Significant Genotypic Association Research Articles

AA genotype of cyclin D1 G870A polymorphism increases breast cancer risk: Findings of a case-control study and meta-analysis.

Cyclin D1 (CCND1) polymorphisms, a regulator of the cell cycle progress from G1 to the S phase, may lead to uncontrolled cell proliferation and lack of apoptosis. G870A, a common single-nucleotide polymorphism in CCND1 influences breast cancer risk. However, the association between G870A polymorphism and breast cancer risk is ambiguous so far. In this case-control study, we analyzed the role of G870A polymorphism with breast cancer risk in Indian women. A meta-analysis of 18 studies was also performed to elucidate this association by increasing statistical power. In our case-control study, significant risk association of the CCND1 G870A AA genotype with breast cancer in total cohort (odds ratio [OR], 2.98; 95% confidence interval [CI], 1.64-5.42; P value, 4.96e-04) and premenopausal women (OR, 3.31; 95% CI, 1.54-7.08; P value, .003) was found. The results of the meta-analysis showed that AA genotype of the CCND1 G870A polymorphism significantly increases breast cancer risk in total pooled data (AA vs GG+GA: OR = 1.20; 95% CI = 1.03 to 1.39; P value, 0.016*) and Caucasian (AA vs GG+GA: OR = 1.22; 95% CI = 0.99 to 1.51; P value, .056*) but not in Asian population. Further, a significant protective association with breast cancer was also found in the GA vs AA comparison model in pooled data (OR = 0.73; 95% CI = 0.58 to 0.92; P value, .007*) as well as in Caucasian subgroup (OR = 0.62; 95% CI = 0.49 to 0.94; P value, .022*). CCND1 G870A AA genotype was found associated with breast cancer risk. Future association studies considering the environmental impact on gene expression are required to validate/explore this association.

ICAM1 gene polymorphism in late-onset Alzheimer’s disease

Intercellular Adhesion Molecule-1 (ICAM-1) is a cell surface glycoprotein with possible involvement in the pathogenesis of Alzheimer’s disease (AD). Therefore, sequence variations in the ICAM1 gene affecting ICAM-1 structure or expression level may play a role in the genetic susceptibility to AD. The aim of the current study was to examine the potential associations of two functional ICAM1 gene polymorphisms rs1799969 and rs5498 with the risk of AD development. 123 unrelated AD subjects (mean age 79.5 ± 6.0 years) and 265 controls (mean age 73.2 ± 9.4 years) of Slovak origin were involved in the study. Genotyping of ICAM1 rs1799969 and rs5498 SNPs was performed by PCR-RFLP. The APOEe4 allele carriage status as the major known risk factor for AD development was determined by direct sequencing. Possible association of ICAM1 gene variants with AD risk was evaluated by logistic regression analysis. Our study revealed no statistically significant association of ICAM1 rs1799969 and rs5498 polymorphisms with risk of AD development. Stratification of study groups according to their APOEe4 carriage status showed only moderate changes. Analysis of influence of ICAM1 genotypes on clinical findings such as age at disease onset and degree of cognitive impairment in AD patients showed modest, but significant association of the rs5498 AA genotype with higher severity of cognitive decline. In conclusion, our findings do not support the role of ICAM1 polymorphism as an independent genetic factor for Alzheimer’s disease susceptibility.

Additive Genetic Effects of RNF4, RBP4, and IGF2 Polymorphisms on Litter Size in Landrace and Yorkshire Sows

The association of the RNF4, RBP4, and IGF2 genotypes and their additive genetic effects with litter size in purebred Landrace and Yorkshire sows were studied. The results revealed significant associations between the RNF4 and RBP4 genotypes with the total number of piglets born (TNB) and number of piglets born alive (NBA) traits (P <0.05). The RNF4 CC genotype had greater TNB and NBA than the TT genotype in both breeds. The RBP4 BB genotype had greater TNB and NBA than the AA genotype in the Landrace breed. Significant additive effects of the RNF4 and RBP4 genes on the TNB and NBA were detected (P <0.05). No significant associations of the IGF2 genotypes and their additive effects with any reproductive traits were observed in both Landrace and Yorkshire sows (P >0.05). The results suggested that the RNF4 and RBP4 genes could be useful in selection for increasing TNB and NBA traits in pigs.

