Functional Genetic Polymorphisms Research Articles

Association Between Cyclooxygenase-2 Gene Polymorphisms and Head and Neck Squamous Cell Carcinoma Risk

Cyclooxygenase-2 (COX-2) is an inducible enzyme that catalyzes prostaglandins through inflammatory response, which may be involved in autoimmune diseases and cancer pathogenesis. Two potentially functional genetic single-nucleotide polymorphisms (COX-2 -1195G>A and 8473T>C) were supposed to contribute to head and neck squamous cell carcinoma (HNSCC) susceptibility. The aim of this study was to determine the association of these polymorphisms with HNSCC susceptibility in a Chinese Han population. In this study, 2 SNPs were genotyped by TaqMan methods in a patient-control study including 260 patients with HNSCC and 1047 cancer-free controls in a Chinese Han population. We found significant difference in the frequency of alcohol consumption between the patients with HNSCC and controls (P < 0.001), but the genotype frequencies of the 2 polymorphisms were not significantly different between the patients and controls. Further stratified analysis indicated that none of the genotypes were associated with increased risk for HNSCC. This research indicated that the COX-2 -1195G>A and 8473T>C polymorphisms may not be involved in the development of HNSCC in the Chinese Han population. However, further perspective studies are warranted to test these findings and further investigate the potential interactions involving the COX-2 polymorphism and HNSCC.

In women with previous pregnancy hypertension, levels of cardiovascular risk biomarkers may be modulated by haptoglobin polymorphism.

Preeclampsia (PE) may affect the risk for future cardiovascular disease. Haptoglobin (Hp), an acute phase protein with functional genetic polymorphism, synthesized in the hepatocyte and in many peripheral tissues secondary of oxidative stress of PE, may modulate that risk through the antioxidant, angiogenic, and anti-inflammatory differential effects of their genotypes. We performed a prospective study in 352 women aged 35 ± 5.48 years, which 165 had previous PE, 2 to 16 years ago. We studied demographic, anthropometric, and haemodynamic biomarkers such as C-reactive protein (CRP), myeloperoxidase (MPO), and nitric oxide metabolites (total and nitrites), and others associated with liver function (AST and ALT) and lipid profile (total LDL and cholesterol HDL, non-HDL, and apolipoproteins A and B). Finally, we study the influence of Hp genetic polymorphism on all these biomarkers and as a predisposing factor for PE and its remote cardiovascular disease prognosis. Previously preeclamptic women either hypertensive or normotensive presented significant differences in those risk biomarkers (MPO, nitrites, and ALT), whose variation may be modulated by Hp 1/2 functional genetic polymorphism. The history of PE may be relevant, in association with these biomarkers to the cardiovascular risk in premenopausal women.

EPA-1313 - Influence of il6-174g>c, il6-6331t>c and il6r d358a a>c il-6 genetic polymorphisms in antidepressant treatment phenotypes

Introduction Several studies associated Major Depressive Disorder (MDD) with an increased production of pro-inflammatory cytokines, such as interleukin 6 (IL-6). Serum IL-6 levels were found to be significantly increased in subjects with MDD and with Treatment Resistant Depression (TRD). Moreover, ketamine, a drug with fast-acting antidepressant properties, has proven to reduce IL-6 levels in rat prefrontal cortex and hippocampus. However, despite the clear influence of IL-6 in the pathophysiology of depression and in antidepressant response, studies evaluating the impact of IL-6 functional genetic polymorphisms on treatment response phenotypes are scarce. Objectives We aim to evaluate the role of IL6-174G>C, IL6-6331T>C and IL6R D358A A>C functional polymorphisms in antidepressant treatment phenotypes, specifically remission, relapse and TRD. Methods We genotyped the referred polymorphisms in a subset of 80 MDD patients followed at Hospital Magalhaes Lemos, Portugal, within a period of 18 months. Results We found that patients carrying IL6-174 GG genotype are more prone to develop TRD (OR=4.125; 95%CI: [1.151-14.786]; p=0.038). We also observed that patients carrying IL6-6331 TC genotype have a higher risk of relapse (OR=3.988; 95%CI: [1.176-13.516]; p=0.022), and present a lower time to relapse, TC: 26 weeks vs. TT: 45 weeks (p=0.041, Log-rank test). No association was found between IL6R D358A genetic polymorphism and any of treatment phenotypes. Conclusions The IL6-174G>C and IL6-6331T>C polymorphisms influence antidepressant treatment response in our subset of MDD patients. These polymorphisms may possibly contribute to the elevated IL-6 levels found in patients with TRD. This research was partially supported by an AstraZeneca Grant

