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PubMed1998

The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction.

P-selectin is an adhesion molecule, expressed at the surface of activated cells, that mediates the interaction of activated endothelial cells or platelets with leukocytes. P-selectin expression is increased in atherosclerotic plaques, and high plasma levels of this molecule have been observed in patients with unstable angina. We investigated the P-selectin gene as a possible candidate for myocardial infarction (MI). The P-selectin gene is situated on chromosome 1q21-q24, spans >50 kb and contains 17 exons. The sequences of the 5'-flanking region and exons of 40 alleles from patients with MI were screened for polymorphisms using polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) and sequencing. Thirteen polymorphisms were identified: five in the 5'-flanking and eight in the exonic sequences. Four polymorphisms (Ser290Asn, Asn562Asp, Leu599Val and Thr715Pro) predicted a change in the amino acid sequence of the P-selectin protein. All P-selectin polymorphisms as well as a common E-selectin polymorphism, Ser128Arg which has been reported as being associated with an increased risk of premature coronary heart disease (CHD), and is in tight linkage disequilibrium with several P-selectin polymorphisms, were investigated in 647 patients with MI and 758 control subjects from four regions of France and Northern Ireland (the ECTIM study). The entire set of P-selectin polymorphisms provided a heterozygosity of 91%. The polymorphisms were tightly associated with one another and displayed patterns of linkage disequilibrium suggesting the existence of highly conserved ancestral haplotypes. The five polymorphisms in the 5'-flanking region of the gene were unrelated to MI or any relevant phenotype measured in the ECTIM study. We inferred that the four missense variants identified in the coding region predicted eight common forms of the P-selectin protein. The Pro715 allele which characterizes one of these forms was less frequent in France than in Northern Ireland ( P < 0.002) and in cases than in controls ( P < 0.002; P < 0.02 after correction for the number of tests). We conclude that the P-selectin gene is highly polymorphic and hypothesize that the Pro715 variant may be protective for MI. Whether this variant affects the properties of the P-selectin protein in a way which is compatible with this hypothesis needs to be checked experimentally.

Adult↗

PubMed2003

Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis.

Candidate gene polymorphisms related to inflammation, thrombosis and lipid metabolism have been implicated in the development of ischemic stroke. Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we genotyped 92 polymorphisms from 56 candidate genes among 319 individuals who subsequently developed ischemic stroke and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years to prospectively determine whether candidate gene polymorphisms contribute to stroke risk. After adjustment for multiple comparisons and age, smoking, body mass index, hypertension, hyperlipidemia and diabetes, two related to inflammation [a val640leu polymorphism in the P-selectin gene (OR=1.63, 95% CI 1.22-2.17, P=0.001) and a C582T polymorphism in the interleukin-4 gene (OR=1.40, 95% CI 1.13-1.73, P=0.003)] were found to be independent predictors of thrombo-embolic stroke. In bootstrap replications, the inclusion of genetic information from these two polymorphisms improved prediction models for stroke based upon traditional risk factors alone (ROC 0.67 versus 0.64). Two polymorphisms related to thrombosis (an arg353gln polymorphism in the factor VII gene and a T11053G polymorphism in the plasminogen activator inhibitor type-1 gene) and one related to lipid metabolism [a C(-482)T polymorphism in the apolipoprotein CIII gene] achieved nominal significance, but were not found to be independent predictors after multiple comparison adjustment. Two inflammatory candidate gene polymorphisms were identified which were independently associated with incident stroke. These population-based data demonstrate the ability of prospective, epidemiological studies to test candidate gene associations for athero-thrombotic disease.

Aged↗

PubMed1996

A nonlinear method for estimating nucleotide polymorphism from restriction maps.