Local and regional scale habitat heterogeneity contribute to genetic adaptation in a commercially important marine mollusc (Haliotis rubra) from southeastern Australia.

Characterising adaptive genetic divergence among conspecific populations is often achieved by studying genetic variation across defined environmental gradients. In marine systems this is challenging due to a paucity of information on habitat heterogeneity at local and regional scales and a dependency on sampling regimes that are typically limited to broad longitudinal and latitudinal environmental gradients. As a result, the spatial scales at which selection processes operate and the environmental factors that contribute to genetic adaptation in marine systems are likely to be unclear. In this study we explore patterns of adaptive genetic structuring in a commercially- harvested abalone species (Haliotis rubra) from southeastern Australia, using a panel of genome-wide SNP markers (5,239 SNPs), and a sampling regime informed by marine LiDAR bathymetric imagery and 20-year hindcasted oceanographic models. Despite a lack of overall genetic structure across the sampling distribution, significant genotype associations with heterogeneous habitat features were observed at local and regional spatial scales, including associations with wave energy, ocean current, sea surface temperature, and geology. These findings provide insights into the potential resilience of the species to changing marine climates and the role of migration and selection on recruitment processes, with implications for conservation and fisheries management. This study points to the spatial scales at which selection processes operate in marine systems and highlights the benefits of geospatially-informed sampling regimes for overcoming limitations associated with marine population genomic research.

Association of TNF-α gene alterations (c.-238G>A, c.-308G>A, c.-857C>T, c.-863C>A) with primary glaucoma in north Indian cohort

BackgroundTumor Necrosis Factor-alpha (TNF-α) a pleuripotent pro-inflammatory cytokine, is involved in retinal ganglion cells apoptosis in glaucoma. Thus present study aimed to analyze the association of TNF-α promoter region alterations (c.-238G>A (rs361525), c.-308G>A (rs1800629), c.-857C>T (rs1799724) and c.-863C>A (rs1800630)) with glaucoma in north Indian cohort. MethodsPresent hospital based case control study involved 286 glaucoma patients (Primary Open Angle Glaucoma [POAG], Primary Angle Closure Glaucoma [PACG], Primary Congenital Glaucoma [PCG]) and 300 controls. TNF-α gene alteration (c.-238G>A (also referred as c.-418G>A; NM_000594.3)), c.-308G>A (c.-488G>A; NM_000594.3), c.-857C>T (c.-1037C>T; NM_000594.3) and c.-863C>A (c.-1043C>A; NM_000594.3) harboring regions were PCR amplified and sequenced by Sanger sequencing. Allele frequency and genotype distribution in glaucoma cases and controls were compared using chi-square test and genetic association tested using different genetic models. ResultsStatistically significant genotype and allelic association was observed between glaucoma cases and controls for c.-308G>A and c.-863C>A alterations (p = 0.001, p = 0.001; p = 0.001, p = 0.001 respectively). AA genotype of c.-308G>A conferred ~7 fold increased risk towards glaucoma (OR = 6.82, 95% CI = 2.82–16.53, p = 0.001). c.-863C>A alteration under dominant, recessive and co-dominant genetic models conferred ~2 fold increased risk for glaucoma. However, no association for c.-238G>A and c.-857C>T variants with glaucoma was observed. Further, three haplotypes (GGCA, GACC and GACA) (OR = 0.48, 95% CI = 0.35–0.67, p = 0.001; OR = 0.58, 95% CI = 0.36–0.91, p = 0.019 and OR = 0.16, 95% CI = 0.05–0.51, p = 0.002, respectively) conferred protective role towards glaucoma. ConclusionsPresent study is the first to indicate significant association of c.-308G>A and c.-863C>A alterations with glaucoma in cases from north Indian cohort. Also it is the first study from India to analyze the association and interaction of four promoter region alterations (c.-238G>A, c.-308G>A, c.-857C>T and c.-863C>A) in TNF-α resulting in three protective haplotypes.