Genetic susceptibility to family environment: BDNF Val66met and 5-HTTLPR influence depressive symptoms.

Functional genetic polymorphisms associated with Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HTTLPR) have demonstrated associations with depression in interaction with environmental stressors. In light of evidence for biological connections between BDNF and serotonin, it is prudent to consider genetic epistasis between variants in these genes in the development of depressive symptoms. The current study examined the effects of val66met, 5-HTTLPR, and family environment quality on youth depressive symptoms in adolescence and young adulthood in a longitudinal sample oversampled for maternal depression history. A differential susceptibility model was tested, comparing the effects of family environment on depression scores across different levels of a cumulative plasticity genotype, defined as presence of both, either, or neither plasticity alleles (defined here as val66met Met and 5-HTTLPR 'S'). Cumulative plasticity genotype interacted with family environment quality to predict depression among males and females at age 15. After age 15, however, the interaction of cumulative plasticity genotype and early family environment quality was only predictive of depression among females. Results supported a differential susceptibility model at age 15, such that plasticity allele presence was associated with more or less depressive symptoms depending on valence of the family environment, and a diathesis-stress model of gene-environment interaction after age 15. These findings, although preliminary because of the small sample size, support prior results indicating interactive effects of 5-HTTLPR, val66met, and environmental stress, and suggest that family environment may have a stronger influence on genetically susceptible women than men.

Functional IL-23R rs10889677 Genetic Polymorphism and Risk of Multiple Solid Tumors: a Meta-Analysis

Interleukin-23 receptor (IL23R) can interact with IL-23 and, thus, is involved in the T-helper 17 (Th17) cell-mediated inflammatory process as well as tumorigenesis. Recently, a functional single nucleotide polymorphism (SNP) rs10889677 has been identified in the 3’-untranslated region of IL-23R. It has been showed that the rs10889677AC SNP could increase the binding affinity of microRNA let-7f and downregulate IL-23R expression. Several case-control studies have examined the association between this SNP and genetic susceptibility of multiple solid tumors. However, the conclusions are conflicting. Therefore, we conducted this meta-analysis to systematically study the role of this functional IL-23R SNP in development of multiple solid tumors. There are a total of 5 studies are eligible (6731 cases and 7296 healthy controls). Either fixed-effect model or random-effect model was used to calculate pooled odds ratios (ORs) and the 95% confidence interval (95% CI). Significant association between this functional rs10889677 genetic variant and risk of multiple solid tumors were observed (CC genotype vs. AA genotype: OR = 0.59, 95% CI = 0.53-0.66, P < 0.001). These findings demonstrated that the IL-23R rs10889677 genetic variant might play an important part during malignant transformation of multiple solid tumors.