Restriction mapping is used to estimate nucleotide sequence polymorphism when the regions to be studied are too long or too numerous to be sequenced. Restriction mapping is less costly than DNA sequencing, but it does not allow direct measurement of underlying nucleotide polymorphism. It is therefore useful to be able to estimate underlying nucleotide polymorphism from observations of polymorphism in restriction maps, as this offers some of the resolution afforded by DNA sequencing at a reduced cost. Previous estimators of underlying nucleotide polymorphism have assumed that each restriction-enzyme-binding site contains, at most, a single polymorphic nucleotide position (the low-polymorphism-frequency assumption), and this assumption has placed an upper limit on the level of polymorphism that can be resolved by these estimators. The present study documents an estimator which allows relaxation of this assumption. The new estimator more accurately estimates underlying nucleotide polymorphism when the polymorphism level is high enough to falsify the low-polymorphism-frequency assumption. The new estimator therefore yields good results for data sets that are too divergent for analysis by present methods.

Animals↗

PubMed2003

Linkage disequilibrium between tumor necrosis factor (TNF)-alpha-308 G/A promoter and TNF-beta NcoI polymorphisms: Association with TNF-alpha response of granulocytes to endotoxin stimulation.

OBJECTIVE: Controversial data have been reported on the association between the tumor necrosis factor (TNF)-alpha-308 G[U279C]A promoter polymorphism or the TNF-alpha I polymorphism with TNF-alpha plasma concentrations. The purpose of this study was to evaluate whether there is a linkage disequilibrium between the two polymorphisms. Moreover, the influence of these polymorphisms on the TNF-alpha synthesis of activated granulocytes was studied. DESIGN: Analysis of TNF-alpha concentrations of human whole blood after endotoxin stimulation. SETTING: Medical research laboratory. PATIENTS: Healthy human volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Healthy human volunteers were genotyped for both TNF polymorphisms by means of polymerase chain reaction. TNF-alpha plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p <.0001) linkage disequilibrium was found for the TNF-beta I and the TNF-alpha-308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-beta I polymorphism were also TNF-alpha-308 G homozygotes. Carriers of the TNF-alpha-308 genotype AG had a significantly higher TNF-alpha production capacity than G homozygotes. The TNF-beta I genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-alpha concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-alpha-308 G alleles had a significantly reduced TNF-alpha response compared with individuals heterozygous for both TNF polymorphisms. CONCLUSIONS: A linkage disequilibrium between the two TNF polymorphisms was found. This study revealed a significant association between genotype and phenotype for both TNF polymorphisms. Heterozygosity for both TNF polymorphisms is associated with an increased TNF-alpha response.

Granulocytes↗

PubMed2006

Genetic association between Notch4 polymorphisms and Japanese schizophrenics.

The objective of this study was to investigate whether three single nucleotide polymorphisms of the Notch4 gene are associated with the onset of schizophrenia. To confirm the linkage disequilibrium among these three single nucleotide polymorphisms of the gene, the three single nucleotide polymorphisms were genotyped by a polymerase chain reaction-restriction-fragment length polymorphism method for all samples. The genotypic frequencies of each single nucleotide polymorphism in the schizophrenic were compared with respective controls using a chi method. To check linkage disequilibrium, the haplotype frequency program was utilized. No statistical association between the two single nucleotide polymorphisms of the Notch4 gene and schizophrenia was observed in our Japanese samples. Although one nonsynonymous single nucleotide polymorphism did show a weakly significant P-value, its allelic frequencies are not positive. Two of the single nucleotide polymorphisms showed strong linkage disequilibrium in our Japanese samples. The single nucleotide polymorphism between the other two single nucleotide polymorphisms showed a weaker linkage disequilibrium with the others. Our study suggests that the three single nucleotide polymorphisms are not associated with the onset of schizophrenia. The linkage disequilibrium of this locus indicates that there is genetic heterogeneity in the Notch4 gene. Linkage disequilibrium may differ among ethnic groups, and so a larger study should be performed in this region.

5' Untranslated Regions↗

PubMed1996

Frequencies of five genetic polymorphisms in coronarographed patients and effects on lipid levels in a supposedly healthy population.

