Carriers Of Single Nucleotide Polymorphism Research Articles

The rs216009 single-nucleotide polymorphism of the CACNA1C gene is associated with phantom tooth pain.

Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.

Relapse-like behavior in a mouse model of the OPRM1 (mu-opioid receptor) A118G polymorphism: Examination with intravenous oxycodone self-administration

The widely abused prescription opioid oxycodone is a mu-opioid receptor (MOP-r) agonist and addiction to such opioids is a relapsing disorder. The human MOP-r gene (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G, which affects risk of severe opioid use disorders. A112G (G/G) knock-in mice are models of human A118G carriers. We examined oxycodone self-administration (SA) in male and female G/G versus wild type (A/A) mice in SA sessions and in relapse-like behavior. Adult male and female G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, FR1) for 10 consecutive days. Following 10-day home cage drug free withdrawal, the mice were re-exposed to oxycodone SA for a further 10 days. MOP-r receptor mRNA in various brain regions were examined immediately after the last re-exposure session.We found that G/G mice had greater oxycodone SA than A/A mice in the initial and in re-exposure sessions. Mice of both genotypes had greater oxycodone intake during the re-exposure period than during the initial exposure. We also detected differences in MOP-r gene expression due to genotype, sex and oxycodone SA history in the dorsal striatum, hippocampus, and prefrontal cortex. These studies may improve our understanding of MOP-r-agonist self-exposure and relapse in human carriers of the A118G SNP.

TaqI and ApaI Variants of Vitamin D Receptor Gene Increase the Risk of Colorectal Cancer in a Saudi Population.

Background:Polymorphisms in the gene encoding the vitamin D receptor (VDR) affect the protective role of vitamin D against many types of cancers, including colorectal cancer (CRC).Objective:The objective of this study was to assess the effect of four major polymorphisms of the VDR gene (ApaI, TaqI, BsmI and FokI) on the risk of CRC in a Saudi population.Materials and Methods:This case–control study recruited 132 CRC patients from the oncology clinics at King Abdulaziz University Hospital and 124 healthy controls from the blood bank at King Fahad General Hospital, Jeddah, Saudi Arabia, between September 2017 and August 2018. All participants were Saudis and aged 20–80 years. Genomic DNA samples were extracted from the peripheral blood cells and amplified with polymerase chain reaction. The resulting fragments were digested with different endonucleases to reveal the genotypes using the restriction fragment length polymorphism technique. The genotype distribution and allele frequency, odds ratio (OR), risk ratio (RR) and P values were determined with contingency table analysis following Hardy–Weinberg equilibrium equation.Results:For the ApaI single-nucleotide polymorphism (SNP) (rs7975232), only the heterozygous (Aa) genotype increased the risk of CRC (OR = 3.4, RR = 2.3, and P < 0.0001), whereas the TaqI SNP (rs731236) carriers with either the heterozygous (Tt) or homozygous (tt) genotype displayed an increased risk for the disease (OR = 6.18, RR = 4, P < 0.0001; OR = 3, RR = 2.4, P = 0.02, respectively). In contrast, heterozygous (Bb) and homozygous (bb) carriers of the BsmI SNP (rs1544410) had significantly lower risk for CRC (P < 0.0001). Finally, for the FokI SNP (rs2228570), there was no association with CRC risk.Conclusion:This study found that VDR SNPs ApaI and TaqI increase the risk of CRC, whereas BsmI reduces the risk of CRC in the selected Saudi population. Therefore, ApaI and TaqI SNPs could potentially be used as a diagnostic biomarker for CRC. However, the molecular mechanisms by which these variants increase or decrease the risk of CRC need to be investigated.

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry.

