic peptide (ANP) considerably influences blood pressure regulation through water and sodium homoeostasis. Several of the studies have utilized anonymous genetic polymorphic markers and made inconsequent claims about theANPrelevant disorders. Thus, we screened Insertion/Deletion (ID) and G191A polymorphisms ofANPto discover sequence variations with potential functional significance and to specify the linkage disequilibrium pattern between polymorphisms. The relationships of detected polymorphisms with EH with or without Type 2 Diabetes Mellitus (T2DM) status were tested subsequently.Method.ANPgene polymorphisms (I/DandA191G) were specified utilizing mutagenically separated Polymerase Chain Reaction (PCR) in 320 subjects including 163 EH case subjects and 157 controls.Result. This case-control study discovered a significant association betweenI/Dpolymorphisms ofANPgene in EH patient without T2DM. However, the study determined no association between G191A polymorphisms ofANPin EH with or without T2DM. In addition, sociodemographic factors in the case and healthy subjects exhibited strong differences (P<0.05).Conclusion. As a risk factor,ANPgene polymorphisms may affect hypertension. Despite the small sample size in this study, it is the first research assessing theANPgene polymorphisms in both EH and T2DM patients among Malaysian population.

Download Full-text