Minor Allele Homozygotes Research Articles

Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects

Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations. We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, P=1×10-41). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (R2=1.0) linkage disequilibrium with rs9912468 within intron 2 of PRKCA. We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The PRKCA enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations. These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.

IGF1 gene polymorphisms associated with diabetic retinopathy risk in Chinese Han population.

ObjectiveThis study aimed to explore the association of insulin-like growth factor 1 gene (IGF1) polymorphisms with diabetic retinopathy (DR) in a Chinese Han population.MethodsPolymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Genotype frequencies were compared by chi-square test. Odds ratio (OR) with 95% confidence interval (95%CI) was calculated to express the risk intensity of DR. Linkage disequilibrium between IGF1 polymorphisms was analyzed by Haploview. Serum IGF1 concentration was measured by enzyme-linked immunosorbent assays (ELISA) and assessed by student's t test.ResultsAG genotype of rs6218 and TT genotype of rs35767 were significantly associated with the elevated risk of DR (rs6218: OR=1.77, P=0.04; rs35767: OR=2.32, P=0.03) and type II diabetes mellitus (T2DM) (rs6218: OR=1.92, P=0.00. rs35767: OR=2.29, P=0.02). Only T allele of rs35767 significantly increased the risk of DR (OR=1.45, P=0.04), however, rs6218 (OR=1.92, P=0.00), rs35767 (OR=0.02, P=0.02) and rs5742612 (OR=2.21, P=0.04) showed obvious association with T2DM. Haplotypes were only associated with T2DM, but not DR. Minor allele homozygote of rs35767 was obviously correlated with serum IGF1 level.ConclusionIGF1 rs6218 and rs35767 polymorphisms contribute to the risk of DR. IGF1 rs35767 polymorphism may participate in the regulation of serum IGF1 concentration in DR.

Comparison of the role of HHIP SNPs in susceptibility to chronic obstructive pulmonary disease between Chinese Han and Mongolian populations

The contribution of risk alleles to chronic obstructive pulmonary disease (COPD) may vary between populations. This study aimed to investigate the role of single nucleotide polymorphisms (SNPs) in HHIP on COPD susceptibility in the Chinese Mongolian and Han populations from Inner Mongolia autonomous region. In this case-control study, five SNPs in HHIP gene were detected in 700 COPD patients (350 Chinese Han and 350 Chinese Mongolian) and 700 healthy controls (350 Chinese Han and 350 Chinese Mongolian). The genotype, the association with COPD, and the differences between Chinese Han and Mongolian populations were evaluated using the chi-squared (χ2) test, genetic models, and logistic analysis. The minor allele C in SNP rs10519717 was associated with COPD in Mongolian (Odds ration (OR)=1.401, 95% confidence interval (CI): 1.110–1.769, P=0.044); however, not in the Han. The CC genotype in SNP rs10519717 was a risk factor for COPD in Mongolian (OR=2.667, 95% CI: 1.479–4.809, P=0.044); however, the TC genotype in Han played the same role (OR=1.396, 95% CI: 1.018–1.915, P=0.044). The GG genotype in SNP rs13147758 was protective in the Han (OR=0.546, 95% CI: 0.332–0.897, P=0.017). The homozygote of the minor alleles in SNPs rs12504628, rs1828591, and rs13118928 had a protective role in the both of COPD populations. For the minor allele distribution, the differences between the Han and Mongolian were presented only in the case group for rs12504628 (P=0.003), rs13147758 (P=0.002), rs1828591 (P=0.001), and rs13118928 (P=0.002); for the genotypes, differences was presented at the frequency of the minor allele homozygote in rs13147758 (P=0.048), rs10519717 (P=0.027), rs1828591 (P=0.041), and rs13118928 (P=0.044) in Mongolian. Our findings suggested that HHIP rs10519717 might be associated with susceptibility of Mongolian COPD. For the other SNPs, the differences between the two populations were represented by minor allele distribution and frequency of the minor allele homozygotes.

BDNF genotype is associated with hippocampal volume in mild traumatic brain injury.