Mu-opioid receptors (MORs) are the primary site of action of opioid drugs, both licit and illicit. Susceptibility to opioid addiction is associated with variants in the gene encoding the MOR, OPRM1 Varying with ethnicity, ∼25% of humans carry a single nucleotide polymorphism (SNP) in OPRM1 (A118G). This SNP produces a nonsynonymous amino acid substitution, replacing asparagine (N40) with aspartate (D40), and has been linked with an increased risk for drug addiction. While a murine model of human OPRM1 A118G (A112G in mouse) recapitulates most of the phenotypes reported in humans, the neuronal mechanisms underlying these phenotypes remain elusive. Here, we investigated the impact of A118G on opioid regulation of synaptic transmission in mesolimbic VTA dopaminergic neurons. Using electrophysiology, we showed that both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to the NAc medial shell were suppressed by the MOR agonists DAMGO and morphine, which caused a shift in the excitatory/inhibitory balance and an increased action potential firing rate. Mice carrying the 112G/G allele exhibited lower sensitivity to DAMGO and morphine compared with major allele carriers (112A/A). Paradoxically, DAMGO produced facilitatory effects on mEPSCs, which were mediated by presynaptic GABAB receptors. However, this was only prominent in homozygous major allele carriers, which could explain a stronger shift in action potential firing in 112A/A mice. This study provides a better understanding on the neurobiological mechanisms that may underlie risk of addiction development in carriers of the A118G SNP in OPRM1SIGNIFICANCE STATEMENT The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the μ-opioid receptor (MOR), encoded by the OPRM1 gene, which is highly polymorphic in humans. Using a mouse model of the human OPRM1 A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABAB signaling coordinate in regulating mesolimbic dopamine neuronal firing via presynaptic regulation. The A118G SNP affects MOR-mediated suppression of GABA and glutamate release, showing weaker efficacy of synaptic regulation by MORs. These results may shed light on whether MOR SNPs need to be considered for devising effective therapeutic interventions.

A SOD2 Polymorphism is Associated with Abnormal Quantitative Sensory Testing in Type 2 Diabetic Patients.

Diabetes mellitus (DM) affects peripheral nerves inducing diabetic polyneuropathy (DPN). Mitochondrial dysfunction and oxidative stress are potential causes of DPN. Nerve conduction studies were performed in 20 type 2 DM patients (11 with DPN) and 15 healthy controls. Perception threshold values of cold, warm and vibration were measured by quantitative sensory testing. Variants of a superoxide dismutase 2 (SOD2) gene single nucleotide polymorphism (SNP) (rs5746136) were determined by polymerase chain reaction (PCR) and following NexteraXT DNA Library. DPN patients showed significantly increased threshold values. DM patients without DPN and healthy controls showed comparable values. TT variant of the SOD2 SNP was more prevalent in DM and DPN patients. DM patients with the TT variant displayed increased perception threshold values. Quantitative sensory testing is not superior to standard nerve conduction studies in DPN. Carriers of SOD2 SNP manifested increased sensory threshold levels which is important in further corroborating the link between oxidative stress and DPN.

FTO rs 9939609 SNP Is Associated With Adiponectin and Leptin Levels and the Risk of Obesity in a Cohort of Romanian Children Population.

Obesity is a disorder with increasing frequency in children and adolescents, directly linked with various diseases. Variants in the FTO (fat mass and obesity-related) gene have been associated with body mass index and waist and hip circumferences in widespread populations.The aim of this case-control study was to assess if there is any association between FTO gene variants rs9939609, respectively, rs17817449 with anthropometric and metabolic biomarkers (fasting glucose, TC, HDL-cholesterol, LDL-cholesterol, triglycerides) and adipokines (adiponectin and leptin), in Romanian obese children.A total of 387 children, 201 obese and 186 nonobese individuals, were included in this prospective study. Genotyping of the FTO gene polymorphisms for all subjects was performed using the restriction fragment length polymorphism (PCR–RFLP) method.Significant associations were found between FTO rs9939609 single nucleotide polymorphism (SNP) and obesity. AA genotype carriers have a 2.02 times higher risk for obesity compared with AT+TT genotype carriers. Risk allele carriers of rs17817449 SNP had somewhat higher values of weight, body mass index, waist and hip circumference, total cholesterol, triglycerides, adiponectin, and fasting glucose.This study revealed the genetic association between rs9939609 SNP of FTO and obesity in a Romanian population, and to the authors’ knowledge, this is the first study to investigate this association in a Romanian population. This study also established that combined variant genotypes (AA/GG) of FTO rs9939609 /rs17817449 are strongly associated with several measures of adiposity (weight, BMI-SD, mid-upper arm circumference, tricipital skinfold thicknesses) and are also associated with total cholesterol, triglyceride, and LDL-cholesterol levels.

