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PubMed1995

Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism.

Monocytes from different individuals show variable cytokine production in response to a variety of stimuli. We wished to determine the sets of conditions (cytokine combinations) that would enable us to demonstrate stable inter-individual differences in the production of IL-1 alpha, IL-1 beta, IL-1Ra, on-6 and tumour necrosis factor-alpha (TNF-alpha) by monocytes. We assessed the ability of a number of recombinant human cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), TNF-alpha, IL-4, IL-6, transforming growth factor-beta (TGF-beta), IL-10 and IL-1Ra)) to stimulate or inhibit the production of one or more of these monocyte products. GM-CSF was found to stimulate the production of all five of these cytokines in a highly reproducible manner. TNF-alpha also up-regulated production of IL-1 alpha, IL-1 beta, IL-1Ra and IL-6 by monocytes, but the variability in the results of cells cultured from the same individuals on different occasions was greater. Other cytokines either stimulated production of only some of the five cytokine products tested, or stimulated the production of some cytokine products while inhibiting production of others. This was especially evident when cytokines were used in combination with GM-CSF: IFN-gamma down-regulated production of IL-1Ra while up-regulating the production of IL-1 alpha/beta, IL-6 and TNF-alpha, while IL-4 had the exact opposite effect. Polymorphisms in regions of cytokine genes that affect transcription may account for some of the interindividual variation in cytokine production. We have shown that a stable estimate of cytokine production phenotype can be obtained when monocytes collected on at least two separate occasions are stimulated by GM-CSF in vitro. We have looked for a relationship between IL-1 production and an 86-bp variable repeat polymorphism in intron 2 of the IL-1Ra gene. A less common allele of this polymorphism (allele 2) was associated with increased production of IL-1Ra protein, and also reduced production of IL-1 alpha protein by monocytes.

Cells, Cultured↗

PubMed2006

Association of interleukin-1 gene cluster polymorphisms with ischemic stroke in a Chinese population.

BACKGROUND AND AIMS: Chronic inflammatory process plays an important role in atherothrombosis. Interleukin-1 (IL-1) is one of the key modulators of the inflammatory response and its activity is critically regulated by its receptor antagonist (IL-1Ra). A variable number tandem repeat polymorphism in intron 2 of IL-1Ra gene and a C to T single base polymorphism in the promoter of IL-1beta gene (C(-511)-->T) have been reported to affect the levels of IL-1 as well as its antagonist, IL-1Ra. It is also reported in several studies that these polymorphisms are associated with the susceptibility to cardio-cerebral vascular disease. However, data are limited in China. In this article, we studied the relationships between these polymorphisms and the risk of ischemic stroke in China. MATERIALS AND METHODS: One hundred and twelve patients committed ischemic stroke were compared with 95 demographically matched healthy volunteers. RESULTS: The frequencies of the IL-1Ra 1/1 genotype and IL-1Ra allele 1 (Ra*1 allele) in stroke patients were significantly higher than those in healthy volunteers [93.7% vs. 82.1%, P =0.014; 0.964 vs. 0.905, P =0.007]. No significant differences were found in the IL-1beta -511 genotype and the allele distribution between the two groups. CONCLUSIONS: Our results implicated that IL-1 gene polymorphism might be associated with the susceptibility to ischemic stroke.

Aged↗

PubMed2003

Polymorphisms in OPA1 are associated with normal tension glaucoma.