Phenotypic variability, path analysis and molecular diversity analysis in chickpea (Cicer arietinum L.)

The existence and degree of genetic variability and its documentation in a gene-pool is obligatory in plant breeding. Along with variability, the comprehension of genetic parameters is indispensible for understanding and its administration during crop improvement. With this opinion, 12 phenotypic traits, one biochemical parameter and 23 microsatellite markers were used to examine the genetic variability in 58 chickpea genotypes. With immense heritability (> 60.20%), the genotypes exhibited lavish variability for most of the traits. Secondary branches per plant, pods per plant, seeds per pod, seeds per plant, hundred seed weight, seed yield per plant and harvest index demonstrated a high PCV than GCV. Seed yield per plant illustrated a significant genotypic level association with pods per plant (0.728**), seeds per plant (0.648**), 100 seed weight (0.338**) and harvest index (0.683**). Pods per plant (0.198), seeds per plant (0.672), harvest index (0.170) and 100 seed weight (0.665) showed significant direct effect on seed yield per plant during path analysis. Manhattan distance produced seven clusters, at cut-off value of 0.15, during phenotypic based clustering. Microsatellite markers amplified 296 loci. The polymorphic information content confined between 0.32 (TR3) − 0.93 (CAM0443) with an average of 0.83. The DNA marker based clustering generated three discrete clusters. Faint correlation (0.097) was found between the Manhattan’s and Nei’s distance. The outcomes of the current experiment advocated that both phenotypic as well as DNA markers should be practiced jointly to arrest the true genetic diversity and to reap heterosis during hybridization.

GENETIC SUSCEPTIBILITY OF TRANSCRIPTION FACTOR 7-LIKE 2 GENE VARIANT AND RISK OF TYPE 2 DIABETES IN ASIAN INDIANS

Background: The variants of transcription factor 7-like 2 (TCF7L2) gene have been shown to be associated with type 2 diabetes mellitus (T2DM) and its related complications.
 Objectives: We aimed to explore the possible association of rs7903146 (C/T) variant in TCF7L2 with the risk of T2DM in the North Indian population.
 Methods: The present case–control study included a total of 638 human subjects (318 T2DM subjects and 320 healthy controls). Various anthropometric, biochemical, and genetic parameters were studies in all the subjects. Genotyping of TCF7L2 gene was carried out using allele-specific polymerase chain reaction method.
 Results: The results of this study indicate significantly higher values of body mass index, waist circumference, waist-to-hip ratio, and body fat (%) in T2DM subjects than controls (p≤0.001). Dyslipidemia represented by higher levels of triglycerides and reduced values of high-density lipoprotein was more predominant in diabetic subjects compared to healthy subjects. The frequency of risk genotype (TT) frequency was significantly higher in T2DM subjects (16.4%) compared to controls (11.6%). The “T” allele was more dominant in diabetic subjects than controls. Logistic regression analysis of the data revealed a significant association of TT genotype with 2-fold (odds ratio with 95% of confidence interval; 2.09 [1.29–3.42] p=0.003) and CT genotype with 1.7-fold (1.73 [1.23–2.44] p=0.002) increased risk of developing T2DM.
 Conclusions: The present study demonstrated a significant association of rs7903146 (C/T) variant in TCF7L2 with the augmented risk of T2DM in North Indian population.

Association of rs10490924 in ARMS2/HTRA1 with age-related macular degeneration in the Pakistani population.