Fabry disease: experience of screening dialysis patients for Fabry disease

The prevalence rate for Fabry disease is conventionally considered to be 1 case in 40,000; however, due to increased screening accuracy, reports now suggest that prevalence is 1 case in 1,500 among male children, and it is likely that the clinical importance of the condition will increase in the future. In dialysis patients to date, prevalence rates are between 0.16 and 1.2 %. Globotriaosylsphingosine (Lyso-GL-3), which is a substrate of α-galactosidase A (α-Gal A), has surfaced as a new biomarker, and is also effective in the determination and monitoring of the effects of enzyme replacement therapy. In terms of genetic abnormalities, the E66Q mutation has recently become a topic of discussion, and although doubts have been expressed over whether or not it is the gene responsible for Fabry disease, there is still a strong possibility that it is a functional genetic polymorphism. At present, the standard treatment for Fabry disease is enzyme replacement therapy, and in order to overcome the problems involved with this, a method of producing recombinant human α-Gal A using methanol-assimilating yeast, and chemical or medicinal chaperone treatment are of current interest. Migalastat hydrochloride is known as a pharmacological chaperone, but is currently in Phase III global clinical trials. Adding saposin B to modified α-N-acetyl galactosaminidase is also under consideration as a treatment method.

Functional Genetic Polymorphisms in PP2A Subunit Genes Confer Increased Risks of Lung Cancer in Southern and Eastern Chinese

Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and functions as a tumor suppressor that negatively regulates the activity of some oncogenic kinases. Recent studies have reported that PP2A expression was suppressed during lung carcinogenesis, we there hypothesized that the single nucleotide polymorphisms (SNPs) in PP2A subunit genes may affect PP2A function and thus contribute to lung cancer susceptibility. In a two-stage case-control study with a total of 1559 lung cancer patients and 1679 controls, we genotyped eight putative functional SNPs and one identified functional SNP (i.e., rs11453459) in seven major PP2A subunits (i.e., PPP2R1A, PPP2R1B, PPP2CA, PPP2R2A, PPP2R2B, PPP2R5C, PPP2R5E) in southern and eastern Chinese. We found that rs11453459G (-G/GG) variant genotypes of PPP2R1A and the rs1255722AA variant genotype of PPP2R5E conferred increased risks of lung cancer (rs11453459, -G/GG vs. –: OR = 1.31, 95% CI = 1.13–1.51; rs1255722, AA vs. AG/GG: OR = 1.27, 95% CI = 1.07–1.51). After combined the two variants, the number of the adverse genotypes was positively associated with lung cancer risk in a dose-response manner (P trend = 5.63×10−6). Further functional assay showed that lung cancer tissues carrying rs1255722AA variant genotype had a significantly lower mRNA level of PPP2R5E compared with tissues carrying GG/GA genotypes. However, such effect was not observed for the other SNPs and other combinations. Our findings suggested that the two functional variants in PPP2R1A and PPP2R5E and their combination are associated with lung cancer risk in Chinese, which may be valuable biomarkers to predict risk of lung cancer.

Lectin pathway of complement activation and relation with clinical complications in critically ill children

Critically ill children are susceptible to nosocomial infections, which contribute to adverse outcomes. Deficiencies in the innate immunity lectin pathway of complement activation are implicated in a child's vulnerability to infections in conditions such as cancer, but the role during critical illness remains unclear. We hypothesized that low on-admission levels of the pathway proteins are, in part, genetically determined and associated with susceptibility to infectious complications and adverse outcomes. We studied protein levels of mannose-binding lectin (MBL), H-ficolin and M-ficolin, three MBL-associated-serine proteases (MASPs) and MBL-associated protein (MAp44), and relation with functional genetic polymorphisms, in 130 healthy children and upon intensive care unit (ICU) admission in 700 critically ill children of a randomized study on glycemic control. Levels of MASP-1, MASP-2, MASP-3, and MAp-44 were lower and the levels of M-ficolin were higher in ICU patients on admission than those in matched healthy controls. Only a low on-admission MASP-3 level was independently associated with risk of new ICU infections and prolonged ICU stay, after correcting for other risk factors. On-admission MASP-3 varied with age, illness severity, and genetic variation. Low on-admission MASP-3 levels in critically ill children were independently associated with subsequent acquisition of infection and prolonged ICU stay. The biological explanation needs further investigation.

