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PubMed2003

Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease.

Growth factor-related genes regulate cell growth, differentiation and apoptosis in the kidney in response to cellular injury. One of the theories of stone formation is that cellular injury, and thus growth factors, play a role. We therefore investigated the association between growth factor genes and calcium oxalate stone disease. The most frequently seen polymorphism of the vascular endothelial growth factor (VEGF) gene is Bst U I C/T, which is located upstream at the -460th nucleotide. Other growth factor-related gene polymorphisms include the cytochrome P450c17alpha enzyme (CYP17) gene MspA I C/T polymorphism at the 5'-UTR promoter region, the epidermal growth factor receptor (EGFR) gene Bsr I polymorphism (A to T) at position 2,073, and the insulin-like growth factor-2 (IGF-2) gene Apa I A/G at exon 9. All four polymorphisms were used as genetic markers in this study in the search for an association between stone disease and growth factor related genes. A normal control group of 230 healthy people, and 230 patients with calcium oxalate stone, were examined. The polymorphism was seen following polymerase chain reaction based restriction analysis. The result revealed a significant difference between normal individuals and stone patients (P=0.0003, Fisher's exact test) in the distribution of the VEGF gene polymorphism as well as an odds ratio of 1.30 (95% confidence interval=0.993-1.715) per copy of the "T" allele. Whereas, the IGF-2, EGFR and CYP17 gene polymorphisms did not reveal a significant association with stone disease. We conclude that the VEGF gene Bst U I polymorphism is a suitable genetic marker of urolithiasis.

Adult↗

PubMedDate not supplied

1173C>T polymorphism in VKORC1 modulates the required warfarin dose.

The response to warfarin is highly variable among individuals and such variability is likely to have some genetic basis. We evaluted the effect of VKORC1 polymorphisms on warfarin response among Japanese, taking advantage of its unique population structure in which CYP2C9 *2 and *3 alleles are relatively rare. Thirty-one patients (12-34 years old; median, 22) on warfarin were recruited from a pediatric cardiology clinic. Genotyping of the C>T polymorphism at position 1173 in intron 1 of VKORC1 revealed that 26 patients (84%) were T/T homozygotes at nucleotide 1173, whereas 5 (16%) were C/T heterozygotes. Complete linkage disequilibrium was observed between the 1173C > T polymorphism and another polymorphism, the 3730G > A, in the 3' untranslated region. The C/T heterozyogtes at the 1173C > T polymorphism tended to require more warfarin than the T/T homozygotes, when adjusted for international normalized ratio (p = 0.003). Both the 1173C > T polymorphism and the 3730G > A polymorphism are likely to be inert from a functional standpoint. Rather, based on the complete linkage disequilibrium between 1173C > T and 3730G > A polymorphisms, we suspect that the actual change that defines the relative resistance to warfarin may be present in the proximity of these two polymorphisms.

Adolescent↗

PubMed2001

Polymorphisms in the apolipoprotein E (APOE) gene in gerontopsychiatric patients.

Two recently described polymorphisms in the promoter region of the apolipoprotein E (APOE), the -491A/T and Th1/E47csT/G polymorphism, have been suggested to be associated with an increased risk for Alzheimer's disease (AD) independent from the APOE epsilon 4 carrier status. We studied the association between the APOE epsilon 4 polymorphism and the -491A/T and Th1E47csT/G polymorphisms in a sample of 118 healthy, non-demented controls and 239 consecutively recruited gerontopsychiatric patients diagnosed as: Alzheimer's disease (N = 89), age mild cognitive impairment (N = 32), memory complainers without any cognitive deficit (N = 54) and depression/other psychiatric disorders (N = 64), to test whether the investigated polymorphisms have a high enough selectivity and specificity to distinguish between the different gerontopsychiatric disorders or to differentiate AD genetically from other forms of dementia, respectively. Also a possible association with the APOE epsilon 4 polymorphism was examined. We found a statistically significant association between the APOE epsilon 4 allele and Alzheimer's disease (p = 0.0001) and age associated memory impairment (p = 0.006). Our study failed to show an association between the promoter polymorphisms -491A/T and Th1E47csT/G in the APOE gene and gerontopsychiatric disorders either alone or in relationship to the APOE epsilon 4 polymorphism. However, if we combine our results with three previous published positive reports there seems to be an association between the -491A/T polymorphism and AD, though its size is less than found in the original publication.

Aged↗

PubMed2007

Endothelial nitric oxide synthase gene polymorphisms in non-arteritic anterior ischemic optic neuropathy.