The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

Study to determine whether SNPs in CYP17A1, ESR1, and TNRC9 loci correlate with increased breast cancer risk and serum 25-OH vitamin D levels.

e13086 Background: Low serum 25-OH vitamin D (25-OH Vit.D) level is associated with a higher risk of breast cancer. Many single nucleotide polymorphisms (SNP) are associated with breast cancer risk, although the mechanisms underlying this association in most cases remain unclear. We attempted to address this issue by determining whether specific SNPs were correlated with breast cancer-associated biomarkers (BM). Methods: We analyzed estrogen receptor (ER)-positive breast cancer patients treated between Jan 2011 and Dec 2014. We measured serum testosterone and 25-OH Vit.D in pre- and post-menopausal women, and also measured estradiol in the latter group. We genotyped 7 individual SNPs both in premenopausal and postmenopausal women. We then looked for correlations between BMs and SNPs in all three genotypes (homozygotes of major alleles, heterozygotes and homozygotes of minor alleles) using the Kruskal-Wallis test. For each SNP locus associated with a trend or significant effect with regard to BM levels, a t-test was then applied to determine which of the two genotypes was responsible for the effect. Results: Four hundred thirteen women were enrolled (163 premenopausal patients, and 250 postmenopausal patients). There was a trend difference between CYP17A1 rs743572 and 25-OH Vit.D (p = 0.0888), ESR1 rs204210 and 25-OH Vit.D (p = 0.0534) in premenopausal women, and a significant difference between TNRC9 rs3803662 and 25-OH Vit.D (p = 0.026) in postmenopausal women. Among premenopausal women, 25-OH Vit.D levels were significantly lower in those with the high-risk rs743572 genotype TC when compared with TT individuals (19.2 +/- 6.7 ng/ml vs 22.9 +/- 8.7 ng/ml; p = 0.0125). Similarly, 25-OH Vit.D was significantly lower in women with the high-risk rs204210 genotype AG when compared with GG individuals (19.1 +/- 6.9 ng/ml vs 21.7 +/- 6.4 ng/ml; p = 0.0219). In postmenopausal women, 25-OH Vit.D was significantly lower in women with the high-risk rs3803662 genotype GG than those with the AA genotype (20.5 +/- 9.2 ng/ml vs 24.4 +/- 8.0 ng/ml; p = 0.0104). Conclusions: Specific SNPs in CYP17A1, ESR1, and TNRC9 genes may modulate breast cancer risk due to their influence on serum 25-OH Vit.D levels.

Interaction effect of PGC-1α rs10517030 variants and energy intake in the risk of type 2 diabetes in middle-aged adults.

PGC-1α is an important regulatory factor for energy and glucose metabolism. Therefore, we investigated whether the PGC-1α genotype (rs10517030 and rs10212638) affects the incidence of type 2 diabetes mellitus (T2DM) and sought to explain the interactions between their variants and nutrient intake on the development of T2DM. Subjects aged 40-65 years of both genders were from the Ansung/Ansan cohorts (8842 adults) in Korea. Associations of PGC-1α variants rs10517030 and rs10212638 with T2DM were analyzed in a dominant genetic model, and were tested for interactions of genotypes and nutrients with T2DM risk. It was adjusted for covariates related to glucose metabolism. Three variants, rs10517030, rs10517032 and rs10212638, were positively associated with T2DM prevalence. Single-nucleotide polymorphisms, rs10517030 and rs10517032, had strong association (r2=0.963). In the glucose tolerance tests, odds ratios (ORs) for serum glucose levels at 120 min were higher for subjects who were in the minor-allele group (minor allele homozygotes and heterozygotes) than for the major-allele group (major allele homozygotes) for rs10517030 variants. Serum insulin levels at 60 min had a lower ORs in the minor-allele group of rs10517030 variants. The interaction between energy intake and PGC-1α rs10517030 variants also affected T2DM risk. PGC-1α minor alleles were linked to T2DM prevalence and homeostasis model assessment estimate of insulin resistance (HOMA-IR) only in the low-energy groups, and HOMA-B was significantly negatively associated with the minor-allele group of PGC-1α rs10517030 variants, only in the low-energy-intake groups. These data suggest that Koreans with the minor alleles of PGC-1α rs10517030, rs10517032 and rs10212638 are at greater risk of T2DM, and that a low-energy diet is more protective against the development of T2DM in subjects with the major alleles of rs10517030 and rs10517032.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

BackgroundPlatelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population.MethodsIn 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus.ResultsOver a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056).ConclusionsIn a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine

Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.

Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene

Background and aimsAnnexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. ResultsThe ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r2 > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10−05). ConclusionsBoth rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.

Obesity-related genetic polymorphisms and adiposity indices in a young Italian population.

Pediatric obesity develops when a complex biological predisposition collides with an obesogenic environment. To further elucidate the role of genetics in obesity onset, we performed a candidate-gene association study in a young and sportive Italian population by testing the association of functional polymorphisms in ACE (rs4646994), FTO (rs9939609), MC4R (rs17782313) and PPARG (rs1801282) genes with body mass index (BMI) and waist-to-height ratio (WHtR). We also tested the combinations of identified risk genotypes and epistatic interactions among them to determine the existence of cumulative effects in predicting the predisposition to gain weight. Our results confirm a significant direct influence of MC4R rs17782313 and PPARG rs1801282 on body composition, that is, minor allele homozygotes showed significantly higher BMI (rs17782313, β = 1.258, P = 0.031; rs1801282, β = 6.689, P = 1.2 × 10-4 ) and WHtR (rs17782313, β = 0.021, P = 0.005; rs1801282, β = 0.069, P = 0.003) values. Moreover, by leveraging multifactor dimensionality reduction and general linear model (GLM) approaches we identified an epistatic interaction between ACE and MC4R, where heterozygosity at ACE rs4646994 seems to protect from the unfavorable predisposition to gain weight given by C/C genotype at MC4R rs17782313 (GLM, P = 0.004). In conclusion, to clarify the role of genetics in multifactorial diseases remains a difficult goal, even for the most investigated polymorphisms and in controlled populations. Further studies on epistasis and gene-gene interaction will help to elucidate this complex scenario. © 2017 IUBMB Life, 69(2):98-105, 2017.

Pharmacogenetic association of MBL2 and CD95 polymorphisms with grade 3 infection following adjuvant therapy for breast cancer with doxorubicin and cyclophosphamide

Life-threatening infection as an adverse reaction to cytotoxic therapy of cancer remains a major problem, potentially limiting efficacy. Administration of colony-stimulation factors benefits only a minority of patients, and improved stratification guidelines are needed to identify those patients likely to benefit.We investigated single nucleotide polymorphisms (SNPs) in two genes related to immune function to identify associations with severe infection following treatment of breast cancer with doxorubicin and cyclophosphamide. CD95 mediates the extrinsic apoptosis pathway in haematopoietic cells and a CD95 promoter SNP (rs2234767) has been shown to result in reduced expression of the receptor. MBL2 activates the classical complement pathway in the presence of pathogens and independently of antibodies. Numerous SNPs have been described including a promoter SNP (rs7096206) which results in decreased expression of the protein.Homozygotes for the CD95 minor allele were more likely to experience a grade 3 infection than heterozygote and homozygote wild-type patients (29%, 3% and 5%, respectively p=0.048). CD95 minor allele homozygotes also had higher basal white blood cell and neutrophil counts compared with wild-type allele carriers, which was sustained throughout therapy. There was an allele-dose association between the MBL2 SNP and grade 3 infection, with 2, 8 and 17% of wild-type homozygotes, heterozygotes and minor allele homozygotes, respectively, experiencing grade 3 infection (p=0.02).These associations demonstrate the utility of a pharmacogenetic approach to identify individuals more likely to acquire a life-threatening infection during chemotherapy. The apparent association with a CD95 SNP and a mild neutrophilia merits further investigation.

IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort.

IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4+ CD25high FOXP3+ Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years. rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95%CI = 1.02-3.08; OR = 1.79, 95%CI = 1.04-3.11) and CD4+ CD25high FOXP3+ Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004; p(LPS) = 0.005; p(U) = 0.001; p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p(rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs. IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.

Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure.