Allele frequencies of genetic polymorphisms were compared between supposedly healthy subjects and angiographically proven coronary artery disease patients. The polymorphic candidate loci investigated were the apolipoprotein (apo) B signal peptide and XbaI polymorphism, the apo E polymorphism and two polymorphism of lipoprotein lipase (LPL) gene: Hind/III and PvuII. Apo B signal peptide and HindIII/LPL polymorphisms showed significant differences in allele partition between cases and controls; the rare alleles of both polymorphisms were less frequent (p < 0.05) in cases. We looked for associations between the polymorphisms and lipid concentration variability in a supposedly healthy population (145 men and 144 women). Apo B signal peptide, apo E and PvuII/LPL polymorphisms seem to influence some lipid metabolism parameters significantly. Apo AI and LpCIII levels were significantly different among apo B signal peptide genotypes: Del homozygotes had the highest concentrations of both variables. The epsilon 4 allele of apo E polymorphism was associated with increased concentrations of total cholesterol, LDL cholesterol and apo B. Increased LpAI:AII levels observed in E3 homozygotes (p < 0.01) have not previously been reported. LpAI:AII concentration was also influenced by PvuII/LPL polymorphisms.

Adult↗

PubMed1991

Clinical consequences of polymorphic drug oxidation.

Many characters are genetically regulated as polymorphisms. This means that discrete groups are seen within the distribution of a certain character. Drug metabolism is no exception and the polymorphism of acetylation is recognised since the 50's. Polymorphic drug oxidation was discovered in the 70's and has been extensively studied. There are two fully established polymorphisms in drug oxidation named as the debrisoquine/sparteine and the s-mephenytoin hydroxylation polymorphisms. The metabolism of a number of important drugs cosegregates with that of debrisoquine. Among these drugs are beta-blockers, antiarrhythmics, tricyclic antidepressants and neuroleptics. Apart from accumulation of parent drug and active metabolite, also reduced formation of active metabolite occur for some drugs in slow metabolisers. There are, however, few cases where the presence of polymorphic drug metabolism is of significant disadvantage. The polymorphisms will add to variability in drug clearance but the potential clinical importance should be evaluated for each drug. The cytochrome P-450 isozyme responsible for debrisoquine hydroxylation is of high affinity-low capacity character, which means that it can be saturated under certain circumstances. This will decrease the difference in drug metabolic rate between rapid and low metabolisers as will inhibitors of the debrisoquine isozyme like cimetidine, quinidine and propafenone. The debrisoquine isozyme is not readily inducible. In cases where a major metabolic route or the formation of an active metabolite are polymorphically controlled, knowledge about a patient's oxidator status might be of practical value for dose adjustments especially if there is a narrow therapeutic ratio or an established concentration-effect relationship. For some drugs it is difficult to differentiate between insufficient therapeutic effect and symptoms of overdosage. Tricyclic antidepressants and neuroleptics meet some of these criteria and patients who get recurrent treatment may benefit if the physician has knowledge about debrisoquine metabolic phenotype. Otherwise, the clinical consequences of polymorphisms in drug oxidation seem so far to be limited, considering that a number of disease conditions have not shown any clear association with oxidation status. The polymorphisms in drug metabolism should be considered as a part of natural variability which could in fact be larger with other drugs that do not show polymorphic elimination.

Debrisoquin↗

PubMedDate not supplied

CYP1A1 polymorphism and risk of gynecological malignancy in Japan.

The incidence of endometrial cancer and ovarian cancer in Japan has been increasing in recent years. Results of epidemiologic studies suggest that the onset and multiplication of these cancers are associated with estrogen. Estrogens are metabolized by cytochrome P450 1A1 (CYP1A1) and converted into catecholestrogens, which are carcinogens. CYP1A1 has several polymorphisms, the major one being T6235C transition in the non-coding 3'-flanking region (MspI polymorphism), and another being A4889G transition in exon 7 (Ile/Val polymorphism). These polymorphisms can affect the metabolites of estrogens and contribute to the susceptibility to gynecological malignancy. In this study, to determine whether CYP1A1 polymorphism plays a role in the development of gynecological malignancy in the Japanese population, we assessed the association of CYP1A1 polymorphism in Japanese patients with gynecological malignancy in comparison to that in controls. The odds ratios (ORs) of Ile/Val polymorphism were 1.16 in ovarian cancer patients and 1.70 in endometrial cancer patients. The ORs of MspI polymorphism were 1.33 in ovarian cancer patients and 0.88 in endometrial cancer patients. No significant association was found between these CYP1A1 polymorphisms and gynecological malignancy. Although the frequency of CYP1A1 polymorphism in the Japanese population is higher than that in the Caucasian population, CYP1A1 polymorphism is not related to gynecological malignancies in Japanese population.

Case-Control Studies↗

PubMed2005

Functional polymorphisms in the alpha-subunit of the human epithelial Na+ channel increase activity.

Activity of the epithelial Na(+) channel (ENaC) is limiting for Na(+) reabsorption at the distal nephron. Gain-of-function mutations in ENaC cause Liddle's syndrome: a severe form of inheritable hypertension. Several polymorphisms in alpha-hENaC possibly associated with abnormal Na(+) handling by the kidney and the salt-sensitive hypertension prevalent in black populations have been reported. The functional effects of alpha-hENaC polymorphisms on channel activity, however, remain controversial and have not been directly tested in a mammalian background. We ask here whether polymorphisms at positions 334, 618, and 663 in alpha-hENaC influence channel activity. Activity of wild-type (A334, C618, A663) and polymorphic ENaC expressed in Chinese hamster ovary cells was assessed with patch-clamp electrophysiology. While the A334T polymorphism had little effect on macroscopic ENaC currents, the C618F and A663T polymorphisms significantly increased ENaC activity >3.3- and 1.6-fold, respectively. Similarly, polymorphic ENaC had greater activity compared with wild-type channels in excised patches with activity of C618F and A663T channels increased 3.8- and 2.6-fold, respectively. Unitary channel conductances and reversal potentials were not different for polymorphic and wild-type ENaC. Increases in activity resulted primarily from increases in the apparent number of active (polymorphic) channels in the plasma membrane. Moreover, addition of a reducing agent to the cytosol significantly increased activity of wild-type ENaC equal to that of C618F polymorphic channels but had no effect on these latter channels. These results are consistent with the C618F and A663T polymorphisms leading to elevated ENaC activity with the possibility that they facilitate altered Na(+) handling by the kidney.

Animals↗

PubMed2005

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.

Aged↗

PubMed2002

T(-786)-->C polymorphism of the endothelial nitric oxide synthase gene influences the progression of renal disease.

BACKGROUND/AIMS: Polymorphism of the endothelial nitric oxide synthase (ecNOS) gene may be involved in renal disease. Recently, T(-786)-->C polymorphism affecting ecNOS gene transcription has been reported. To clarify the role of T(-786)-->C polymorphism in renal disease, we investigated hemodialysis patients and healthy controls for this polymorphism and we compared its frequency with that of intron 4 polymorphism in the hemodialysis patients. METHODS: The subjects were 252 patients who had been on hemodialysis for less than 2 years (168 with nondiabetic nephropathy and 84 with diabetic nephropathy) and 187 healthy controls. T(-786)-->C polymorphism was detected using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The frequencies of the T/C and C/C genotypes were significantly higher in the nondiabetic hemodialysis patients than in the controls (odds ratio 1.41; 95% Cl 1.03-2.00), and were also significantly higher in the diabetic hemodialysis patients than in the controls (odds ratio 1.56; 95% Cl 1.02-2.41). In addition, T(-786)-->C polymorphism and intron 4 polymorphism showed strong linkage disequilibrium. CONCLUSION: T(-786)-->C polymorphism may be involved in the progression of both nondiabetic and diabetic nephropathy, along with intron 4 polymorphism.