BACKGROUND: To examine the association between the polymorphisms of the endothelial nitric oxide synthase (eNOS) gene and the occurrence of non-arteritic anterior ischemic optic neuropathy (NAION). METHODS: We studied 15 patients with NAION (mean age, 62 years; 60% male). We investigated two polymorphisms of the eNOS gene, Glu298Asp polymorphism of exon 7 and T(-786)C polymorphism of the promoter region. The genotype distribution in NAION was compared with the control (mean age, 63 years; 63% male) distribution. RESULTS: There was no significant difference in the genotype distribution of the Glu298Asp polymorphism between the NAION and control groups (P = 1.000), whereas the genotype dis-tribution of the T(-786)C polymorphism varied significantly between the patients with NAION and control subjects (P = 0.002). After adjusting on covariates, individuals with the CC genotype of the T(-786)C polymorphism were more likely to develop NAION compared with those with TT genotype (odds ratio = 0.09: 95% CI 0.01-0.86). CONCLUSIONS: We found an increased prevalence of T(-786)C polymorphism of the eNOS gene in patients with NAION. Our data suggest that the T(-786)C polymorphism of the eNOS gene may be an important risk factor in the development of NAION in Japanese subjects.

Aged↗

PubMed2000

Association of ACE I/D polymorphism with cardiovascular risk factors.

Since the identification of an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene, the D allele has been recognized to be associated with cardiovascular disease. Moreover, significant associations of this polymorphism with multiple cardiovascular risk factors have been reported, although some studies failed to detect such associations. In the present study, we investigated the association of the ACE gene polymorphism with the parameters of multiple risk factors in 300 Japanese men who participated in a medical check-up. This investigation detected a significant association of the polymorphism with systolic blood pressure (P=0.007) and diastolic blood pressure (P=0.026), with their highest values in DD subjects and lowest values in II subjects. This significant association is consistent with the proposition that the polymorphism influences blood-pressure variability in men. Furthermore, we investigated the association of the polymorphism with four major disorders (obesity, hyperlipidemia, hypertension, diabetes mellitus) correlated with the risk for cardiovascular disease in the same 300 subjects. This investigation failed to detect any significant association of the polymorphism with each disorder. However, there was a trend that all four disorders were more frequent in ID and DD subjects than in II subjects. We therefore analyzed the association between the ACE gene polymorphism and having at least one of the four disorders in the same population. This analysis detected a significant difference: that ID and DD subjects had at least one of the four disorders more frequently than II subjects (P=0.008; odds ratio=1.89, 95% confidence interval= 1.19-2.99). Taken together, the results of this study are compatible with the proposition that the ACE polymorphism is associated with cardiovascular disease partially mediated through the four disorders in our population.

Adult↗

PubMed2006

Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans.

The role of drug transporters in pravastatin disposition is underlined by the fact that pravastatin does not undergo significant cytochrome P-450 (CYP)-mediated biotransformation. The organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, and multidrug resistance-associated protein 2 [MRP2 (ABCC2)], are thought to be the major transporters involved in the pharmacokinetics of pravastatin in humans. Other transporters that may play a role include OATP2B1, organic anion transporter 3 (OAT3), bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). OATP1B1 and MRP2 mediate the hepatic uptake and biliary excretion of pravastatin, respectively. The SLCO1B1 and ABCC2 polymorphisms probably contribute to the high interindividual variability in pravastatin disposition. Recent small studies have characterized the impact of the SLCO1B1 polymorphism on pravastatin in humans, and especially the c.521T>C single-nucleotide polymorphism (SNP) seems to be an important determinant of pravastatin pharmacokinetics. Pravastatin plasma concentrations may be up to 100% higher in subjects carrying the c.521C variant, as found in the *5, *15, *16, and *17 haplotypes, reflecting diminished OATP1B1-mediated uptake into the major site of pravastatin elimination, the liver. The SLCO1B1 polymorphism seems to have a similar impact on the pharmacokinetics of single- and multiple-dose pravastatin. Overall, 2-5% of individuals in various populations may be expected to show markedly elevated plasma pravastatin concentrations due to the SLCO1B1 polymorphism. Of note, the impact of the SLCO1B1 polymorphism on statins may be dependent on ethnicity. Although individuals with a diminished hepatic uptake of pravastatin might be expected to show reduced cholesterol-lowering efficacy due to lower intracellular pravastatin concentrations, there is preliminary evidence to suggest that the SLCO1B1 polymorphism is not a major determinant of non-response to pravastatin. The possible consequences of drug transporter polymorphisms, especially the SLCO1B1 and ABCC2 polymorphisms, for the lipid-lowering efficacy and tolerability of pravastatin in various ethnic groups warrant further study.