Age-related macular degeneration (AMD) is a disease of the elderly in which central vision is lost because of degenerative changes of the macula. The current study investigated the association of single-nucleotide polymorphisms (SNPs) with AMD in the Pakistani population. Four SNPs were analyzed in this study: rs1061170 in the CFH, rs429608 near CFB, rs2230199 in the C3, and rs10490924 in ARMS2/HTRA1. This case-control association study was conducted on 300 AMD patients (125 wet AMD and 175 dry AMD) and 200 unaffected age- and gender-matched control individuals. The association of the SNP genotypes and allele frequency distributions were compared between patients and healthy controls, keeping age, gender, and smoking status as covariates. A significant genotype and variant allele association was found of rs10490924 in ARMS2/HTRA1 with wet AMD, while the SNPs in CFH, CFB, and C3 were not associated with AMD in the current Pakistani cohort. The lack of association of CFH, CFB, and C3 may be attributed to limited sample size. This study demonstrates that genetic causative factors of AMD differ among populations and supports the need for genetic association studies among cohorts from various populations to increase our global understanding of the disease pathogenesis.

Nodulation pattern and its association with seed yield in chickpea (Cicer arietinum L.) germplasms

The present research was designed to ascertain some new high yielding chickpea germplasms with associated desirable nodulation pattern. Evaluation of sixty chickpea germplasms collected from different sources were assessed at Calcutta University’s experimental farm during rabi season for four consecutive years from which twenty five were selected as high yielding germplasms. These high yielding germplasms were chosen to evaluate the nodulation pattern at various physiological stages under field conditions. In all three physiological stages, highly significant differences were observed for the traits like the number of nodules plant-1, nodule fresh weight, nodule dry weight and seed yield plant-1 except nodule size. Positive and significant genotypic associations were found between numbers of nodule plant-1, nodule fresh weight, nodule dry weight with seed yield plant-1. Digbijoy, CUSL4 and CUML4 could be considered as worthy resources in future due to high nodulation pattern and presence of active nitrogenase enzymes at pod initiation stage.

ERAP, KIR and HLA-C gene interaction in susceptibility to recurrent spontaneous abortion in the Polish population

Endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to generate stable antigenic epitopes for their presentation by HLA class I (HLA-I) molecules to T cell receptor. By influencing the peptide repertoire of HLA-I molecules, they affect also the interactions of HLA-I with killer cell immunoglobulin-like receptors (KIRs) of natural killer (NK) cells. HLA-C is the only polymorphic HLA-I molecule present on the trophoblast.In this study we investigated the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in women suffering from recurrent spontaneous abortion (RSA) in the Polish population. We used TaqMan genotyping assays for ERAP1 rs27044, rs30187, rs2287987, rs26618, rs2665 and ERAP2 rs2248374; PCR-SSP methods for KIR and HLA-C genotyping. We tested 285 women who experienced recurrent spontaneous abortion (RSA) and 319 fertile women.We observed a significant association of ERAP1 rs30187TT genotype with RSA (p = 0.02, OR = 1.89, 95%CI = 1.11–3.21), however the most striking association was found in comparison of patients and controls with ERAP1 rs30187TT and KIR Bx genotypes (p = 0.006, pcorr. = 0.036, OR = 2.40, 95%CI = 1.27–4.52). Moreover, this effect was even stronger in HLA-C2 positive patients (p = 0.0031, pcorr. = 0.019, OR = 3.46, 95%CI = 1.48–8.11). Other weaker associations of the remaining tested ERAP single nucleotide polymorphisms with RSA were also presented.In conclusion, ERAP1 rs30187TT genotype itself increased susceptibility to RSA but this effect was much stronger in patients positive for HLA-C2 and KIR Bx genotypes.