Posttraumatic seizures (PTS) commonly occur following severe traumatic brain injury (sTBI). Risk factors for PTS have been identified, but variability in who develops PTS remains. Excitotoxicity may influence epileptogenesis following sTBI. Glutamate transporters manage glutamate levels and excitatory neurotransmission, and they have been associated with both epilepsy and TBI. Therefore, we aimed to determine if genetic variation in neuronal glutamate transporter genes is associated with accelerated epileptogenesis and increased PTS risk after sTBI. Individuals (N = 253) 18-75 years of age with sTBI were assessed for genetic relationships with PTS. Single nucleotide polymorphisms (SNPs) within SLC1A1 and SLC1A6 were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure rates from injury to 3 years postinjury for SNPs by genotype. Hazard ratios (HRs) were estimated using Cox proportional hazards regression for SNPs significant in Kaplan-Meier analyses adjusting for known PTS risk factors. Thirty-two tagging SNPs were examined (SLC1A1: n = 28, SLC1A6: n = 4). Forty-nine subjects (19.37%) had PTS. Of these, 18 (36.7%) seized within 7 days, and 31 (63.3%) seized between 8 days and 3 years post-TBI. With correction for multiple comparisons, genotypes at SNP rs10974620 (SLC1A1) were significantly associated with time to first seizure across the full 3-year follow-up (seizure rates: 77.1% minor allele homozygotes, 24.8% heterozygotes, 16.6% major allele homozygotes; p = 0.001). When seizure follow-up began day 2 postinjury, genotypes at SNP rs7858819 (SLC1A1) were significantly associated with PTS risk (seizure rates: 52.7% minor allele homozygotes, 11.8% heterozygotes, 21.1% major allele homozygotes; p = 0.002). After adjusting for covariates, we found that rs10974620 remained significant (p = 0.017, minor allele versus major allele homozygotes HR 3.4, 95% confidence interval [CI] 1.3-9.3). rs7858819 also remained significant in adjusted models (p = 0.023, minor allele versus major allele homozygotes HR 3.4, 95%CI 1.1-10.5). Variations within SLC1A1 are associated with risk of epileptogenesis following sTBI. Future studies need to confirm findings, but variation within neuronal glutamate transporter genes may represent a possible pharmaceutical target for PTS prevention and treatment.

No Interaction with Alcohol Consumption, but Independent Effect of C12orf51 (HECTD4) on Type 2 Diabetes Mellitus in Korean Adults Aged 40-69 Years: The KoGES_Ansan and Ansung Study.

Previously, genetic polymorphisms of C12orf51 (HECTD4) (rs2074356 and/or rs11066280) have been shown to be related to alcohol consumption and type 2 diabetes (T2D). This study aimed to prospectively examine whether C12orf51 had an interaction with or independent effect on alcohol consumption and the risk of T2D. The present study included 3,244 men and 3,629 women aged 40 to 69 years who participated in the Korean Genome and Epidemiology Study (KoGES)_Ansan and Ansung Study. Cox proportional hazards models were used to estimate HRs and 95% CIs for T2D. rs2074356 and rs11066280 were associated with the risk of T2D after adjusting for alcohol consumption (rs2074356 for AA: HR = 0.39 and 95% CI = 0.17–0.87 in men, and HR = 0.36 and 95% CI = 0.13–0.96 in women; rs11066280 for AA: HR = 0.44 and 95% CI = 0.23–0.86 in men, and HR = 0.39 and 95% CI = 0.16–0.94 in women). We identified that the association of each variant (rs2074356 and rs11065756) in C12orf51 was nearly unchanged after adjusted for alcohol consumption. Therefore, the association of 2 SNPs in C12orf51 with diabetes may not be mediated by alcohol use. There was no interaction effect between alcohol consumption and the SNPs with T2D. However, even in never-drinkers, minor allele homozygote strongly influenced T2D risk reduction (rs2074356 for AA: HR = 0.35, 95% CI = 0.14–0.90, and p-trend = 0.0035 in men and HR = 0.34, 95% CI = 0.13–0.93, and p-trend = 0.2348 in women; rs11066280 for AA: HR = 0.36, 95% CI = 0.16–0.82, and p-trend = 0.0014 in men and HR = 0.39, 95% CI = 0.16–0.95, and p-trend = 0.3790 in women), while alcohol consumption did not influence the risk of T2D within each genotype. rs2074356 and rs11066280 in or near C12orf51, which is related to alcohol drinking behavior, may longitudinally decrease the risk of T2D, but not through regulation of alcohol consumption.