Association between environmental tobacco smoke exposure and lung cancer susceptibility: Modification by antioxidant enzymes genetic polymorphisms

BackgroundEnvironmental tobacco smoke (ETS) is the primary etiological factor of lung cancer. However, only 10–15% of smokers develop lung cancer, suggesting genetic role in modifying individual susceptibility to lung cancer. Antioxidant enzyme functional genetic polymorphisms should be considered. Aim of the workThe present study aimed to evaluate the role of antioxidant enzyme activity and genetic polymorphisms in modifying the susceptibility to lung cancer among individuals exposed to ETS. Subjects and methodsA total of 150 male subjects were divided into three groups: 50 lung cancer patients, 50 chronic smokers and 50 passive smokers. Genotyping of mEH exon 3 (Tyr113Hist) and exon 4 (Hist139Arg) polymorphisms was done by PCR–RFLP technique. MnSOD (Val16Ala) polymorphism was detected by Real time-TaqMan assay. Erythrocyte MnSOD activity was measured spectrophotometrically. ResultsETS exposed individuals (both active and passive smokers) who carried His allele of mEH exon3 have 2.9-folds increased risk of lung cancer (OR 2.9 P<0.001). Also ETS exposed carriers of Arg allele of mEH exon 4 have 2.1-folds higher risk to lung cancer (OR 2.1 P=0.024). However no association between MnSOD Val16Ala polymorphism and lung cancer was detected among ETS (OR 1.6 P=0.147), although lung cancer group had significantly lower MnSOD activity than chronic or passive smokers groups (P=0.03). ConclusionExons 3 and 4 polymorphisms of the mEH gene may contribute to lung cancer susceptibility through disturbed antioxidant balance. However, this was not the case with MnSOD Val16Ala SNP. Antioxidant enzymes may modulate the influence of ETS exposure on lung cancer risk.

Functional Genetic Polymorphisms of Monocyte Chemoattractant Protein 1 and C-C Chemokine Receptor Type 2 in Ischemic Stroke

Recent findings indicated that monocyte chemoattractant protein 1 (MCP1) and its C-C chemokine receptor type 2 (CCR2) play a key role in ischemic stroke (IS) progression. This study was aimed at evaluating the potential association of the MCP1 gene (MCP1) rs1024611 (-2518 A>G) and CCR2 gene (CCR2) rs1799864 (V64I; 190 G>A) functional single nucleotide polymorphisms (SNPs) with IS in the Armenian population. For the purpose of this study, genomic DNA samples of 100 patients with the first-episode IS and 115 healthy subjects (controls) were genotyped for the selected SNPs using a polymerase chain reaction with sequence-specific primers. The results obtained demonstrated that while the CCR2 rs1799864 SNP genotypes were equally distributed among patients and controls, the frequency and carriage rate of the of the MCP1 rs1024611*G minor allele were higher in patients. While a potential association between IS and CCR2 rs1799864 SNP was evaluated for the first time, the latest finding was in agreement with the earlier data reported for some other populations. In summary, this study revealed no association of CCR2 rs1799864 SNP with IS, and a positive association between G minor allele of MCP1 rs1024611 SNP and IS in the Armenian population. Based on the present and earlier reported data, we concluded that the minor G allele of the MCP1 rs1024611 SNP might be considered a risk factor for IS.

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT).The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk.Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1–3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2–16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7–1.2).The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults

Objectives. Studies have reported an association between serotonin reuptake inhibitors (SRIs) and accelerated bone loss. Genetic variation in the serotonin system might modulate bone metabolism changes during SRI treatment. In a clinical trial we examined functional genetic polymorphisms of serotonin transporter and receptors involved in bone metabolism to determine whether they predict changes in bone metabolism during SRI treatment. Methods. In 69 adults (age ≥ 60) participating in a 12-week, open-label trial of the SRI venlafaxine for major depression, serum markers of bone formation (P1NP) and resorption (β-CTX) were assayed before and after treatment. Participants were genotyped for putative high- versus low-expressing polymorphisms in the serotonin transporter (5HTTLPR) and 1B receptor (HTR1B) genes. Results. Bone formation was significantly reduced with administration of venlafaxine in participants with the high-expressing 5HTTLPR genotype and those with the low-expressing HTR1B genotype. This primarily occurred in individuals with the combination of the high-expressing 5HTTLPR genotype and the low-expressing HTR1B genotype. Conclusions. These preliminary findings indicate that genetic variation in the serotonin receptors predicts changes in bone metabolism during SRI use. If these results are replicated and clinically confirmed, we will have identified a genetic subgroup at high risk for deleterious bone outcomes with the use of SRIs.

Functional Genetic Polymorphisms inCYP2C19Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort

Abstract Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram (p=0.021), and the Treatment Emergent Symptom Scale (TESS) total score (p=0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone (p=0.035), and showed a lower plasma R-methadone/methadone dose ratio (p=0.007) in urine opiate test negative patients, as well as a greater QTc change (p=0.008) and higher total scores of TESS (p=0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.

Effects of CYP2C19 genotype on vascular function in patients with coronary artery disease receiving clopidogrel

Purpose: The role of CYP2C19*2 polymorphism in plasma clopidogrel active drug metabolite concentrations, in platelet inhibition and in cardiovascular prognosis has come under question in recent studies. We examined the impact of functional genetic polymorphism CYP2C19*2 on endothelial function and arterial stiffness in patients with CAD treated with clopidogrel regimen. Methods: We consecutively enrolled 408 patients with stable CAD receiving clopidogrel regimen (75mg/d), one month after percutaneous coronary intervention. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as an index of arterial wave reflections. CYP2C19*2 genotyping was performed by real-time polymerase chain reaction. High on treatment platelet reactivity was evaluated using VerifyNow Assay. VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230 PRU. Results: From the study population 150 patients (36.8%) were carriers of at least one CYP2C19*2 reduced-function allele and 258 patients (63.2%) were non carriers. There was no statistically significant difference between carriers and non carriers in age, male sex and the presence of hyperlipidemia, diabetes mellitus, arterial hypertension, in smoking habits, in anticoagulant and statin treatment. Importantly, there was no difference in FMD (4.88±2.34% vs. 4.83±2.21%, p=0.83), PWV (8.53±2.54m/sec vs. 8.85±2.33m/sec, p=0.19) and AIx values (22.87±10.04% vs. 23.82±8.43%, p=0.31) between carriers and non carriers respectively. Finally, carriers of two CYP2C19*2 reduced-function allele had significantly increased PRU (292±53 vs. 198±83, p=0.007). Conclusions: The presence of CYP2C19*2 loss of action polymorphism displays no impact on arterial wall properties in patients with CAD treated with clopidogrel regimen. Moreover, carriers of two CYP2C19 reduced-function alleles had significantly increased platelet reactivity.

Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer

Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

Pharmacogenetic Study of Deferasirox, an Iron Chelating Agent

Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing −1774 del and/or −24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79–28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7–43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34–150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.

The tricks of the trait: Neural implementation of personality varies with genotype-dependent serotonin levels

Gray's Reinforcement Sensitivity Theory (RST) has developed into one of the most prominent personality theories of the last decades. The RST postulates a Behavioral Inhibition System (BIS) modulating the reaction to stimuli indicating aversive events. A number of psychiatric disorders including depression, anxiety disorders, and psychosomatic illnesses have been associated with extreme BIS responsiveness. In recent years, neuroimaging studies have implicated the amygdala-septo-hippocampal circuit as an important neural substrate of the BIS. However, the neurogenetic basis of the regulation of this behaviorally and clinically essential system remains unclear. Investigating the effects of two functional genetic polymorphisms (tryptophan hydroxylase-2, G-703T, and serotonin transporter, serotonin transporter gene-linked polymorphic region) in 89 human participants, we find significantly different patterns of associations between BIS scores and amygdala–hippocampus connectivity during loss anticipation for genotype groups regarding both polymorphisms. Specifically, the correlation between amygdala–hippocampus connectivity and Gray's trait anxiety scores is positive in individuals homozygous for the TPH2 G-allele, while carriers of at least one T-allele show a negative association. Likewise, individuals homozygous for the 5-HTTLPR LA variant display a positive association while carriers of the S/LG allele show a trend towards a negative association. Thus, we show converging evidence of different neural implementation of the BIS depending on genotype-dependent levels of serotonin. We provide evidence suggesting that genotype-dependent serotonin levels and thus putative changes in the efficiency of serotonergic neurotransmission might not only alter brain activation levels directly, but also more fundamentally impact the neural implementation of personality traits. We outline the direct clinical implications arising from this finding and discuss the complex interplay of neural responses, genes and personality traits in this context.

Update meta-analysis on MMP-7 − 181A>G polymorphism and cancer risk: Evidence from 25 studies

BackgroundThe matrix metalloproteinase (MMP) can degrade various components of the extracellular matrix and its functional genetic polymorphism may be associated with cancer development. The common MMP-7 (−181A>G) genetic polymorphism has been reported to be functional and may contribute to genetic susceptibility to cancers. However, the association between MMP-7 (−181A>G) and cancer risk remains inconclusive. MethodsTo better understand the role of MMP-7 (−181A>G) polymorphism in global cancer, we conducted this comprehensive meta-analysis encompassing 6392 cases and 7665 controls. ResultsOverall, the MMP-7 (−181A>G) polymorphism was associated with higher cancer risk. In the stratified analyses, significant associations were found between the MMP-7 (−181A>G) polymorphism and gastric cancer, ESCC and gynecologic cancer. We also observed that the GG genotype might modulate colorectal cancer risk comparing with the AA genotype (OR=1.31[1.02–1.69]). Moreover, a significantly increased cancer risk was found among Asian populations. When stratified by study design, significantly elevated susceptibility to cancer was found among population-based studies. ConclusionsThese findings suggested that the MMP-7 (−181A>G) genetic polymorphism may contribute to the susceptibility of cancers, especially among Asian population.

Association of Anthracycline-Related Cardiac Histological Lesions With NADPH Oxidase Functional Polymorphisms

Treatment with anthracyclines may cause cardiac dysfunction, but the sequence of anthracycline-induced heart lesions has been incompletely characterized. NADPH oxidase, a key mediator of oxidative cardiac damage and remodeling, modulates anthracycline clinical cardiotoxicity. Our aim was to determine which cardiac histological lesions are specifically induced by anthracycline treatment and to investigate the role of NADPH functional genetic polymorphisms in their development. Using a retrospective case-control design, we evaluated cardiac histological lesions and NADPH genotype (polymorphisms rs1883112, rs4673, and rs13058338) in 97 consecutive decedents with a cancer diagnosis (48 treated with anthracyclines). Myocytolysis (60%), patched myocardial necrosis (19%), and myocardial fibrosis (diffuse and patched; 62% and 23%, respectively) were associated with anthracycline treatment. In patients receiving anthracyclines, NADPH oxidase polymorphism rs4673 protected against focal myocardial necrosis (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.20-0.63) whereas rs1883112 was strongly associated with cardiac fibrosis (OR, 5.11; 95% CI, 1.59-16.43), which was present in all homozygotes. Anthracyclines induce a cardiac remodeling pattern characterized by interstitial or patched fibrosis. The contribution of the functionally relevant NADPH polymorphisms rs1883112 and rs4673 to anthracycline-related heart lesions provides a plausible explanation for their modulation of cardiotoxicity. If confirmed, these findings may lead to better individualized strategies for early detection and prevention of anthracycline cardiotoxicity.

Genetic variation in the serotonin transporter and serotonin 1B receptor predicts reduced bone formation during serotonin-reuptake inhibitor treatment in older adults

Evidence suggests an association between serotonin reuptake inhibitors (SRIs) and accelerated bone loss. SRIs and bone metabolism share a common serotonergic mechanism, generating the hypothesis that genetic variation in the serotonin system might modulate bone metabolism changes during SRI treatment. We examined functional genetic polymorphisms within serotonin receptors involved in bone metabolism, to determine whether they predict changes in bone metabolism during SRI treatment.