Pemberian Anti-Myostatin pada Induk Serta Keragaman Gen Myostatin dan Asosiasinya terhadap Potongan Karkas Anak Ayam Sentul (F1)

Myostatin (MSTN), a member of the transforming growth factor β (TGF-β) superfamily, is a negative regulator of skeletal muscle growth. Improving muscle growth is very important to increase the economic value of Indonesian indigenous chicken especially in sentul chicken. This study was aimed to identify the polymorphism of the Myostatin gene in sentul indonesian indigenous chicken with maternal immunization against Myostatin on post hatch and to evaluate its effect on carcass traits. In this study, 48 Sentul hens for up to 6 months have been divided into three groups with 16 birds in each group: CON, KLH, and KLH-MSTN. The CON group has not received immunization, the KLH group has been immunized with 1 mg of KLH, and KLH-MSTN has been immunized with 1 mg of KLH-MSTN conjugate intramuscularly. The effects of each group have been observed on F1 carcass production.The gene polymorphism was identified using PCR-RFLP and the effect of genotype on carcass chacteristics were analyzed using SAS General Linear Model Procedure. The product of amplification was 247 bp. This locus was polymorphic in sentul chicken with two alleles (G and T) and three genotypes (GG, GT, TT). Association analysis were not significant in carcass characteristics. The result of this study showed that interaction of each group with genotype not significant on carcass weight of F1 chicken sentul each age group. F1 sentul chicken 12 week-old significant association of genotype was observed only in thighs weight while 20 week-old was significant in live weight, carcass weight, breast weight, wings weight, thighs weight, drum sticks weight, breast muscle weight, thighs muscle weight and drum sticks muscle weight. These results suggest that no effect genotype on maternal immunization against myostatin to stimulate carcass characteristic in sentul chickens.

The Association of CEP135 rs4865047 and NPY2R rs1902491 Single Nucleotide Polymorphisms (SNPs) with Rapid Progression of Proliferative Diabetic Retinopathy in Patients with Type 1 Diabetes Mellitus

BackgroundDiabetic retinopathy has a varied prevalence, severity, and rate of progression. The aim of this study was to determine whether the single nucleotide polymorphisms (SNPs) of the gene encoding a 135-kD centrosomal protein CEP135 rs4865047 and the gene encoding the type 2 NPY protein NPY2R rs1902491 were associated with the development of rapidly progressive proliferative diabetic retinopathy in patients with type 1 diabetes mellitus.Material/MethodsPatients with rapidly progressive proliferative diabetic retinopathy (n=48) were included in the study group. The control group (n=84) consisted of diabetes mellitus patients who had no proliferative diabetic retinopathy up to 15 years of diabetes duration. The reference group (n=90) included non-diabetic individuals who matched the study group by age and gender. The SNPs in the three groups were analyzed using real-time polymerase chain reaction (PCR) amplification.ResultsThe analysis of the distribution of genotypes in CEP135 rs4865047 and NPY2R rs1902491 detected significant differences only in the single nucleotide polymorphism rs4865047 genotype between the case and control group in comparison to the reference group. The co-dominant model showed that CEP135 rs4865047 was significantly associated with patients with rapidly progressive proliferative diabetic retinopathy (OR 7.2, 95% CI, 2.28–22.74, p=0.001). No significant association was found for the NPY2R SNP rs1902491 genotype.ConclusionsOur study reports a significant association of the CEP135 single nucleotide polymorphism rs4865047 genotype with rapidly progressive proliferative diabetic retinopathy and the control group. No significant association was found of the NPY2R single nucleotide polymorphism rs1902491 genotype.