Association of RAC1 Gene Polymorphisms with Primary End-Stage Renal Disease in Chinese Renal Recipients

Background/ObjectiveRAC1 gene could influence susceptibility to renal failure by altering the activity and expression of Rac1, which is a member of the Rho family of small GTP-binding proteins. In clinical practice, renal transplantation provides the optimal treatment for people with end-stage renal disease (ESRD). The objective of this present study was to determine whether the RAC1 gene polymorphisms were associated with primary ESRD susceptibility in Chinese renal recipients.MethodsSix single nucleotide polymorphisms (SNPs) of RAC1 gene, including rs836488 T>C, rs702482 A>T, rs10951982 G>A, rs702483 A>G, rs6954996 G>A, and rs9374 G>A, were genotyped in 300 renal transplant recipients (cases) and 998 healthy Chinese subjects (controls) by using TaqMan SNP genotyping assay. Allele, genotype, and haplotype frequencies of the six SNPs were compared between cases and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated in logistic regression models to evaluate the associations of the six SNPs with ESRD risk.ResultsThe genotype distributions for the six SNPs in controls were consistent with Hardy-Weinberg equilibrium (P > 0.05). Association analysis revealed that three SNPs were significantly associated with ESRD risk. Positive associations with ESRD risk were found for the rs836488, rs702482, and rs702483 in the co-dominant model (minor allele homozygotes versus major allele homozygotes); specifically, the frequencies of the minor allele homozygotes and the minor allele for the three SNPs were higher in the cases than in the controls. In addition, these three SNPs also had associations with increased ESRD risk under the additive model (P < 0.05), and positive associations were also found for the rs836488 in the dominant model (P < 0.05) and for the rs702483 in the recessive model (P < 0.05). All these associations were independent of confounding factors. The other three SNPs (rs10951982, rs6954996, and rs9374), in all comparison models, were not associated with ESRD risk (P > 0.05). In haplotype analysis, carriers with "C-T-G-G-G-G" haplotype had a significantly higher risk of ESRD compared with the most common haplotype "T-A-G-A-G-G" (P = 0.011, OR = 1.46, 95% CI = 1.09–1.94).ConclusionThis study suggested that polymorphisms of RAC1 gene might influence the susceptibility to ESRD in Chinese Han population. Further studies are necessary to confirm our findings.

Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women.

Sex hormones play important roles in breast cancer (BC) development. This study investigated associations between BC risk and hormone-related gene variants in Chinese women. In a cohort of 336 patients with histopathologically confirmed BC and 390 age-matched controls, we genotyped seven single nucleotide polymorphisms (SNPs) in five hormone-related genes: estrogen receptor-α (ESR1), aromatase (CYP19), catechol-O-methyl transferase (COMT), sex hormone-binding globulin (SHBG), and glutathione S-transferase (GSTP1). Among these seven SNPs, the SNPs in GSTP1 rs1695 [A/G; odds ratio (OR): 1.68; 95% confidence interval (CI): 1.23-2.30] and ESR1 rs2046210 (C/T; OR: 1.39; 95%CI = 1.02-1.91) were associated with an increased risk among heterozygote carriers. Homozygotes of minor alleles of CYP19 rs10046 (CC) were associated with a reduced risk of BC with OR: 0.61 (95%CI = 0.39-0.95). In addition, a stratified analysis by menopausal status indicated that the association of the CYP19 polymorphisms (rs10046 and rs700519) with BC risk was mainly evident in premenopausal women, and the association of CYP19 rs700519 with BC risk was significant in women less than 50 years old. Haplotype analysis identified 15 common haplotypes (>1%). The haplotype TGGGGTC was significantly associated with BC risk compared with the reference haplotype CGAGGTC (OR > 1000, P < 0.0001). Our data demonstrate that these ESR1, GSTP1, and CYP19 polymorphisms are associated with risk of BC, and the risk haplotype TGGGGTC could help to identify populations with high susceptibility to BC in Chinese women.

Associations between single nucleotide polymorphisms in the FAS pathway and acute kidney injury.