Adult↗

PubMed2003

Apolipoprotein H gene polymorphisms and risk of primary cerebral hemorrhage in a Chinese population.

BACKGROUND AND PURPOSE: Apolipoprotein H (ApoH) has been implicated in several physiologic pathways including lipid metabolism, coagulation and the production of hypertension, which are related to the pathogenesis of primary cerebral hemorrhage (PICH). The gene coding for ApoH is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can effect lipid metabolism and the production of hypertension. We determined the distribution of ApoH gene polymorphisms in Chinese people and investigated whether these polymorphisms were associated with increased risk of PICH in a Chinese population. METHODS: We studied polymorphisms of the ApoH gene by the polymerase chain reaction-single strand conformation polymorphism technique and DNA sequencing in 140 PICH patients and 100 healthy control subjects. Serum antiphospholipid antibodies and lipid levels were also examined in all subjects. RESULTS: Four polymorphisms of the ApoH gene have been identified in Chinese people. No difference in genotype frequencies of G817T (Leu247Val) polymorphism, G1025C (Try316Ser) polymorphism and C1080T polymorphism was observed between PICH patients and control subjects (p > 0.05). The G341A (Ser88Asn) polymorphism correlated significantly with PICH. The frequencies of the A allele were significantly higher in PICH patients than in controls, especially in PICH patients with hypertension and a family history of stroke. CONCLUSIONS: Our results suggest that the G341A (Ser88Asn) polymorphism might be associated with increased risk of PICH in a Chinese population. The association appeared to be mediated by the generation of hypertension.

Adult↗

PubMed2005

Effect of gene polymorphisms on lipoprotein levels in patients with dyslipidemia of metabolic syndrome.

Dyslipidemia in the metabolic syndrome (MS) is considered to be one of the most important risk factors for atherosclerosis. It is characterized by hypertriglyceridemia, low concentration of plasma HDL-cholesterol, predominance of small dense LDL particles and an increased concentration of plasma apolipoprotein B (apoB). The pathogenesis of this type of dyslipidemia is partially explained, but its genetic background is still unknown. To evaluate the influence of cholesterol ester transfer protein (CETP) TaqIB polymorphism, lipoprotein lipase (LPL) PvuII and HindIII polymorphisms, hepatic lipase (LIPC) G-250A polymorphism and apolipoprotein C-III (APOC3) SstI gene polymorphism on lipid levels in dyslipidemia of the metabolic syndrome, 150 patients with dyslipidemia of metabolic syndrome were included. 96 % of patients had type 2 diabetes. The patients did not take any lipid lowering treatment. The exclusion criterion was the presence of any disease that could affect lipid levels, such as thyroid disorder, liver disease, proteinuria or renal failure. Gene polymorphisms were determined using the polymerase chain reaction and restriction fragment length polymorphisms. The genotype subgroups of patients divided according to examined polymorphisms did not differ in plasma lipid levels with the exception of apoB. The apoB level was significantly higher in patients with S1S1 genotype of APOC3 SstI polymorphism when compared with S1S2 group (1.10+/-0.26 vs. 0.98+/-0.21 g/l, p=0.02). Similarly, patients with H-H- genotype of LPL HindIII polymorphism had significantly higher mean apoB, compared with H+H- and H+H+ group (1.35+/-0.30 vs. 1.10+/-0.26 g/l, p=0.02). In the multiple stepwise linear regression analysis, apoB level seemed to be influenced by APOC3 SstI genotype, which explained 6 % of its variance. The present study has shown that the S1 allele of APOC3 SstI polymorphism and the H- allele of LPL HindIII polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome.

Aged↗

PubMed2002

[Influence of insertion-deletion polymorphism of the angiotensin converting enzyme gene on left ventricular hypertrophy in patients with aortic stenosis--differences in men and women].