Identification of the Genetic Variant Responsible for Variable Platelet CD36 Expression By Massively Parallel Reporter Assay

CD36 is a platelet membrane glycoprotein whose engagement with oxidized low density lipoprotein (oxLDL) results in platelet activation. Deletion of CD36 in mice fed a high fat diet results in attenuation of the pro-thrombotic state and platelet hyper-activity. The CD36 gene has been associated with platelet count, platelet volume, as well as lipid levels and CVD risk. Platelet CD36 expression is highly variable with 3-8% of non-white populations displaying a complete lack of expression. Platelet CD36 expression levels have been shown to be associated with both the platelet oxLDL response and an elevated risk of thrombo-embolism. Several genomic variants have been identified as associated with platelet CD36 levels, however none have been conclusively demonstrated to be causative.We have previously reported platelet expression Quantitative Trait Loci (eQTLs) that associate single nucleotide polymorphisms (SNPs) with platelet RNA levels, indicating genetic influence on gene expression. CD36 is one of the 612 platelet-expressed RNAs whose abundance has significant genotypic associations, suggesting a mechanism by which CD36 level is regulated. 86 eQTL SNPs located within a +/- 100kb window of the CD36 gene are associated with platelet CD36 mRNA levels at a significance of P<1x10-6, spanning a range of 125kb. Rather than prioritizing these 86 variants for functional testing based on genomic annotation, we opted to use an approach termed a Massively Parallel Reporter Array (MPRA), in which all 86 SNPs were tested simultaneously. A library of plasmids was generated in which both alleles of the variants including 150bp of surrounding genomic context were cloned 5' to a minimal promoter and unique barcode. For statistical robustness, 40 barcodes were constructed per allele, resulting in a library containing a total of ~5000 plasmids that were generated and transfected into K562 erythroleukemia cells. RNA-Seq was then conducted on the transfected cells and the abundance of individual barcodes was quantified, normalized to the DNA plasmid library, and then compared across variant alleles.The MPRA analysis led to identification of 5 SNPs located within a 35kb region 5‘ to the CD36 transcription start site that had significantly different barcode production between alleles. These 5 SNPs are in linkage disequilibrium with one another, with variants reported to be associated with CD36 level, and with variants reported to be associated with platelet count and volume by GWAS. To verify the functionality of these variants, we conducted luciferase assays in which the genomic sequence surrounding the variants were inserted 5‘ to the reporter gene. The genomic fragment containing the alternate alleles of two of these SNPs, rs2366739 and rs1194196, located within 29bp of each other, demonstrated 25-40% lower transcriptional activity than the reference alleles. Next, to determine if these two variants altered the interaction of DNA-binding proteins with the locus, we conducted electromobility-shift assays (EMSA) using probes derived from both alleles of the genomic sequence. As with the MPRA and luciferase assays, the alternative alleles of rs2366739 and rs1194196 resulted in lower levels of DNA:protein complexes, indicating an altered affinity for regulatory complexes. Finally, to further confirm the role of this genomic locus in regulating CD36 expression levels, we deleted a 596bp region containing these two SNPs from the K562 erythroleukemia cell genome using CRISPR/Cas. Deletion of this region resulted in an approximately 10-fold increase in CD36 RNA in these cells, confirming a role for this loci in the regulation of CD36 expression.These data indicate that we have identified a regulatory locus for CD36 expression, which has important implications for platelet function in cardiovascular disease. These variants are located within a retrotransposon long-terminal repeat and alter a putative GATA1 binding site, suggesting that these variants may alter binding of that transcription factor to the locus. Platelet CD36 expression level has been linked to the platelet response to oxLDL and may modulate the thrombotic response in hyperlipidemic conditions. Therefore, the mechanism described here, in which a genetic variant alters platelet CD36 levels, and thus the platelet response to hyperlipidemic conditions, may serve as an important biomarker for increased thrombotic potential. DisclosuresNo relevant conflicts of interest to declare.

Sex-specific association of a common GNAS polymorphism with self-reported cognitive empathy in healthy volunteers.