Connectivity across recognition memory circuits is reduced in carriers of the BDNF Val66Met single nucleotide polymorphism.

Event Abstract Back to Event Connectivity across recognition memory circuits is reduced in carriers of the BDNF Val66Met single nucleotide polymorphism. Nicole Mckay1* and Ian Kirk1 1 University of Auckland, Psychology, New Zealand A common single nucleotide polymorphism (SNP) within the gene for brain derived neurotrophic factor (BDNF) is known to impact both brain structure and memory performance. One area that has not been extensively researched is whether the BDNF genotype influences recognition memory performance and related brain structures. Recognition memory is comprised of two subcomponents, familiarity and recollection, that are dependent upon related but distinct neural circuits. The network that underlies processing of familiarity-based recognition judgments is dependent upon the medial dorsal thalamic nucleus, while the anterior thalamic nucleus has been linked to the circuit that underlies recollection-based processing. Carriers of at least one copy of the BDNF SNP were compared with non-carriers on two recognition memory tasks. Connectivity analyses were conducted to determine whether differences exist in white matter connectivity across familiarity- or recollection-associated tracts seeded from the relevant thalamic nuclei. In order to do this, probabilistic tractography was conducted. No performance differences were observed between SNP carriers and non-carriers on either recognition memory task. However, connectivity differences were found across both familiarity- and recollection-associated tracts: carriers of the BDNF SNP displayed lower connectivity compared to non-carriers. This result is consistent with the findings of previous studies that have shown carriers of the BDNF SNP to perform worse on memory tasks, and to have abnormal gray matter structure. Furthermore, white matter microstructural differences might help to explain the mechanism through which behavioural differences might occur in these two genetic groups. It is possible that performance on tasks that recruit these pathways might be reduced in those who have less connectivity across these tracts. Keywords: Diffusion Tensor Imaging, recognition memory, Probabilistic Tractography, structural MRI, brain derived neurotrophic factor Conference: XII International Conference on Cognitive Neuroscience (ICON-XII), Brisbane, Queensland, Australia, 27 Jul - 31 Jul, 2014. Presentation Type: Poster Topic: Memory and Learning Citation: Mckay N and Kirk I (2015). Connectivity across recognition memory circuits is reduced in carriers of the BDNF Val66Met single nucleotide polymorphism.. Conference Abstract: XII International Conference on Cognitive Neuroscience (ICON-XII). doi: 10.3389/conf.fnhum.2015.217.00287 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Feb 2015; Published Online: 24 Apr 2015. * Correspondence: Ms. Nicole Mckay, University of Auckland, Psychology, Auckland, New Zealand, nicole.mckay@auckland.ac.nz Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Nicole Mckay Ian Kirk Google Nicole Mckay Ian Kirk Google Scholar Nicole Mckay Ian Kirk PubMed Nicole Mckay Ian Kirk Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice.

Mu-opioid receptors (MOPRs) are the target of heroin and other prescription opioids, which are currently responsible for massive addiction morbidity in the US. The gene coding for the human MOPR (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G. The OPRM1 A118G genotype results in substantially increased risk of heroin addiction in humans; however, the neurobiological mechanism for this increased risk is not fully understood. This study examined heroin self-administration (SA) behavior in A112G (G/G) mice, harboring a functionally equivalent SNP in Oprm1 with a similar amino acid substitution, in extended (4 h) SA sessions. Adult male and female G/G mice and 'wild-type' litter mates (A/A) were allowed to self-administer heroin (0.25 mg/kg/unit dose, FR1 with a nose poke response) for 4 h/day, for 10 consecutive days. Half of the mice then continued in a heroin dose-response study, while extinction from heroin SA was studied in the other half. In vivo microdialysis was used to measure acute heroin-induced increases of striatal dopamine in the GG vs AA genotypes. Male and female G/G mice responded for heroin significantly more (and thus had greater intake) than A/A mice, in the initial 10 days of heroin SA, and in the subsequent dose-response study. There were no significant differences in extinction of SA between the A/A and G/G mice. Heroin-induced increases in striatal dopamine levels are higher in the GG mice than in the AA mice. Both male and female G/G mice self-administered more heroin than did A/A mice over a 10-day period, possibly because of the greater increases of heroin-induced striatal dopamine in the GG mice. Furthermore, G/G male mice escalated the amount of heroin self-administration across 10 extended-access sessions more than A/A male mice did. These are the first studies to examine the acquisition of heroin SA in this mouse model. These studies may lead to a better understanding of the neurobiological and behavioral mechanisms that underlie greater risk of heroin addiction in carriers of the A118G SNP.