PURPOSE: [corrected] To confirm whether specific polymorphisms in intron 8 (IVS8) of the OPA1 gene are found more commonly in patients with normal tension glaucoma (NTG) compared to normal controls. METHODS: This is a cohort study of 61 patients with NTG, 49 known healthy controls and 119 individuals from the general population. The DNA sequence was determined at the +4 and +32 positions of IVS8 of the OPA1 gene. Hardy-Weinberg equilibrium was confirmed in our population by comparing the allele frequencies in two additional genes, TP53 and TYRP1. Genotypes for the NTG and control groups were compared for statistically significant differences. RESULTS: There were no differences in the OPA1 genotypes of the NTG and control groups at the +4 location, as had been suggested in a previous study, but a significant difference was observed at the +32 location of IVS8. The CC genotype was found in 28% of NTG patients compared to 13% of controls (p=0.006). The TC genotype was more prevalent in the control population (p=0.02) but this difference did not reach statistical significance when the Bonferroni adjustment was made for multiple analyses. CONCLUSIONS: We have refined the previously reported association between OPA1 sequence changes and NTG by identifying a specific CC genotype at position +32 in IVS8 of the OPA1 gene that acts as a marker for NTG. At the current time, NTG is frequently diagnosed late when loss of neurons has already caused significant and irreversible peripheral field loss. If a test could be designed to identify those people at risk of developing NTG, then careful screening might detect earlier signs of disease allowing commencement of treatment before significant field loss has occurred.

Aged↗

PubMed1996

Two additional polymorphisms within the hypervariable MUC1 gene: association of alleles either side of the VNTR region.

The gene MUC1 codes for a mucin-type glycoprotein and like most of the other mucin genes shows variable number tandem repeat (VNTR) polymorphism within the coding region. A polymorphism due to a G/A substitution in exon 2, responsible for a genetically determined variation in splicing of the MUC1 transcript, has also been reported (Ligtenberg et al. 1990, 1991). Here we describe the detection of this nucleotide substitution polymorphism by single stranded conformational analysis of genomic DNA and we also report a CA repeat polymorphism within intron 6 of the gene. Haplotypes were determined in a series of families and the common alleles of these two polymorphisms were found to be associated. These results support the notion that the VNTR polymorphism in the coding sequence of MUC1 is not caused by unequal reciprocal recombination at meiosis.

Base Sequence↗

PubMed1999

The insulin-like growth factor-I (IGF-I) gene in individuals born small for gestational age (SGA).

OBJECTIVE: To investigate the association of genetic variation of the insulin-like growth factor-I (IGF-I) gene with birth size small for gestational age (SGA). SUBJECTS: We have studied a cohort of 120 SGA patients and 147 appropriate for gestational age (AGA) controls from Haguenau, France. METHODS: PCR-SSCP analysis was performed to detect sequence variation in the coding region of the IGF-I gene. Microsatellite markers near the IGF-I gene (intronic and D12S78) were selected and amplified to perform further analysis by association studies. RESULTS: A novel polymorphism in intron 2 was discovered, but allele-specific PCR analysis in the 120 SGA patients and 147 AGA controls found no association between this polymorphism and birth size SGA. Chi squared (chi2) analysis found no statistically significant association between the allele distribution of the microsatellite markers in the SGA subjects and the AGA controls. Power calculations estimate that the D12S78 marker has an 80% chance of detecting a 10-15% difference. CONCLUSIONS: These studies suggest that genetic variation of IGF-I alone does not result in birth size small for gestational age in this population. Thus, if this gene influences fetal size, it plays only a minor role in a multifactorial disorder which involves other genetic and environmental factors.

Case-Control Studies↗

PubMed1998

A tetranucleotide polymorphic microsatellite, located in the first intron of the tyrosine hydroxylase gene, acts as a transcription regulatory element in vitro.

The polymorphic HUMTH01 microsatellite, located in the first intron of the tyrosine hydroxylase gene is characterized by a tetranucleotide core motif. The 10 repeat allele of this microsatellite exhibits two sequence variants: an imperfect repeat and a perfect repeat. Here we present evidence that this tetrarepeat is endowed with regulatory properties. Constructions were made linking the 10 repetition alleles to the luciferase reporter gene under the control of a thymidine kinase minimal promoter. In transient transfection experiments in HeLa, PC12 and SK-NSH cell lines these repeated sequences increased the basal transcription up to 9-fold. This effect was independent of the sequence orientation, a feature characteristic of an enhancer element. In electrophoretic mobility shift assays these tetrameric repeated sequences form specific complexes with HeLa cell nuclear extracts. Competition experiments with heterologous sequences suggest that proteins of the Fos-Jun family may be involved in the formation of these complexes, although other unidentified transacting factors bind to these sequences. These results thus implicate the HUMTH01 microsatellite in the regulation of tyrosine hydroxylase gene expression. Tetrarepeated sequences of this type may constitute a new class of regulatory elements.