BackgroundIn a recent study, we found associations of a common oxytocin receptor (OXTR) polymorphism with inter-individual differences in empathy, especially with emotional empathy in women. Many other studies found specific associations of oxytocin, arginine-vasopressin, serotonin and dopamine receptor gene polymorphisms with various aspects of trait empathy. As all these receptors belong to the guanine-binding protein (G protein) coupled receptor family, it is a reasonable assumption, that alterations in genes encoding G protein subunits also influence the signal transduction in empathy related circuits. However, to the best of our knowledge, these genomic variations have not yet been studied in genetic research on empathy.MethodsHere, we analysed associations of a common polymorphism of the GNAS gene (C393T) in a previously characterized sample of 421 healthy blood donors (231 M, 190 F; age 18–74). The GNAS gene encodes the G protein adenylyl cyclase stimulator (Gαs) G protein subunit, which activates cyclic adenosine monophosphate (cAMP)-dependent pathways by stimulating the adenylyl cyclase. Cognitive and emotional aspects of dispositional empathy were tested using Davis’ Interpersonal Reactivity Index (IRI).ResultsIn the complete sample, associations of C393T genotype with IRI empathy scores, including cognitive empathy (p = 0.055) and perspective taking (p = 0.057) scores did not reach a level of significance. None of the IRI scores was near to being significantly associated with C393T genotype for men alone. In females, however, genotype was significantly associated with cognitive empathy (r = -.204, p = 0.005) and perspective taking (r = -.209, p = 0.004), accounting for 4.2% and 4.4% of variability. The association of genotype with perspective taking remained significant after adjustment for multiple comparisons (p = 0.045). The 393C-allele, which had been identified as a risk factor in several medical conditions such as hypertension, obesity and diabetes, was associated with higher cognitive empathy compared to the T allele in our sample.ConclusionsThe results suggest a significant association of GNAS C393T genotypes with the cognitive empathic capacity of perspective taking. This association could only be found in female participants.

Association of genetic polymorphisms in the pore domains of mechano-gated TREK-1 channel with overactive lower urinary tract symptoms in humans.

Mechanosensitivity of the urinary bladder is regulated by many factors including mechano-gated two-pore domain (K2 P, KCNK) potassium channels. TWIK-related K+ channel, TREK-1, is a predominantly expressed member of K2 P channel family in the human detrusor, and its expression and function are diminished in patients with overactive lower urinary tract symptoms (LUTS). The changes in channel activity may result from spontaneously occurring gene mutations. The aim of this study was to compare single nucleotide polymorphisms (SNPs) in TREK-1 channel between patients with LUTS and healthy donors. Six SNPs (rs370266806, rs373919966, rs758937019, rs769301539, rs772497750, and rs775158737) in two pore domains of human TREK-1 gene were analyzed using TaqMan SNP genotyping assay with manufacturer-designed primers and allele-specific probes. The screening was done in control bladders and detrusor specimens from patients with overactive LUTS. Statistical analyses were performed using R, Fisher's exact test and Hardy-Weinberg Equilibrium. Six SNPs in two pore domains of the human TREK-1 gene were analyzed in human bladder specimens. The frequencies of rs758937019-CT genotype (P = 0.0016) and rs758937019-T allele (P = 0.0022) were significantly higher in the group with overactive LUTS. There was no significant association of rs775158737-GA genotype and rs775158737-A allele with the overactive LUTS, though they were present only in the overactive LUTS group. Our results provide evidence that altered expression and function of TREK-1 channel in patients with overactive LUTS could be due to genetic polymorphisms in the pore domains of TREK-1 channel (rs758937019).

Oxytocin and its association with reward-based personality traits: A multilocus genetic profile (MLGP) approach