IntroductionTo determine whether single nucleotide polymorphisms (SNPs) in FAS and related genes are associated with acute kidney injury (AKI) in patients with acute respiratory distress syndrome (ARDS).MethodsWe studied 401 (Caucasian N = 310 and African-American N = 91) patients aged ≥ 13 years with ALI who enrolled in the Fluid and Catheter Treatment Trial (FACTT) between 2000 and 2005 from 20 North American centers. We genotyped 367 SNPs in 45 genes of the Fas/Fas ligand pathway to identify associations between SNPs in Fas pathway genes and the development of AKI by day 2 after enrollment in FACTT, adapting Acute Kidney Injury Network (AKIN) criteria. Written informed consent was obtained from participants or legally authorized surrogates in the original FACTT study and available to use for secondary analysis.ResultsIn Caucasian patients, we identified associations between two SNPs and the incidence of AKI (stage 1 and above): rs1050851 and rs2233417; both are found within the gene for nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA). For rs1050851 and rs2233417, the odds ratios (ORs) were 2.34 (95 % confidence interval (CI) = 1.58–3.46, p = 1.06 × 10−5, FDR = 0.003) and 2.46 (CI = 1.61–3.76, p = 1.81 × 10−5, FDR = 0.003) for each minor allele, respectively. The associations were stronger still for AKIN stage 2–3 with respective ORs 4.00 (CI = 2.10–7.62, p = 1.05 × 10−5, FDR = 0.003) and 4.03 (CI = 2.09–7.77, p = 1.88 × 10−5, FDR = 0.003) for each minor allele homozygote. We observed no significant association between these SNPs and AKI in the smaller subset of African Americans.ConclusionIn Caucasian patients with ALI, the presence of minor alleles in two SNPs in NFKBIA was strongly associated with the development of AKI.Trial registrationNCT00281268. Registered 20/01/2006.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1084-5) contains supplementary material, which is available to authorized users.

Stromal cell-derived factor-1 rs2297630 polymorphism associated with platelet production and treatment response in Chinese patients with chronic immune thrombocytopenia

Stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in megakaryopoiesis and platelet production. SDF-1 rs2297630 is a functional polymorphism in linkage disequilibrium with other functional variants in SDF-1. This study aimed to investigate the role of SDF-1 rs2297630 in chronic ITP. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. Immature platelet fraction (IPF) was performed using Sysmex XE-2100. Anti-platelet autoantibodies were assayed by enzyme-linked immunosorbent assay. The main characteristics at diagnosis and the outcome of chronic ITP in 201 Chinese patients were retrospectively reviewed. There was no significant difference in either genotype or allelic distribution between ITP patients and the controls (p = 0.114; p = 0.787). However, both heterozygote (GA) and homozygote minor allele (AA) patients had significantly increased megakaryocyte quantity compared to homozygote genotype (GG) patients at diagnosis (p = 0.011). The mean IPF values of GA and AA genotype patients were higher than those observed in the GG genotype patients when platelet counts ≤50 × 109/L at diagnosis (p = 0.007). Patients with GA and AA genotype showed a higher response rate to standard treatments than patients with GG genotype (p < 0.001). In particular, GA and AA genotype patients had a significantly increased chance of responding to steroids, intravenous immunoglobulin (IVIG), and thrombopoietin analogs (p = 0.007; p = 0.029; p = 0.034, respectively). No significant difference was found between anti-platelet antibodies and genotypes (p = 0.296). In summary, the SDF-1 rs2297630 was associated with platelet production and treatment response in Chinese patients with chronic ITP.

Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension.

The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)- rs2802292 , rs2253310 , and rs2802288 -are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set. Replication of rs2802292 with EHT was attempted in Japanese SONIC study subjects and of each SNP in a meta-analysis of genome-wide association studies of BP in individuals of European ancestry. In Americans of Japanese ancestry, women homozygous for the longevity-associated (minor) allele of each FOXO3 SNP had 6mm Hg lower systolic BP and 3mm Hg lower diastolic BP compared with major allele homozygotes (Bonferroni corrected P < 0.05 and >0.05, respectively). Frequencies of minor allele homozygotes were 3.3-3.9% in women with EHT compared with 9.5-9.6% in normotensive women ( P = 0.03-0.04; haplotype analysis P = 0.0002). No association with BP or EHT was evident in males. An association with EHT was seen for the minor allele of rs2802292 in the Japanese SONIC cohort ( P = 0.03), while in European subjects the minor allele of each SNP was associated with higher systolic and diastolic BP. Longevity-associated FOXO3 variants may be associated with lower BP and EHT in Japanese women.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BackgroundIn mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD).ResultsIn 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25–2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16–3.31), 1.87 (1.20–2.91) and 3.16 (1.41–7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %).ConclusionsGenetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0272-2) contains supplementary material, which is available to authorized users.