Alleles↗

PubMed2005

Aromatase gene and osteoporosis: relationship of ten polymorphic loci with bone mineral density.

Aromatase activity appears to be important for bone homeostasis in postmenopausal women. In fact, therapy with aromatase inhibitors is associated with bone loss and fractures. A common biallelic A/G polymorphism in the 3'-untranslated region (UTR) of CYP19-aromatase gene has been associated with differences in gene transcription and the risk of estrogen-responsive tumors. We explored the relationship of such a polymorphism and other 9 polymorphisms situated within or near CYP19 gene with bone mass. The study group comprised 286 postmenopausal women. DNA was isolated from peripheral blood. Biallelic and insertion/deletion polymorphisms were analyzed with exonuclease assays using TaqMan probes. A microsatellite polymorphism in intron 4 was studied by capillary electrophoresis. Bone mineral density (BMD) was determined by DXA. In this cross-sectional study, the postmenopausal decrease in bone mass appeared to be slower in women with AA genotype in the 3'UTR, than in those with AG or GG genotypes. Consequently, there were significant genotype-related differences in BMD. In women after age of 60, hip T-scores were: AA -1.3 +/- 0.1, AG -1.3 +/- 0.2, GG -1.9 +/- 0.1 (P = 0.002). Lumbar spine T-scores were: AA -1.9 +/- 10.2, AG -2.2 +/- 0.1, GG -3.0 +/- 0.2 (P = 0.001). Moreover, GG genotype showed a trend for lower free estrogen levels. This polymorphism was strongly linked to a tetranucleotide repeat in intron 4, as well as to other biallelic polymorphisms situated between 3'UTR and I.2 promoter regions. They all were associated with BMD. However, biallelic polymorphisms in the extreme 5' region of CYP19 and two polymorphisms in neighbor genes were not associated with BMD. In conclusion, common variations of CYP19-aromatase are associated with differences in BMD that seem to be important from an individual as well as from a population perspective.

Aromatase↗

PubMedDate not supplied

The role of angiotensin-converting enzyme polymorphism in congestive heart failure.

Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase, with primary known functions of converting angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II and inactivating bradykinin. There is high variability among individuals in ACE concentrations, mainly due to the presence of a genetic polymorphism. The ACE gene has, in fact, insertion/deletion polymorphism in intron 16, consisting of a 287-base pair Alu repeat sequence, with three genotypes: insertion polymorphism, insertion/deletion polymorphism, and deletion polymorphism. The genetic effect accounts for 47% of the total variance of serum ACE. The determination of this polymorphism has allowed researchers to study the implications of the ACE gene in many case-control studies of cardiovascular disease, including myocardial infarction and hypertrophic and dilated cardiomyopathy. We review the current knowledge about the ACE gene polymorphism and its implications in heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Interpretation of the results of studies about the role of this polymorphism are controversial. The repetition of epidemio-genetic studies and the creation of adequate experimental studies will help to definitively establish the pathogenetic role of the permanent increase in ACE expression associated with the deletion polymorphism genotype.

Heart Failure↗

PubMed2000

Genetic analysis of the atrial natriuretic peptide gene in essential hypertension.

Atrial natriuretic peptide (ANP) plays an important role in the regulation of blood pressure through sodium-water homoeostasis. Accordingly, several investigators have raised the question of whether the gene encoding ANP is involved in the aetiology of essential hypertension or related phenotypes such as salt sensitivity. Most of the studies have used anonymous polymorphic markers of the gene, and made inconclusive claims about the disease relevance of ANP. Therefore, in order to find sequence variations with potential functional significance and to characterize the pattern of linkage disequilibrium between polymorphisms, we screened a 3368-bp genomic fragment of ANP. Subsequently we tested the association of detected polymorphisms with plasma ANP levels and with hypertension status. Two new polymorphisms were identified, in the 5'-untranslated region and exon 1 respectively, as well as three previously reported polymorphisms in intron 2 and exon 3. When analysed in 102 healthy normotensive subjects, none of the polymorphisms appeared to significantly affect plasma ANP levels. A case-control study in a Japanese population (255 hypertensive and 225 normotensive individuals) revealed a marginally significant association (P=0.026) between an ANP polymorphism located in the 5'-untranslated region (C-664G) and hypertension, but no association for the other polymorphisms. Each of the uncommon variants has an allele frequency of less than 10% in Japanese people, which may have hampered our detection of a significant association between ANP variants and hypertension status (and plasma ANP levels). The pathophysiological relevance of ANP, however, needs to be further defined in relation to hypertension-associated phenotypes, and also should be examined in different ethnic groups.

Aged↗

PubMed2004

The role of a common TNNT2 polymorphism in cardiac hypertrophy.

We found a five-basepair insertion/deletion polymorphism in intron 3 of TNNT2, one of the genes responsible for hypertrophic cardiomyopathy. These five bases may be part of an intronic polypyrimidine tract sequence that may affect splicing. The purpose of the study was to examine the association of the polymorphism with cardiac hypertrophy. The study population consisted of 151 subjects with prominent concentric left ventricular hypertrophy, and 987 healthy subjects recruited from medical checkups (control population). The deletion/deletion genotype tended to be associated with a larger left ventricular mass/height ratio in the HCM population ( p<0.0001). Multiple regression analyses indicated that the left ventricular mass/height ratio was determined ( p<0.0001, R=0.738) by the TNNT2 genotype. Moreover, the frequency of the deletion allele was significantly higher in the hypertrophy population than in the control population ( p<0.0001). In vitro expression study revealed the deletion allele significantly affected the mRNA expression pattern by skipping exon 4 during splicing. In conclusion, TNNT2 deletion allele could be associated with a predisposition to prominent left ventricular hypertrophy.

Aged↗

PubMed2003

Endothelial nitric oxide synthase gene polymorphisms in giant cell arteritis.

OBJECTIVE: To examine potential associations of the Glu/Asp(298) polymorphism in exon 7 and the 4a/b polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of giant cell arteritis (GCA), particularly in patients with versus those without ischemic complications. METHODS: Ninety-one consecutive patients with biopsy-proven GCA, who were residents of Reggio Emilia, Italy, and 133 population-based controls from the same geographic area were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for eNOS polymorphisms in exon 7 and intron 4. The patients were separated into 2 subgroups according to the presence or absence of ischemic complications (visual loss and/or jaw claudication and/or aortic arch syndrome). RESULTS: The distribution of the Glu/Asp(298) genotype differed significantly between GCA patients and controls (corrected P [P(corr)] = 0.003). Carriers of the Asp(298) allele (Asp/Asp or Glu/Asp) were significantly more frequent among the GCA patients than among the controls (P(corr) = 0.0002, odds ratio 3.3, 95% confidence interval 1.7-6.3). The distribution of the 4a/b genotype was similar in GCA patients and controls. No significant associations were found when GCA patients with and without ischemic complications were compared. CONCLUSION: Our findings show that the Glu/Asp(298) polymorphism of the eNOS gene is associated with GCA susceptibility.

Aged↗

PubMed2001

Genomic growth hormone gene polymorphisms in native Chinese chickens.

Chicken growth hormone (cGH), a polypeptide hormone synthesized in and secreted by the pituitary gland, is involved in a wide variety of physiological functions such as growth, body composition, egg production, aging, and reproduction. Chicken growth hormone polymorphisms have been reported to be associated with certain phenotypes. Our objective is to investigate the GH gene polymorphism in selected strains of native Chinese chickens. Yellow Wai Chow GH gene was characterized by sequencing and was found to have one silent substitution, 31 insertions, and other substitutions spread among the introns. In addition, a novel Mspl site has been identified and characterized in the first intron. Allele frequencies of the intron 1 polymorphism were characterized among 28 populations of native Chinese chickens. Thus, polymorphism of the cGH gene may be useful in phylogenetic analysis, as well as in the design of breeding programs.

Alleles↗

PubMed1999

Allelic polymorphism of the interleukin-1 receptor antagonist gene in patients with acute or stable presentation of ischemic heart disease.

BACKGROUND: One of the most potent pro-inflammatory mediators is the early-acting cytokine interleukin (IL)-1, whose actions are regulated by the structurally related IL-1 receptor antagonist (IL-1 Ra). IL-1 Ra is a competitive IL-1 inhibitor and a powerful anti-inflammatory agent. Several autoimmune and inflammatory diseases have been associated with an allelic polymorphism of the IL-1 Ra gene. METHODS: We investigated the frequency of allele 2 of an intron 2 polymorphism of the IL-1 Ra gene in 115 consecutive patients with ischemic heart disease -74 of which had a previous myocardial infarction (48 +/- 11 years), 21 chronic stable angina (54 +/- 10 years), and 20 unstable angina (54 +/- 9 years)--and in 80 healthy controls, matched for age and sex to patients with myocardial infarction (47 +/- 10 years). An 86 base pair variable tandem repeat in intron 2 of the IL-1 Ra gene was determined by a polymerase chain reaction-based method. RESULTS: The frequency of allele 2 was 15% in controls (carriage rate 25%) and 17% in ischemic heart disease patients (carriage rate 28%; p = 0.70). The allele 2 frequency did not differ significantly among the three patient groups. Among patients with myocardial infarction, the allele 2 frequency tended to be higher in patients with myocardial infarction < 40 years compared to those > or = 40 years (20 vs 11%, p = 0.20, OR 1.85, 95% CI 0.70-4.90), and in patients with C-reactive protein levels > or = 3 mg/l compared to those with values < 3 mg/l (31 vs 16%, p = 0.15, OR 2.38, 95% CI 0.64-9.25). CONCLUSIONS: These data do not show a clear-cut association between the allele 2 of this IL-1 Ra gene polymorphism and ischemic heart disease. Among patients with myocardial infarction, the increased allele 2 frequency in those of younger age and with higher levels of C-reactive protein merits further investigation.

Adult↗

PubMed2004

Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS?

OBJECTIVE: Endometriosis is a steroid-dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease. DESIGN: In a case-control study, we examined the PROGINS polymorphism of the progesterone receptor gene in 131 Italian women affected by endometriosis diagnosed according to published criteria for the definition of the definite disease. Control subjects were represented by 127 Italian women without laparoscopic evidence of the disease. MEASUREMENTS: Peripheral blood samples, DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: We found a statistically significant difference in the distribution of PROGINS genotypes between patients with and without endometriosis. The frequency of the PROGINS allele T2 was 17.2% and 11%, respectively, in affected women and in controls [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.0-2.8]. This association was stronger in patients with more severe forms of endometriosis, such as an infiltrating disease or a disease characterized by severe pelvic adhesions (OR 2.4, 95% CI 1.2-4.8; and OR 2.7, 95% CI 1.4-5.3, respectively). Combination of the results from an earlier study and the current data indicates that carrying the allele variant T2 is associated with a twofold increase in the risk of developing endometriosis (OR 2.0, 95% CI 1.3-2.9). CONCLUSIONS: Our results further support the idea that the PROGINS polymorphism of the progesterone receptor may be associated with an increased risk of endometriosis.

Adult↗

PubMed2002

Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease.

OBJECTIVE: To analyze potential associations of Glu-Asp298 polymorphism in exon 7 and 4 a/b polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene with susceptibility for Behçet's disease (BD). METHODS: Seventy-three consecutive Italian patients who satisfied the International Study Group criteria for BD and 135 healthy blood donor controls from the same geographic area were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for eNOS polymorphisms in exon 7 and in intron 4. RESULTS: The distribution of the Glu-Asp298 genotype differed significantly between BD patients and controls (p(corr) = 0.00009). Allele Asp298 was significantly more frequent in BD patients than in controls (p(corr) = 0.0006, OR 2.1, 95% CI 1.5-3.3). The distribution of 4 a/b genotype was similar in patients and controls. CONCLUSION: Our findings show that Glu-Asp298 polymorphism of eNOS gene is associated with BD susceptibility.

Adult↗

PubMed2005

Association of the endothelial nitric oxide synthase (ecNOS) gene polymorphism with carotid atherosclerosis in type 2 diabetes.

This study was done to see whether 27-base pair repeats polymorphism in intron 4 of ecNOS gene is associated with carotid atherosclerosis in type 2 diabetic patients. The polymorphism was identified by polymerase chain reaction (PCR). Ultrasound parameters of carotid atherosclerosis were analyzed in relation to the genotype in 210 patients with type 2 diabetes. The ecNOS4a allele was detected in 34 (16.2%) of this study group. With the exception of the plaque count (P = 0.069), all other parameters obtained by ultrasound examination of carotid arteries were significantly correlated with presence of ecNOS4a allele (P < 0.05). As all the measured carotid parameters correlated well each other, we selected the total mean carotid IMT (intima-media thickness) value to be used for this analysis. In the multivariate analysis including several variables such as age, sex, hypertension, LDL cholesterol, waist-hip ratio, and fasting insulin, all determined to be significant by univariate analysis, ecNOS4a allele had a significant correlation with total mean IMT (P < 0.001). In conclusion, the ecNOS4a allele is associated with carotid atherosclerosis in type 2 diabetic patients in Korea.

Adult↗

PubMed2005

Association between polymorphisms in the progesterone receptor gene and endometriosis.

The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a complex disease with strong hormonal features, common in women of reproductive age. We typed the 306 base pair Alu insertion (AluIns) polymorphism in intron G of PR in 101 individuals, estimated linkage disequilibrium (LD) between five single-nucleotide polymorphisms (SNPs) across the PR locus in 980 Australian triads (endometriosis case and two parents) and used transmission disequilibrium testing (TDT) for association with endometriosis. The five SNPs showed strong pairwise LD, and the AluIns was highly correlated with proximal SNPs rs1042839 (delta2 = 0.877, D9 = 1.00, P < 0.0001) and rs500760 (delta2 = 0.438, D9 = 0.942, P < 0.0001). TDT showed weak evidence of allelic association between endometriosis and rs500760 (P = 0.027) but not in the expected direction. We identified a common susceptibility haplotype GGGCA across the five SNPs (P = 0.0167) in the whole sample, but likelihood ratio testing of haplotype transmission and non-transmission of the AluIns and flanking SNPs showed no significant pattern. Further, analysis of our results pooled with those from two previous studies suggested that neither the T2 allele of the AluIns nor the T1/T2 genotype was associated with endometriosis.

Adolescent↗

PubMed1996

DNA-based rhesus typing: simultaneous determination of RHC and RHD status using the polymerase chain reaction.

We describe a PCR-based method of performing RHD and C/c typing in a single reaction. The method is based on an earlier observation of a polymorphism in intron 2 of both genes which, in addition to detecting the RHD deletion responsible for most known D-negative phenotypes, is also associated with C/c serological type. Using this assay, we typed 105 unrelated individuals from at least four different population groups and compared the results to those obtained using conventional serological testing of red cells. An absolute correlation, with no exceptions, was seen. We also showed that the method has potential in the antenatal determination of RH type, as it was possible to type fetal trophoblasts recovered from the endocervical canal at 9 weeks pregnancy.

Blood Grouping and Crossmatching↗