Oxytocin is an evolutionarily ancient neuropeptide that aids in the regulation of many survival behaviors including affiliation, creativity, and reproduction. The oxytocin system also converges with mesolimbic dopamine pathways and thereby plays a role in reward motivation and hedonic capacity. The present study investigated genetic markers of two oxytocin genes in relation to reward-based personality traits. Since individual polymorphic loci typically contribute only a small proportion of phenotypic variance, we used a MLGP quantitative approach whereby genetic variants are aggregated into composites that reflect a polygenic liability. Eleven single nucleotide polymorphisms (SNPs) on the oxytocin receptor gene (OXTR), and two SNPs on the cluster-of-differentiation 38 gene (CD38) were selected for genotyping. Community-recruited healthy adults (N = 426) participated in the study. Results identified 4 OXTR and 2 CD38 SNPs with a significant genotypic association to the reward-based traits. The MLGP accounted for greater phenotypic variance than any of the SNPs individually. Findings confirm links between the oxytocin system and reward responsiveness —an important relationship in the preservation of evolutionarily significant survival behaviors. Future research would benefit from targeting additional SNPs that influence oxytocin levels in the brain, in order to enhance the predictive utility of the current MLGP.

The Role of Transforming Growth Factor-β1 Gene Polymorphism and Its Serum Levels in Hashimoto's Thyroiditis.

TGF-β1 gene (TGFB1) is one of the target genes involved in genetic predisposition to autoimmune diseases, particularly Hashimoto's thyroiditis (HT). In the present study, we attempted to investigate whether -509C/T SNP (rs1800469) in the promoter of TGFB1 is associated with the genetic susceptibility and clinical characteristics of Bulgarian patients with HT. We also analyzed serum TGF-β1 levels in different stages of the disease and its association with the -509C/T polymorphism in the TGFB1 promoter. The study recruited 121 female out-patients with autoimmune thyroiditis and 250 agematched healthy women (HC). Genotyping of the rs1800469 was performed by restriction fragment length polymorphism (RFLP)-PCR assay. The serum concentrations of latent acid-activated TGF-β1 protein were determined by the quantitative sandwich ELISA method. Upon testing different types of inheritance, a significant risk was found for heterozygotes (CT) with OR=1.640; p=0.05 under the codominant model. The significantly higher risk for developing Hypothyroidism was calculated again for CT-genotype patients with OR=1.789. According to the hormone reference values, a significant association of CT genotype with decreased TSH (75.4%) simultaneously with increased free T4 hormone (94%) levels was also calculated. When patients were stratified by genotype and compared to the same genotype in HC, we observed that the decreased levels in serum TGF-b1 were significant for patients who carried the C-allele in their genotype. We suggest that heterozygous genotype CT is a genetic risk factor for developing more severe HT due to enhanced free T4 serum level at the onset of the disease, before developing the hypothyroid stage.

Highlights From the Circulation Family of Journals

Highlights From the <i>Circulation</i> Family of Journals

Association of Genetic Variants in NF-kB with Susceptibility to Breast Cancer: a Case Control Study.

Insofar as altered NF-κB signaling stemming from the presence of specific genetic variants in NF-κB gene contribute to cancer pathogenesis, this study evaluated the association between NF-κB rs147574894/I552V, rs148626207/M860T rs3774937 and rs1598859 variants and breast cancer and associated features and complications. This was a retrospective case-control study, which involved 207 women with breast cancer, and 214 cancer-free women who served as controls. NF-κB genotyping was done by real-time PCR. Significantly higher rs3774937 minor allele frequencies (MAF), and lower rs147574894 MAF were seen among breast cancer patients, thereby imparting disease susceptibility and protective nature to these variants, respectively. Significant association of rs3774937 and rs147574894 genotypes with breast cancer was seen under the dominant model. Histological type and grade, molecular type, Her2 positivity and ER+/Her2- correlated positively, while distant metastasis negatively correlated with rs3774937. On the other hand, rs147574894 negatively correlated with histological type and grade, tumor size, Her2 positivity, molecular type, and ER+/Her2-, while rs148626207 correlated positively with histological grade, but negatively with distant metastasis and triple-negative status. Breast cancer-susceptible and -protective 4-locus haplotypes were also identified. This is the first report that addresses the contribution of NF-κB variants to the pathogenesis of breast cancer in Middle Eastern-North African population, and the first to document positive association of rs3774937 with breast cancer.

Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia

Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high-activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample.