Number Tandem Repeat Polymorphism Research Articles

Association between Monoamine Oxidase A Polymorphisms and Anger-Related Personality Traits in Korean Women

It has been suggested that polymorphisms in the monoamine oxidase A (MAO-A) gene are associated with aggressive and impulsive behaviors. In the present study, we investigated the association of the MAO-A variable number of tandem repeat polymorphism in the promoter region (MAO-A uVNTR) with anger-related personality traits. Specifically, MAO-A uVNTR polymorphisms were examined for associations with the State-Trait Anger Expression Inventory (STAXI) scores in 211 normal Korean women. All subjects were assessed using the STAXI and genotyped for MAO-A uVNTR status. The scores on the STAXI subscales differed significantly among the MAO-A uVNTR polymorphism genotypes in terms of anger expression-out (AX-Out) scores. Post hoc comparisons revealed significant differences between the 3/3 and 4/4, and between 3/4 and 4/4 polymorphisms. However, no significant difference was observed in other STAXI subscale scores among these genotypes. Subjects with the high-activity MAO-A uVNTR had significantly higher AX-Out scores than subjects with other genotypes. MAO-A uVNTR polymorphisms may contribute in part to the expression of anger. These findings support the hypothesis that this polymorphism in the MAO-A gene may be associated with anger-related personality traits in Korean women.

Characterization of the DGAT1 K232A and Variable Number of Tandem Repeat Polymorphisms in French Dairy Cattle

A quantitative trait locus (QTL) underlying different milk production traits has been identified with a high significance threshold value in the genomic region containing the acylCoA:diacylglycerol acyltransferase (DGAT1) gene, in the 3 main French dairy cattle breeds: French Holstein, Normande, and Montbéliarde. Previous studies have confirmed that the K232A polymorphism in DGAT1 is responsible for a major QTL underlying several milk production traits in Holstein dairy cattle and several other bovine breeds. In this study, we estimate the frequency of the 2 alternative alleles, K and A, of the K232A polymorphism in French Holstein, Normande, and Montbéliarde breeds. Although the K allele segregates in French Holstein and Normande breeds with a similar effect on production traits, the existence of additional mutations contributing to the observed QTL effect is strongly suggested in both breeds by the existence of sires heterozygous at the QTL but homozygous at the K232A polymorphism. One allele at a variable number of tandem repeats (VNTR) locus in the 5′ noncoding region of DGAT1 has been recently proposed as a putative causative variant. In our study, this marker was found to present a high mutation rate of 0.8% per gamete and per generation, making the allele diversity observed compatible with that expected under neutrality. Moreover, among the sires homozygous at the K232A polymorphism, no allele at the VNTR can fully explain their QTL status. Finally, no allele at the VNTR was found to be significantly associated with the fat percentage variation in the 3 breeds simultaneously after correction for the effect of the K232A polymorphism. Therefore, our results suggest the existence of at least one other causative polymorphism not yet described. Because the A allele is nearly fixed in the Montbéliarde breed, this breed represents an interesting model to identify and confirm other mutations that have a strong effect on milk production traits.

Stable serum levels of relaxin throughout the menstrual cycle: a preliminary comparison of women with premenstrual dysphoria and controls

Serum levels of relaxin in 25 women with premenstrual dysphoria and 25 age-matched controls were determined at three time points during the menstrual cycle. At the same time, levels of estradiol, progesterone, 17-beta-OH-progesterone, free testosterone, total testosterone, sex hormone binding hormone, androstenedione, dehydroepiandrosterone sulphate, and 3-alpha-androstanediol glucuronide were determined. Detectable levels of relaxin were found in all women in both the follicular and luteal phase as well as around ovulation, the inter-individual variations being larger than intra-individual differences. The levels of relaxin were not influenced by the fluctuation of the other reproductive hormones. A significant difference between the two groups of women was observed, subjects with premenstrual dysphoria displaying reduced levels of relaxin (p < 0.05) compared to controls. Also, when analysed with respect to a variable number of tandem repeats polymorphism (CT repeats followed by GT repeats) in the promotor region of the relaxin H2 gene, women with premenstrual dysphoria (n = 29) were found to display significantly longer GT repeats than controls (n = 35).

Serotonin transporter gene (5-Htt): Association analysis with temporal lobe epilepsy

Two functional polymorphisms, a 44bp insertion/deletion polymorphism in the 5' regulatory region and a variable number of tandem repeat polymorphisms in the second intron of the serotonin transporter gene (5-HTT), were previously identified and suggested to modulate transcription. The current study was designed to determine the contribution of these polymorphisms in the 5-HTT gene to susceptibility to temporal lobe epilepsy (TLE). Two hundred and seventy six patients with TLE, and 309 age- and sex-matched healthy controls from Calabria (Southern Italy) were studied. Patients and controls were genotyped using the WAVE TM DNA Fragment Analysis System for the insertion/deletion polymorphism in the promoter region (5-HTTLPR), and the GENESCAN TM System for the variable number tandem repeat (VNTR) in the second intron of the 5-HTT gene (5-HTTVNTR). The program UNPHASED was used to compare genotype, allele and haplotype frequencies between cases and controls, including age and gender as covariates in the model. No significant differences between cases and controls were observed for 5-HTTLPR, but a significant association was obtained for the 5-HTTVNTR polymorphism, both modeling genotypes (P-value=0.0145) or alleles (P-value=0.0086). Patients with TLE showed lower frequencies of the 10 repeat at 5-HTTVNTR than the controls (26.2% in patients versus 40.8% in controls). The frequency of homozygous individuals for the 10 allele was observed to be lower among patients than the controls (5.2% of patients were 10/10 versus 18.8% of controls). Haplotype analysis did not increase the evidence for association. These results suggest that the serotonin transporter gene may play a role in the etiology of TLE.

Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels

Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016-4.9 x 10(-5)). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r(2)=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r(2)=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1beta (P=0.03) level and may also be associated with interferon -gamma (P=0.03), alpha-2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.

Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury

Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3' variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI. Sixty-three patients with severe TBI (Glasgow Coma Scale score < or = 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury. Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002). In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.

Interaction between BDNF Val66Met and Dopamine Transporter Gene Variation Influences Anxiety-Related Traits

The involvement in neural plasticity and the mediation of effects of repeated stress exposure and long-term antidepressant treatment on hippocampal neurogenesis supports a critical role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of affective and other stress-related disorders. A previously reported valine to methionine substitution at amino-acid position 66 (BDNF Val66Met) seems to account for memory disturbance and hippocampal dysfunction. In the present study, we evaluated the impact of the BDNF Val66Met polymorphism on individual differences in personality traits in a sample of healthy volunteers in relation to other common gene variants thought to be involved in the pathophysiology of affective disorders, such as the serotonin transporter promoter polymorphism (5-HTTLPR) and a variable number of tandem repeat polymorphism of the dopamine transporter gene (DAT VNTR). Personality traits were assessed using the NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant DAT VNTR-dependent association between NEO-PI-R Neuroticism and the BDNF Val66Met polymorphism. Among individuals with at least one copy of the DAT 9-repeat allele, carriers of the BDNF Met allele exhibited significantly lower Neuroticism scores than noncarriers. This interaction was also observed for TPQ Harm Avoidance, a personality dimension related to Neuroticism. Our results support the notion that allelic variation at the BDNF locus--in interaction with other gene variants--influences anxiety- and depression-related personality traits.

GENETIC STUDY: Dopamine receptor genes (DRD2, DRD3 and DRD4) and gene–gene interactions associated with smoking‐related behaviors

Cigarette smoking, like many addictive behaviors, has a genetic component, and the dopamine D2-like receptor genes (DRD2, DRD3 and DRD4) are candidates for contributing to these behaviors. Phenotypic information concerning smoking-related behaviors from a nationally representative sample of research volunteers was analyzed for association with polymorphisms in these genes. Genotype status at the DRD2 intron 2 simple tandem repeat was related to cigarettes per day (P = 0.035) and heaviness of smoking index (P = 0.049). The presence of the glycine allele at the S9G polymorphism of the DRD3 gene was associated with frequency/quantity measures of smoking [log-transformed time to first cigarette (P = 0.031) and heaviness of smoking index (P = 0.035)]. There was a trend for DRD4 long alleles of the variable number of tandem repeats polymorphism to be associated with reduced severity of three withdrawal symptoms [desire/craving (P = 0.054); anger/irritability (P = 0.10); and trouble sleeping (P = 0.068)]. Interactions between genotypes at all three genes were associated with nervousness (P = 0.020) and trouble sleeping (P = 0.015). An interaction between DRD2 and DRD3 was found for trouble concentrating (P = 0.020). These relationships present possible dopamine-related responses to nicotine that warrant further study.

Monoamine Metabolites Level in CSF is Related to the 5-HTT Gene Polymorphism in Treatment-Resistant Depression

The serotonin (5-hydroxytryptamine) transporter (5-HTT) is considered to affect the pathogenesis of mood disorders. Large number of genetic association studies between 5-HTT functional polymorphisms and vulnerability of mood disorders and therapeutic response to antidepressants has been carried out. We investigated the influence of 5-HTT-linked polymorphic region (5-HTTLPR) and 5-HTT 17 bp variable number of tandem repeat polymorphism (5-HTTVNTR) polymorphisms on concentrations of monoamine metabolites in cerebrospinal fluid (CSF) among treatment-resistant patients with mood disorders. Subjects were 119 Swedish patients with persistent mood disorders and 141 healthy subjects. In 112 of these patients, we measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol in CSF. Genotyping for 5-HTT polymorphisms from genomic DNA was carried out by PCR. There was no significant difference in allele/genotype frequency between patients and healthy subjects. In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p=0.03). Although the 5-HIAA concentration showed a tendency to be higher in short (S) carriers than in non-S carriers of the 5-HTTLPR in patients (p=0.06), when considering patients with major depressive disorder (MDD), the 5-HIAA concentration was significantly higher among S carriers than among non-S carriers (p=0.02). Moreover, the 5-HIAA concentration was higher in S/S subjects compared to long (L)/L (p=0.0001) and L/S (p=0.002) subjects in patients with MDD. Similarly, there was higher HVA concentration in S/S subjects compared to L/L (p=0.002) and L/S subjects (p=0.002). There was no effect of 5-HTTVNTR. Our findings show that the 5-HTTLPR polymorphism affects 5-HIAA and HVA concentrations among treatment-resistant patients with mood disorders.

Association of interleukin-1 genetic polymorphisms with the risk of rheumatoid arthritis in Chinese population

Previous studies suggest that a variable number of tandem repeats polymorphism in the second intron of the interleukin-1 receptor antagonist gene and two single nucleotide polymorphisms at positions -511 and +3954 of the interleukin-1beta (IL-1B) gene are associated with an increased risk of autoimmune diseases. In the present study, we evaluated associations between these genetic factors and an increased risk of rheumatoid arthritis (RA) in a population from Northwest China. A total of 240 patients with RA and 227 healthy controls from Northwest China were investigated using PCR and PCR-restriction fragment length polymorphism. Genotype and allele distributions and haplotype construction were analyzed. The genotype and allele distributions of IL-1B +3954 and IL-1RN polymorphisms were significantly different in RA patients compared to controls (p<0.001 and p<0.001; p=0.028, p=0.023, respectively). Significant differences were also observed between the RA and control groups for the haplotypes IL-1B -511C/+3954C/IL-1RN *1, IL-1B -511C/+3954T/IL-1RN *1 and IL-1B -511T/+3954T/IL-1RN *1 [p=0.017, odds ratio (OR) 0.721, 95% confidence interval (CI) 0.551-0.944; p=0.030, OR 2.111, 95% CI 1.060-4.204; and p=0.029, OR 2.909, 95% CI 1.066-7.902, respectively]. These findings suggest that IL-1B +3954 and IL-1RN genetic polymorphisms are associated with a significantly increased risk of RA in this Chinese population.

Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with myocardial infarction in Tunisian patients

Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) mediates endothelium-dependent vasodilatation and antithrombotic action. Controversial results regarding the association of eNOS gene (NOS3) polymorphisms with myocardial infarction (MI) have been reported. In the present study, we examined a possible association between a 27-base pair (bp) repeat polymorphism in intron 4 of the NOS3 gene and MI in a subgroup of the Tunisian population. A total of 310 Tunisian patients with MI and 250 healthy controls were included in the study. The NOS3 gene intron 4a4b variable number of tandem repeats polymorphism was analyzed by PCR. A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with MI had a frequency of 4.8% for the 4a4a genotype, 33.9% for the 4a4b genotype and 61.3% for the 4b4b genotype. Controls had a frequency of only 1.6% for the 4a4a genotype, 24.4% for the 4a4b genotype and 74.0% for the 4b4b genotype (chi2=11.81, p=0.003). The MI patient group showed a significant higher frequency of the 4a allele compared to controls (0.218 vs. 0.139; chi2=5.81, p=0.01). In the present study, a significant association between the NOS34a/4b gene polymorphism (presence of 4a allele) and MI in the Tunisian population was found.

Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients

Background The VNTR polymorphism in the Dopamine D4 receptor gene ( DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship. Method Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene ( L ≥ 7 [ n = 25], S = < 7 [ n = 52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge. Results The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes. Discussion Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.

Association between obsessive–compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene

Background Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive–compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. Methods The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. Results Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. Conclusions Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD.

Endothelial Nitric Oxide Synthase Polymorphisms and Susceptibility to Hypertension: Genotype Versus Haplotype Analysis

To the Editor: Zintzaras et al reported interesting results of a meta-analysis of all the available studies on the possible association between endothelial NO synthase ( eNOS ) polymorphisms and hypertension.1 They concluded that there is evidence for significant association between the 4b/4a variable number of tandem repeats polymorphism in intron 4 of the eNOS gene and susceptibility to …

Betaine, Dimethyl Sulfoxide, and 7-Deaza-dGTP, a Powerful Mixture for Amplification of GC-Rich DNA Sequences

Currently, polymerase chain reaction is the most used technique in many laboratories for either diagnostic or molecular biology purposes. Despite the large number of DNA sequences that can be easily analyzed, some GC-rich sequences are refractory to amplification due to the formation of secondary intramolecular structures. To overcome this problem, several molecules have been described to improve polymerization. Here we show that a combination of three additives--betaine, dimethyl sulfoxide, and 7-deaza-dGTP--was essential to achieve amplification of DNA sequences of three disease genes showing a GC content ranging from 67 to 79%.

Endothelial Nitric Oxide Synthase Polymorphisms Do Not Influence Pulmonary Artery Systolic Pressure at Altitude

Previous genetic association studies in high-risk subjects have suggested that polymorphisms in the gene encoding endothelial nitric oxide synthase (eNOS) may be associated with susceptibility to high altitude pulmonary edema (HAPE). We aimed to determine whether eNOS polymorphisms influence systolic pulmonary artery pressure measurements (PASP) in healthy trekkers ascending to high altitude. We examined two polymorphisms of the eNOS gene in Caucasian volunteers: Glu298Asp variant and 27-base pair (bp) variable number of tandem repeats polymorphism (27-bp VNTR). In 33 subjects, the relationships between polymorphisms and absolute pulmonary artery systolic pressure measurements (PASP), determined by echocardiography, were assessed at sea level and 1, 3, and 7 days after acute ascent by vehicle transport to 5200 m. As expected, there was a significant rise in pulmonary artery pressure on ascent to high altitude. By contrast, at sea level and at each time point at high altitude, no difference was found in mean PASP according to eNOS polymorphism. We found no association of Glu298Asp and 27-bp VNTR polymorphisms in the eNOS gene with PASP in a population of healthy trekkers at low or high altitude.

No correlation of five gene polymorphisms with periodontal conditions in a Greek population

Various studies have examined possible correlations between a number of cytokine gene polymorphisms and periodontal disease in populations of different origins. The present study sought the correlation between four single-nucleotide polymorphisms (IL1A+3954, IL1B+4845, TNFA-308, COL1A1 Sp1), a variable number of tandem repeats polymorphism (IL1RN intron 2) and periodontal conditions in subjects of Greek origin. One hundred and ninety-two healthy subjects, stratified as non-periodontitis and periodontitis (chronic and aggressive) cases, participated in the present study. Genotyping was performed by polymerase chain reaction-based techniques using the primers and conditions described in the literature. The frequencies of genotypes between study groups were compared using Genepop v3.3 genetic software and Instat statistical package. No differences were observed among the groups concerning the distributions of genotypes under investigation. Carriage rates of the polymorphisms under investigation in systemically healthy subjects of Greek origin are well within the range reported for Caucasians but these polymorphisms cannot discriminate between non-periodontitis and periodontitis (chronic or aggressive) cases.