The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study.

BackgroundHistidine-rich Glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage.MethodsThe study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP.ResultsThe results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p < 0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p < 0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p < 0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p < 0.05).ConclusionsWomen who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: A retrospective case control study

BackgroundRecurrent miscarriage affects approximately 1% of all couples. There is a known relation between hypothyroidism and recurrent miscarriage. Phosphodiesterase 8B (PDE8B) is a regulator of cyclic adenosine monophosphate (cAMP) with important influence on human thyroid metabolism. Single nucleotide polymorphism (SNP) rs 4704397 in the PDE8B gene has been shown to be associated with variations in serum Thyroid Stimulating Hormone (TSH) and thyroxine (T4) levels. The aim of this study was to investigate whether there is an association between the SNP rs 4704397 in the PDE8B gene and recurrent miscarriage.MethodsThe study was designed as a retrospective case control study. 188 cases with recurrent miscarriage were included and compared with 391 controls who had delivered at least once and with no history of miscarriage or assisted reproduction.ResultsNo difference between cases and controls concerning age was found. Bivariate associations between homozygous A/A (OR 1.57, 95% CI 0.98-2.52) as well as G/G carriers (OR 1.52, 95% CI 1.02-2.25) of SNP rs 4704397 in PDE8B and recurrent miscarriage were verified (test for trend across all 3 genotypes, p = 0.059). After adjustment for known confounders such as age, BMI and smoking the association between homozygous A/A (AOR 1.63, 95% CI 1.01 - 2.64, p = 0.045) and G/G (AOR 1.52, 95% CI 1.02 - 2.27, p = 0.039) carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage remained.ConclusionsOur findings suggest that there is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage.

Sex-specific association of ACAT-1 rs1044925 SNP and serum lipid levels in the hypercholesterolemic subjects

BackgroundAcyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme in cellular cholesterol homeostasis and in atherosclerosis. The cellular cholesterol efflux correlated with serum high-density lipoprotein cholesterol (HDL-C) concentrations has shown to be impaired in hyperlipidemic mice. The present study was carried out to clarify the association of ACAT-1 rs1044925 single nucleotide polymorphism (SNP) and serum lipid levels in the hyperlipidemic subjects.MethodsA total of 821 unrelated subjects (hyperlipidemia, 476; normolipidemia, 345) aged 15-80 were included in the study. Genotyping of the ACAT-1 rs1044925 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.ResultsThere was no significant difference in the genotypic and allelic frequencies of ACAT-1 rs1044925 SNP between the normolipidemic and hyperlipidemic subjects. The levels of total cholesterol (TC), HDL-C and apolipoprotein (Apo) AI in hyperlipidemic subjects were different between the AA and AC/CC genotypes in male but not in female (P < 0.05-0.01), the C allele carriers had higher serum TC, HDL-C and ApoAI levels than the C allele noncarriers. The association of genotypes and serum HDL-C and ApoAI levels in hyperlipidemia was found mainly in the male subjects with hypercholesterolemia but not in those with hypertriglyceridemia. There were no significant differences in serum lipid levels between the AA and AC/CC genotypes in the normolipidemic subjects.ConclusionsThe present study shows that the C allele carriers of ACAT-1 rs1044925 SNP in male hyperlipidemic subjects had higher serum TC, HDL-C and ApoAI levels than the C allele noncarriers. There is a sex (male)-specific association of ACAT-1 rs1044925 SNP and serum HDL-C and ApoAI levels in the hypercholesterolemic subjects.

AQP-1 Association with Body Fluid Loss in 10-km Runners

Intrinsic body fluid regulation is critical for optimizing endurance performance. Aquaporins (AQPs) are a family of transmembrane proteins that transport water and glycerol across cellular membranes. A recent report revealed an association between a single nucleotide polymorphism (SNP) in the 3' untranslated region of the aquaporin-1 (AQP1) gene and endurance performance. The purpose of the study was to explore the association between the AQP1 SNP and acute body fluid loss in long distance runners. The subjects (N=91, Age=26±3 yrs; Ht=170±11 cm; Wt=61±5 kg; mean±SD) were biologically unrelated male long distance runners. Data were collected before and after an international 10 km road race. Body fluid loss was determined by the difference between nude body weight before and after the 10 km run. The AQP1 (G→C) gene variation was detected by the ARMS-PCR procedure. Genotypes were determined by PCR product size. Carriers of the AQP1 SNP had a significantly greater adjusted body fluid loss (3.7±0.9 kg) than non-carriers (1.5±1.1 kg) (P<0.05). In conclusion, our study found an association between the AQP1 SNP and acute body fluid loss in long distance runners.

The I4399M variant of apolipoprotein(a) is associated with increased oxidized phospholipids on apolipoprotein B-100 particles

Objectives The LPA I4399M (rs3798220) single nucleotide polymorphism (SNP) is associated with increased plasma levels of Lp(a) and advanced coronary artery disease (CAD). We hypothesized that carriers of the Met allele of the I4399M SNP would also have elevated levels of oxidized phospholipids (OxPL) on apoB (OxPL/apoB) particles. Methods and results Plasma levels of Lp(a) and OxPL/apoB were measured in non-carriers (TT genotype, n = 116) and carriers (CT/CC genotype, n = 58) of the I4399M SNP. Carriers had significantly higher Lp(a) levels [median (interquartile range, IQR)] [43 (9–57) mg/dl vs. 5.5 (2–20) mg/dl, p < 0.0001] and smaller apolipoprotein(a) isoforms than non-carriers (number of kringle IV repeats: 18(17–20) vs. 22(18–25), p = 0.002). Median (IQR) OxPL/apoB levels were significantly higher in carriers than non-carriers [8019 (6254–31,785) relative light units (RLU) vs. 2168 (1303–5869), p < 0.0001]. Patients with small apolipoprotein(a) isoforms had the highest OxPL/apoB levels. The number of kringle IV repeats was inversely related to Lp(a) ( r = −0.43, p < 0.001) and OxPL/apoB ( r = −0.36, p < 0.0001) levels. Conclusion The CT and CC genotypes of the I4399M SNP in the LPA gene are associated with elevated OxPL/apoB levels, which primarily represent OxPL on Lp(a). The concomitant increase of OxPL/apoB levels in the setting of small apolipoprotein(a) isoforms may potentiate the atherogenic effect on CAD of elevated Lp(a) levels in carriers of the I4399M SNP.

Analysis of a non-synonymous single nucleotide polymorphism of the human diamine oxidase gene (ref. SNP ID: rs1049793) in patients with Crohn's disease

Objective. To analyse the possible influence of a non-synonymous single nucleotide polymorphism (SNP) of the histamine-degrading enzyme diamine oxidase (DAO) on genetic susceptibility to Crohn's disease (CD). Material and methods. In this prospective, case-control study, 210 unrelated Caucasian consecutive CD patients were recruited at the Inflammatory Bowel Disease Unit of a single tertiary centre (Hospital Clínico San Carlos) in Madrid, Spain. A total of 261 healthy volunteers from the same geographic area were also recruited and matched with patients. Both cases and controls were analysed for the presence of a non-synonymous SNP (rs1049793) of DAO using amplification-restriction procedures of the genotype obtained in a blood sample. Results. No significant differences were found in the distribution of carriers of the non-synonymous SNP of DAO between CD patients and controls (OR 1.2 (95% CI 0.9–1.6; p=0.3)). Nor were any differences found between carriers and non-carriers of the non-synonymous SNP in demographic characteristics, phenotypes, complications or treatment of CD. Conclusions. The study of a non-synonymous SNP (rs1049793) of DAO does not seem to be of use in assessing susceptibility to CD, either as a marker of disease activity or as a marker of clinical behaviour in patients with the disease.