Animals↗

PubMed2006

Effects of two common polymorphisms of peroxisome proliferator-activated receptor-gamma gene on metabolic syndrome.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)gamma is involved mainly in adipocyte differentiation and has been suggested to play an important role in the pathogenesis of insulin resistance and atherosclerosis. We investigated the frequencies of two common polymorphisms of PPARgamma gene, exon 6 C-->T substitution and exon B Pro12Ala in healthy subjects and analyzed the correlations between the different genotypes and insulin resistance, metabolic syndrome and cardiovascular risk factors. METHODS: Anthropometric measurements, fasting glucose, insulin and lipid profiles were measured in 253 Korean females. Homeostatic model assessments and quantitative insulin sensitivity check indices were calculated. Metabolic syndrome was diagnosed according to the NCEP-ATP III guidelines and the Western Pacific Region of WHO for obesity criteria for waist circumference. Polymerase chain reaction (PCR)-restriction fragment-length polymorphism and real-time PCR were performed for genotyping of the DNAs. RESULTS: For C161T polymorphism, allele frequencies were 0.804 and 0.196 for T allele, and 0.947 for proline and 0.053 for alanine. There was no Ala12Ala homozygote in the population. No differences were seen in the mean values of age, body mass index (BMI), blood pressure, fasting blood glucose level, fasting insulin levels, HOMA and QUICKI among different genotypes when analyzed as a whole, except that subjects with Pro12Ala had significantly higher body weight than those with Pro12Pro genotype. However, mean BMI, percent body fat and weight showed significant differences between genotypes in younger age group (< or =50 years). Although overall prevalence of metabolic syndrome had no association with the genotypes, the prevalence of decreased high-density lipoprotein cholesterol component was lower in those with the T allele than in those with the CC genotype. There was no association of the genotypes with glucose tolerance status. When the subjects were divided into four groups according to the combination of the genetic alleles of the two polymorphisms, subjects having Pro12Ala and T allele, simultaneously, showed significantly higher mean weight than those without Ala allele. Pro12Ala polymorphism seems to affect body weight, similar to the previous studies, and the effect was potentiated with the presence of T allele of C161T polymorphism. CONCLUSIONS: Although either polymorphism failed to show significant association with insulin resistance, the fact that the prevalence of decreased HDL-C was lower in those with the T allele of C161T polymorphism suggests that this polymorphism might have a protective effect on atherosclerotic lipid profiles, which needs further investigation.

Adult↗

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↗

PubMed2004

Polymorphisms in the estrogen receptor beta gene but not estrogen receptor alpha gene affect the risk of developing endometriosis in a Japanese population.

OBJECTIVE: To determine whether polymorphisms in the estrogen receptor (ER) alpha and beta genes are associated with endometriosis in a Japanese population. DESIGN: Association study. SETTING: University hospital. PATIENT(S): Japanese women diagnosed with endometriosis by laparotomy or laparoscopy. INTERVENTION(S): Determination of polymorphisms in the ERalpha and ERbeta genes was performed by polymerase chain reaction restriction fragment-length polymorphism analysis in 132 affected women and 182 controls. MAIN OUTCOME MEASURE(S): Frequency and distribution of AluI and RsaI polymorphisms in ERbeta gene and of PvuII and XbaI polymorphisms in ERalpha gene. RESULT(S): No significant differences in the frequency of either AluI and RsaI polymorphisms in the ERbeta gene or of XbaI and PvuII polymorphisms in the ERalpha gene were found between endometriosis patients and controls. However, a positive association was noted between the AluI polymorphism in the ERbeta gene and stage IV endometriosis patients in the population studied. CONCLUSION(S): The AluI polymorphism in the ERbeta gene is associated with an increased risk of stage IV endometriosis in a Japanese population.

Asian People↗

PubMed2005

Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants.

BACKGROUND: Eight common (>0.5%) polymorphisms of SCN5A have been described in the US population. Every human also continuously generates two wild-type (WT) splice variants, one with a glutamine residue at position 1077 (Q1077) and one lacking this glutamine (Q1077del). One polymorphism (H558R) has been studied in both splice variants, five polymorphisms (R34C, R481W, S524Y, P1090L,V1951L) have not been previously studied, and two polymorphisms (S1103Y and R1193Q) have been studied in only one of the two splice variants. OBJECTIVES: The purpose of this study was to examine the electrophysiologic molecular phenotype of the eight common polymorphisms in the two human splice variants of SCN5A. METHODS: Currents from 16 channels (all polymorphisms in both splice variants) were determined by voltage clamp and compared with WT after expression in HEK-293 cells. RESULTS: Six of eight polymorphisms showed a distinct phenotype that depended upon the background splice variant used for expression. Only R34C and V1951L showed no functional differences. S524Y showed a dramatic reduction in current density in the Q1077 background similar to that previously described for H558R. Four other polymorphisms (R481W, P1090L, S1103Y, R1193Q) showed shifts in activation, inactivation, or recovery that depended upon the splice variants. Shifts of a similar magnitude have been reported for arrhythmia syndrome mutations and are thought to be pathogenic. CONCLUSION: The majority of common human SCN5A polymorphisms have a distinct molecular phenotype that depends upon the splice variant background. These findings have implications for the interpretation of previous studies of arrhythmia mutations. The significance of these findings for clinical arrhythmia remains to be elucidated.

Alternative Splicing↗

PubMed2005

IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma.

BACKGROUND: Asthmatic airways undergo chronic inflammatory cell infiltration by T cells and eosinophils, which results in sustained airway hyperresponsiveness. IL-5 is important for eosinophil-induced airway inflammation and airway hyperresponsiveness. Thromboxane A2 and its receptor, TBXA2R, are involved in constriction of respiratory smooth muscles and may play a role in thickening and remodeling of airways, which contributes to the severity of asthma. The relationship between IL-5 and TBXA2R gene polymorphisms and pulmonary function in children with asthma has rarely been examined. OBJECTIVE: To determine whether IL-5 (T-746C) and TBXA2R (T924C) gene polymorphisms are associated with asthma phenotype and pulmonary function in Korean children with atopic and nonatopic asthma. METHODS: We conducted an association study between known polymorphisms of IL-5 (T-746C) and TBXA2R (T924C) and asthma phenotype and the parameters of atopy and pulmonary function in atopic and nonatopic Korean children with asthma. The subjects were 240 atopic children with asthma, 70 nonatopic children with asthma, and 106 nonatopic healthy children. Asthma phenotypes and bronchial responsiveness to methacholine were determined by a physician. IL-5 and TBXA2R gene polymorphisms were determined by genotyping by using PCR-RFLP assays. RESULTS: The genotype frequencies of IL-5 and TBXA2R polymorphisms did not differ between healthy controls and atopic or nonatopic children with asthma. A significant association was observed between the IL-5 polymorphism and forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75% ; %; P = .002), and between the TBXA2R polymorphism and FEV 1 (%; P = .035) and FEF 25-75% (%; P = .042) in children with atopic asthma, whereas no such association between the polymorphisms and lung function was observed in nonatopic or control children. In atopic children with asthma, we identified a significant gene-gene interaction in that the combination of the IL-5 (T-746C) and TBXA2R (T924C) mutant alleles was shown to be associated with reduced pulmonary function as determined by FEF 25-75% (%) measurement. CONCLUSION: The current study indicates that IL-5 (T-746C) and TBXA2R (T924C) polymorphisms alone are associated with spirometric markers of asthma severity, whereas they are not associated with presence of asthma per se. In addition, the data suggest that an interaction between IL-5 and TBXA2R genes may contribute to the severity of asthma, especially atopic asthma. These results suggest that IL-5 and TBXA2R genes may be disease-modifying genes in Korean children with atopic asthma.

Asthma↗

PubMed2006

Genetic polymorphisms, hormone levels, and hot flashes in midlife women.

OBJECTIVE: Hot flashes disrupt the lives of millions of women each year. Although hot flashes are a public health concern, little is known about risk factors that predispose women to hot flashes. Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes. METHODS: In a cross-sectional study design, midlife women aged 45-54 years (n=639) were recruited from Baltimore and its surrounding counties. Participants completed a questionnaire and donated a blood sample for steroid hormone analysis and genotyping. The associations between genetic polymorphisms and hormone levels, as well as the associations between genetic polymorphisms, hormone levels, and hot flashes were examined using statistical models. RESULTS: A polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, while a polymorphism in CYP19 (aromatase) was associated with higher testosterone and DHEA-S levels. Lower progesterone and sex hormone binding globulin levels, lower free estradiol index, and a higher ratio of total androgens to total estrogens were associated with the experiencing of hot flashes. A polymorphism in CYP1B1 and a polymorphism in 3betaHSD were both associated with hot flashes. CONCLUSION: Some genetic polymorphisms may be associated with altered levels of hormones in midlife women. Further, selected genetic polymorphisms and altered hormone levels may be associated with the risk of hot flashes in midlife women.

Aryl Hydrocarbon Hydroxylases↗

PubMedDate not supplied

Angiotensin-converting enzyme gene polymorphism significantly affects renal posttransplantation erythrocytosis.

Posttransplantation erythrocytosis (PE) is a frequent problem in renal transplant patients. The pathogenesis and mechanisms of both the problem and therapy strategy are unknown. Since ACE and angiotensin 2 receptor inhibitors have been used to successfully manage PE, we speculated a relation between gene polymorphisms and this complication. Ninety-six ( 30 women, 66 men, age 34.4 +/- 11.0 years) renal transplant patients evaluated retrospectively, for gene polymorphisms of ACE, angiotensinogen, angiotensin 1 and 2 receptors (ATR1 and ATR2), as well as endothelial nitric oxide synthase (ecNOS). They were divided into two groups; patients with versus without PE, which was defined as >15 g/dL hemoglobin levels during the first year after renal transplantation. PE was found to be significantly more prevalent among D/D than I/I gene polymorphism of ACE genes (P <.04). The distribution of D/D, I/D, and I/I polymorphisms were 39.1%, 45.9%, and 7.6%, respectively. There was no difference between D/D and I/D polymorphisms. Comparing the I/D and I/I polymorphisms showed PE to be statistically more prevalent in the I/D polymorphism (P <.01). Logistic regression analysis revealed that D/D and I/D polymorphisms were significant risk factors for PE (P <.05, RR = 7.714 and P <.03, RR = 10.199, respectively). While previous studies revealed a relation between angiotensin II and PE, our study discovered the contribution of ACE gene polymorphism.

Adult↗

PubMed2004

Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer.

OBJECTIVE: Nitric oxide (NO) is involved in angiogenesis and tumor growth. We attempted to establish an association between two polymorphisms of the endothelial nitric oxide synthase (NOS3) gene and vulvar cancer. METHODS: We used peripheral venous blood sampling, DNA extraction, and polymerase chain reaction (PCR) and pyrosequencing to genotype 68 women with vulvar cancer and 227 healthy Caucasian women for the presence of the intron 4 27-bp-repeat [NOS3*A] and exon 7 Glu298Asp polymorphisms. RESULTS: The presence of a polymorphic NOS3*A allele (26.2% vs. 24.6%; OR: 1.01; 95% CI: 0.6-2.0; P = 0.9) or a polymorphic NOS3 exon 7 Glu298Asp allele (41.2% vs. 53.7%; OR: 0.6; 95% CI: 0.3-1.0; P = 0.09) was not associated with vulvar cancer. Within the vulvar cancer group, the presence of a polymorphic NOS3*A or a polymorphic NOS3 exon 7 Glu298Asp allele was not associated with clinico-pathological parameters such as advanced tumor stage, groin lymph node involvement, tumor grading, and age at diagnosis. Survival analysis demonstrated that the presence of a polymorphic NOS3*A allele was associated with a significantly reduced disease-free survival time (P = 0.03), whereas the presence of the polymorphic NOS3 exon 7 Glu298Asp allele was not associated with disease-free survival (P = 0.5). CONCLUSIONS: We are the first to report on NOS3 polymorphisms in vulvar cancer. We found that allelic variation within intron 4, but not ithin exon 7 of NOS3, influences the length of disease-free survival, but not the biological phenotype of vulvar cancer.

Adult↗

PubMed2005

Two functionally relevant polymorphisms in the human progesterone receptor gene (+331 G/A and progins) and the predisposition for breast and/or ovarian cancer.

OBJECTIVE: Two polymorphisms affecting either expression (+331 G/A) or transcriptional activity (progins) of the progesterone receptor have been described. No clear correlation between either polymorphism and breast or ovarian cancer has been shown. Our objective is to clarify whether the two progesterone receptor polymorphisms modify the risk for breast or ovarian cancer. METHODS: Healthy women and women suffering from either ovarian or breast cancer were enrolled in a case-control-based study to compare the frequencies of women carrying either one, both or none of the two polymorphisms. Patient and control populations resided in the same region of South Germany. PCR-RFLP analysis was used to determine the polymorphic alleles. RESULTS: Women diagnosed with ovarian cancer showed a not significant increased frequency of +331 A carriers and a significantly increased frequency of progins carriers. Both polymorphisms appeared to be associated with a significantly increased risk for the disease in women below 51 years [OR: 4.1 (CI: 1.2-13.9) and 3.2 (CI: 1.1-9.1), respectively]. No association was detected between either of the two polymorphisms and breast cancer. Among ovarian and breast cancer patients, the number of individuals carrying both rare polymorphic alleles was significantly higher compared to healthy women. CONCLUSIONS: Our findings support the hypothesis that low penetrant polymorphisms of progesterone receptor may modify the risk for ovarian cancer. Our data do not allow drawing a clear conclusion on the risk for breast cancer.

Adult↗

PubMed2001

Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies. METHODS: The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms. RESULTS: We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele. We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample. CONCLUSIONS: Our results support previous findings of an association between the DAT1 gene and ADHD.

Alleles↗

PubMed2003

APO B gene polymorphisms and coronary artery disease: a meta-analysis.

BACKGROUND: The APO B gene is characterised by numerous polymorphic sites, three of which (XbaI, EcoRI, SpIns/Del) are related to levels of total cholesterol (TC), low-density lipoproteins, apo B and tryglicerides, and to coronary artery disease (CAD) and/or myocardial infarction (MI). Moreover, conflicting results emerge from literature. To assess how each polymorphism of the APO B gene was associated with CAD and MI risk, we carried out a meta-analysis of all published studies. METHODS AND RESULTS: Thirty case-control studies were considered, for a total of 6077, 3870 and 11616 individuals, respectively, for XbaI, EcoRI and SpIns/Del polymorphisms. For each polymorphism we calculated the risk of CAD/MI on the overall sample and for large and small studies separately. No evidence of increased risk emerged for XbaI polymorphism. Whereas, positive associations were detected for EcoRI, SpIns/Del and risk of CAD and MI, with odds ratio (OR) of 1.73 (95% CI, 1.19-2.50) and 1.19 (95% CI, 1.05-1.35) for carriers of AA and DD, respectively. CONCLUSIONS: Despite the small size of most studies and the incomplete understanding of the effects of these polymorphisms on lipid metabolism and on final clinical implications, the findings suggest that EcoRI and SpIns/Del polymorphisms significantly increase the risk of CAD and MI. Despite the rarity of the allelic variant of EcoRI polymorphism, its presence is strongly related to the occurrence of CAD/MI. Moreover, there is a high consistency between small and large studies. The results on SpIns/Del polymorphism seem the most interesting and reliable, considering both the number of subjects analysed and the consistency of the evidence of its effect on lipid levels. These results need to be confirmed by larger and appropriately powered studies.

Adult↗

PubMed1997

The glutamine 27 beta2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families.

BACKGROUND: The beta2-adrenoceptor polymorphisms occurring at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamate) are known to be functionally relevant and also disease-modifying in subjects with asthma. However, the contribution of these polymorphisms to the development of the asthmatic phenotype or other markers for allergic disease remains to be established. OBJECTIVE: This large family study examines the contributions of these polymorphisms in determining the heritable component of markers for allergic disease in asthmatic families. METHODS: Three hundred twenty-four individuals from 60 families multiplex for asthma selected by means of an asthmatic proband were characterized for the following markers of allergic disease: asthma, atopy, and serum IgE. The polymerase chain reaction was used to generate a 234 base pair fragment spanning the region of interest, and the beta2-adrenoceptor polymorphism was then defined by allele-specific oligonucleotide hybridization. Segregation analysis was then performed. RESULTS: We found a significant association (p = 0.009) between the glutamine 27 beta2-adrenoceptor polymorphism and elevated levels of IgE, which was supported by the observation of linkage between IgE and beta2-adrenoceptor polymorphisms at locus 27 (p = 0.037). However, there was no association between either the arginine-glycine 16 or the glutamine-glutamate 27 beta2-adrenoceptor polymorphism and an increased risk of asthma or atopy per se. CONCLUSION: The glutamine 27 beta2-adrenoceptor polymorphism appears to contribute to IgE variability in families with asthma. However, it seems that although both amino acid 16 and 27 beta2-adrenoceptor polymorphisms are disease-modifying in subjects with asthma, they do not contribute markedly to the development of the asthmatic phenotype.

Adult↗