UNLABELLED: The role of different parameters (including genetic factors) on the timing and extend of left ventricle hypertrophy in patients with aortic stenosis is not defined. In our study we analyze the influence of clinical, echocardiographic parameters and I/D polymorphism of the angiotensin converting enzyme gene on the left ventricle hypertrophy (left ventricle mass index) in this group of patients. The study was done with the group of 302 pts with aortic stenosis--120 women and 182 men; mean age 58 +/- 11 yrs. Stepwise (backward) regression was used to assess the influence of the analyzed parameters (age, gender, history of hypertension, EF, MGA, presence of significant coronary artery disease and I/D ACE polymorphism) on the LVH in the all pts and in the women and the men separately. In the whole group the LVMI depends on EF (t = -6.5; p = 0.0001--higher LVMI in lower EF), MGA (t = 3.9; p = 0.0001--higher LVMI in higher MGA) and gender (t = 2.8; p = 0.005--higher LVMI in men). In women LVMI was related with EF (t = -3.6; p = 0.001--higher LVMI in lower EF), age (t = 2.9; p = 0.004--higher LVMI in older pts) and MGA (t = 2.5; p = 0.013--higher LVMI in higher MGA). In men the LVMI depends on EF (t = -4.8; p = 0.0001--higher LVMI in lower EF) and MGA (t = 1.98; p = 0.049--higher LVMI in higher MGA). Significant relationship between LVMI and results of I/D ACE polymorphism was observed both in women and men. I/D polymorphism relationship with LVMI was divergent in these 2 groups--association of higher LVMI with lack of DD type of polymorphism in women and presence of DD polymorphism in men. CONCLUSIONS: 1. Left ventricle hypertrophy in pts aortic stenosis is higher in men than in women. 2. In women left ventricle hypertrophy is related with ejection fraction, maximal aortic gradient, age and I/D ACE polymorphism; in men it is related to EF, MGA and I/D ACE polymorphism. 3. The influence of I/D ACE polymorphism on the left ventricle hypertrophy is divergent in women and men--in women related to the lack of DD polymorphism, in men related to the presence of DD polymorphism.

Adult↗

PubMed2003

Sequence-based polymorphisms in members of the apoptosis Bcl-2 gene family and their association with hematocrit level.

OBJECTIVE: The Bcl-2 family mediates erythropoietin-dependent survival of erythroid progenitor cells and regulates erythropoiesis. We assessed for any association between Bcl-2 family nucleotide variation and hematocrit (HCT) in healthy blood donors. METHODS: We screened Bcl-w, Bcl-x, and Bax (members of Bcl-2 family) using polymerase chain reaction and singlestrand conformation polymorphism analysis. One polymorphism each was found in Bax and Bcl-w. Using these markers, we genotyped the 100 males and 100 females with the highest or lowest HCT in a population of 819 healthy people in Iowa. A comparison of the allelic frequencies and distribution of each polymorphism was made in males versus females, individuals with low versus high HCT, and other subgroups. RESULTS: One sequence-based polymorphism was found in Bax and Bcl-w having three and two alleles, respectively. No polymorphism was found for Bcl-x. The Bax polymorphism is caused by variation in nucleotide A repeat number (19, 25, 27) at position 360 in 5'-region of Bax. The Bcl-w polymorphism is a G to A transition at 123. The allelic frequencies of Bax polymorphism were significantly different between males and females (P = 0.004). There were no significant associations for Bcl-w polymorphism by gender or HCT level (P > 0.05). CONCLUSIONS: Polymorphism in the 5'-region of Bax was associated with gender-based HCT differences. This is theoretically due to gender-based hormonal effects on gene transcription mediated by the different polymorphisms.

Alleles↗

PubMed2007

Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: associations with dopamine and serotonin receptor and transporter polymorphisms.