Personality, Dopamine Receptor D4 Exon III Polymorphisms, and Academic Achievement in Medical Students

This study investigated the relationships between genetic polymorphisms, personality traits, and academic achievement in medical school students. Study subjects were 220 1st-year medical students at Korea University Medical School during two consecutive academic years (2003–2004). Grade-point averages (GPA) during the second semester of the 1st year of the medical school were obtained as a measure of academic achievement. In addition, all participants completed the Temperament and Character Inventory and questionnaires on depression and anxiety. The polymorphisms in exon III of the dopamine D4 receptor (DRD4) were determined using the polymerase chain reaction. Our results revealed that both male and female subjects with a higher GPA may be characterized as having higher persistence and lower novelty seeking traits. In addition, male subjects with high GPA had higher scores in self directedness and female subjects with a higher GPA may be characterized as having higher scores in harm avoidance. Male students with 4-repeat alleles had a significantly lower GPA than male students without 4-repeat alleles.This relationship also remained after controlling for the personality variables, none of which showed a relationship with the polymorphism after Bonferroni correction. For females, however, no associations could be found between GPA and the polymorphism. Thus, the present study demonstrated for the first time a possible influence of the DRD4 48 bp variable number of tandem repeats polymorphism on academic achievement and proved that this was not mediated by performance-associated personality traits.

Characterization of Human Mucin MUC17: COMPLETE CODING SEQUENCE AND ORGANIZATION

With increasing interest on mucins as diagnostic and therapeutic targets in cancers and other diseases, it is becoming imperative to characterize novel mucins and investigate their biological significance. Here, we present the completed coding sequence and genomic organization of the previously published partial cDNA sequence of MUC17. Rapid amplification of cDNA ends with PCR, sequences from the Human Genome databases, and in vitro transcription/translational assays were used for these analyses. The MUC17 gene is located within a 39-kb DNA fragment between MUC12 and SERPINE1 on chromosome 7 in the region q22.1. The full-length coding sequence of MUC17 transcribes a 14.2-kb mRNA encompassing 13 exons. Alternate splicing generates two variants coding for a membrane-anchored and a secreted form. The canonical variable number of tandem repeats polymorphism of the central tandem repeat domain of the MUC genes is not significantly detected in the MUC17 gene. In addition, we show the overexpression of MUC17 by Western blot and immunohistochemical analyses in pancreatic tumor cell lines and tumor tissues compared with the normal pancreas. The expression of MUC17 is regulated by a 1,146-bp fragment upstream of MUC17 that contains VDR/RXR, GATA, NFkappaB, and Cdx-2 response elements.

An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension

Cold-induced autoinflammatory syndrome 1 (CIAS1) gene is a member of the NALP subfamily of the CATERPILLER protein family that is expressed predominantly in peripheral blood leukocytes, which is to regulate apoptosis or inflammation through the activation of NF-kappaB and caspase. Recent genetic analyses suggested an association between inflammation and oxidative stress-related genes in the development of hypertension. This is the first genetic study indicating an association between the CIAS1 gene and susceptibility to essential hypertension (EH). The frequency of subject with the homozygote of 12 repeat allele was significantly higher in patients with hypertension compared with control subjects (987 cases, 924 controls) (P=0.030; odds ratio=1.24) at a novel VNTR polymorphism of CIAS1 intron 4 loci. We also found that the mean of systolic blood pressure of homozygotes of 12 repeat allele was 6.4 mmHg higher than those of homozygotes of non-12 repeat allele in male random population (P=0.009). The frequency of six SNPs spanning of the CIAS1 gene was not significantly between patients and controls. The real-time PCR analysis showed that among healthy young adults, 12-12 subjects expressed CIAS1 mRNA in peripheral leukocytes significantly more abundantly than homozygote of non-12 repeat alleles subjects (P<0.05). Reporter gene assay of the CIAS1-VNTR in HL60 stimulated by lipopolysaccharides showed that the intronic sequence involving 12 repeat increased the expression of luciferase compared with 9, 7, and 6 repeats. Thus, we propose here the CIAS1 is associated with EH through the dominant expression of transcripts, which may depend on the CIAS1-VNTR genotype.