Association between the Polymorphisms of TLR4 and CD14 Genes and Alzheimers Disease

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD patients (427 women and 199 men; age range: 53-98 years; mean age: 74.88+/-8.44) from Northern Italy and age and gender matched controls. Our results demonstrate that the +896A/G TLR4 single nucleotide polymorphism (SNP) is associated with AD, whereas no association has been observed with -260C/T CD14 SNP. Furthermore, no differences have been observed evaluating the combined presence of +896A+TLR4/-260T+CD14 "high responder"(proinflammatory-profile). However, our results showing the involvement of TLR4 in AD pathophysiology, strengthen the suggestion that systemic inflammation plays a key role in AD. Carriers of high responder SNP, affected by mild cognitive impairment might, be the ideal target for a preventive treatment with biologics as monoclonal antibodies directed against the pro-inflammatory cytokines to decrease the level of systemic inflammation involved in AD pathophysiology.

The single nucleotide polymorphism Ser128Arg in the E-selectin gene is associated with enhanced coagulation during human endotoxemia

AbstractThe single nucleotide polymorphism (SNP) Ser128Arg in the E-selectin gene is overrepresented in certain patient groups with atherosclerosis or restenosis. We hypothesized and tested whether it may affect cytokine-induced levels of soluble (s) E-selectin, or be associated with proinflammatory or procoagulant properties in a well-standardized inflammation model. Healthy male volunteers (n = 157) received a lipopolysaccharide (LPS) infusion and were genotyped for the S128R SNP, and outcome parameters were measured by enzyme immunoassays and real-time polymerase chain reaction (RT-PCR, Taqman). The S128R SNP had no pronounced effects on basal or inducible sE-selectin levels, or levels of tumor necrosis factor or interleukin-6. However, carriers of the S128R SNP had 20% higher monocyte counts at 24 hours after LPS infusion. Importantly, the S128R allele enhanced thrombin generation by 50% to 80%, as measured by prothrombin fragment F1+2 (P < .01), and hence fibrin formation (D-dimer) 2-fold (P = .01 to P = .002). However, tissue factor (TF) mRNA levels were not affected. The S128R E-selectin genotype is associated with procoagulant effects in a human model of endotoxin-induced, TF-triggered coagulation. This could contribute to its linkage with various thrombotic cardiovascular disorders.

The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine.

Large individual differences in the clinical response to morphine therapy have been known for a long time by clinicians. The recent advances in genomic research encourage the search for pharmacogenetic causes of that variability. As a measure of central opioid effects, pupil diameters were assessed every 20 min for 18 h after administration of morphine or its active metabolite morphine-6-glucuronide (M6G) in a two-way crossover study. The opioid effects were compared between six subjects with a single-nucleotide polymorphism (SNP) A118G in the mu-opioid receptor gene (five heterozygous, one homozygous) and six control subjects. Non-parametric pharmacokinetic-pharmacodynamic modelling was employed to identify the influence of the A118G SNP on the concentration-response relationship of M6G and morphine, which was described by a sigmoid Emax model. As a measure of potency, the EC50 of the pupil constrictory effects of M6G was 714 +/- 197 nmol/l in wild-type and 1475 +/- 424 nmol/l in heterozygous carriers of the A118G SNP. In the homozygous carrier of the SNP, it had an EC50 of 3140 nmol/l. In addition, the dose-response relationship was flatter in the A118G carriers than in control subjects (shape factor of the sigmoid Emax model: gamma = 3.3 +/- 1.2, 1.7 +/- 0.5 and 1.6 for wild-type, heterozygous and the homozygous A118G carriers, respectively). In contrast, the concentration-response relationship of morphine was not affected by this specific SNP. The A118G SNP in the mu-receptor gene significantly reduces the potency of M6G in humans.