BACKGROUND: Little is known about the influence of polymorphisms of the dopamine and serotonin system on the risk for extrapyramidal symptoms (EPS) during treatment with antipsychotic drugs. METHODS: Of 119 subjects with schizophrenia treated with antipsychotics, 63 had current or previous EPS (acute dystonia, parkinsonism, tardive dyskinesia), and 56 had no such symptoms. All subjects were genotyped for a total of eight dopamine and serotonin receptor and transporter polymorphisms: the Taq1A polymorphism of the dopamine D(2) receptor (DRD2) gene, the Msc1 polymorphism of the dopamine D(3) receptor (DRD3) gene, the variable number of tandem repeat (VNTR) polymorphism of the dopamine transporter (DAT1) gene, four polymorphisms (102T/C, His452Tyr, 516 C/T, and Thr25Asn) of the serotonin 5-HT(2A) receptor (5HTR2A) gene, and the 5HTTLPR polymorphism of the serotonin transporter (5HTT) gene. RESULTS: The frequency of the A1 allele of the DRD2 Taq1A polymorphism was significantly higher in the EPS group than in the control group [16% vs. 7%, P = 0.040; odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.7]. Also, the 9 repeat allele of the DAT1 VNTR polymorphism was significantly more common in the EPS group (42% vs. 28%, P = 0.030; OR 1.9; 95% CI 1.1-3.3). Being a carrier of both DRD2 Taq1A A1 and DAT1 VNTR 9 repeat alleles was also significantly associated with the occurrence of EPS (19% vs. 6%, P = 0.040; OR 4.0; 95% CI 1.05-15.2) No significant differences in allele frequencies were found for the other polymorphisms. CONCLUSION: Presence of the Taq1A A1 allele of the DRD2 and the 9 repeat allele of the DAT1 VNTR polymorphisms might be risk factors for EPS caused by antipsychotic drugs.

Adult↗

PubMed2005

Cross-nucleation between ROY polymorphs.

Cross-nucleation between polymorphs is a newly discovered phenomenon important for understanding and controlling crystal polymorphism. It contradicts Ostwald's law of stages and other theories of crystallization in polymorphic systems. We studied the phenomenon in the spontaneous and seeded melt crystallization of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), currently the most polymorphic system of known structures. We observed extensive and sometimes selective cross-nucleation between ROY polymorphs. Certain polymorphs could not nucleate without the aid of others. The new polymorph was found to be more or less thermodynamically stable than the initial one but to always grow faster than or as fast as the initial one. The temperature and surface characteristics of the seed crystals affected the occurrence of cross-nucleation. Our results show that the pathway of crystallization in polymorphic systems is not determined solely by the initial nucleation, but also by cross-nucleation between polymorphs and the different growth rates of polymorphs. This study identified a new metastable polymorph of ROY, the 10th of the family.

Journal Article↗

PubMed2004

Different packing in three polymorphs of 2,4,6-trimethoxy-1,3,5-triazine.

2,4,6-trimethoxy-1,3,5-triazine was found to exhibit three different polymorphs. The alpha-polymorph undergoes reversible phase transformation to the beta-polymorph at 340 K with an enthalpy of 3.9 kJ mol(-1). The heat of fusion of the beta-polymorph at 404 K is 18.1 kJ mol(-1). The low-temperature phase (alpha-polymorph) crystallizes in the orthorhombic space group Pnma. The high-temperature phase (beta-polymorph) can be obtained from the melt and crystallizes in the monoclinic space group P2(1). The gamma-polymorph is obtained by crystallization from a 1:1 mixture of methanol and methylenechloride from hydrolyzed 2,4-dimethoxy-6-oxybenzophenone-1,3,5-triazine. The gamma-polymorph melts at 409 K with an enthalpy of 11.4 kJ mol(-1). The gamma-polymorph crystallizes in the trigonal space group R3c. The molecules occupy a crystallographic threefold axis. Molecules of 2,4,6-trimethoxy-1,3,5-triazine are planar in all three polymorphs. The major difference between the three polymorphs is the mode of packing of the molecules in the crystal.

Journal Article↗