Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism

BACKGROUND: The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. METHODS: The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for >or=6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. RESULTS: The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m2, n=13) than in children with the G/T genotype (5.7 L/h/m2, n=30; P=0.02) or the G/G genotype (7.0 L/h/m2, n=31; P=0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (>or=5 years of age) (9.7 L/h/m2 vs. 6.6 L/h/m2; P=0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. CONCLUSIONS: CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.     

Endothelial nitric oxide synthase haplotypes are associated with preeclampsia in Maya mestizo women

Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women. A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T→C, intron 4 variants, Glu298Asp of eNOS were determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r^{2}, and haplotype analysis was conducted. Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR =3.01; 95% CI = 1.74-5.23; P =2.9 × 10^{-4}).Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker.     

The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients

Various polymorphisms of the MDR1 gene that encodes for P-glycoprotein (P-gp), a transmembrane pump, have been identified. A silent mutation C3435T in exon 26 and a G2677T mutation in exon 21 have been correlated with P-gp expression and function in humans. The objectives of this study were (a) to determine whether the MDR1 exon 21 and exon 26 polymorphisms were related to steroid weaning in a pediatric heart transplant (HTx) population, and (b) to determine whether an association exist between the MDR1 exon 21 and exon 26 polymorphisms in these patients. Sixty-nine pediatric HTx patients were studied. MDR1 genotyping was determined by polymerase chain reaction amplification, sequencing the DNA, and sequence evaluation using Polyphred software (University of Washington) to identify genotypes. The steroid dose at 1 year post-transplantation was recorded. For steroid weaning at one year post-HTx for MDR1 C3435T, 12 of 18 (67%) patients in the CC genotype were still on prednisone, whereas only 18 of 47 (38%) of the CT/TT group were still receiving prednisone (p = 0.04). Similar results were observed for the MDR1 G2677T genotyping and steroid weaning. Forty-three of 46 patients (93.5%) who have MDR1 C3435T allele also have a mutant G2677T allele (p < 0.001). We conclude that (a) a significantly larger number of MDR1 3435 CC HTx patients remain on steroids at 1 year after transplantation, and (b) the MDR1 C3435T genotype is associated with the G2677 genotype in pediatric HTx patients.     

CYP3A5 3, CYP3A4 1B and MDR1 C3435T genotype distributions in Ecuadorians

Polymorphisms in CYP3A genes, such as CYP3A5} and CYP3A4, as well as in the MDR1 gene, which encodes for P-glycoprotein, have been implicated as genetic markers in several disorders. Differences in the frequency distribution of the allelic variants CYP3A5 3, CYP3A4 1B, and MDR1 3435T have been demonstrated between distinct ethnic groups. In this study we examined the frequency of these allelic variants in 317 healthy Mestizo individuals from Ecuador and made comparisons with results reported in the literature. The genotypes were determined by PCR-RFLP. Allele and genotype differences were studied by chi-square test. The MDR1 T allele frequency was similar to that of Spaniard or Asian populations, which is consistent with the ethnic origin of Ecuadorian Mestizo individuals (Amerindian and Spaniard Caucasians). By contrast, the CYP3A5 3 allele frequency was significantly lower in Ecuadorians than in Spaniards and other white populations and higher than in Central Americans, Asians and blacks. CYP3A4 1B was more common in Ecuadorians than in Caucasian or Asian populations but less present than in blacks. The differences in the polymorphism found in this work should be considered in allele-disease association studies.     

High-resolution melting curve analysis for high-throughput genotyping of NOD2/CARD15 mutations and distribution of these mutations in Slovenian inflammatory bowel diseases patients

Inflammatory bowel diseases (IBD) are usually classified into Crohn's disease (CD) and ulcerative colitis (UC). NOD2/CARD15 was the first identified CD-susceptibility gene and was confirmed as the most potent disease gene in CD pathogenesis. Three NOD2/CARD15 variants, namely two missense polymorphisms R702W (rs2066844) and G908R (rs2066845), and a frame shift polymorphism L1007fs (rs2066847), were associated with CD in Caucasian populations. High resolution melting analysis (HRMA) with saturation LCGreen dyes was previously reported as a simple, inexpensive, accurate and sensitive method for genotyping and/or scanning of rare variants. For this reasons we used qPCR-HRMA for genotyping NOD2/CARD15 variants in 588 Slovenian IBD patients and 256 healthy controls. PCR-RFLP was used as a reference method for genotyping of clinical samples. The optimization of an HRM experiment required careful design and adjustment of main parameters, such as primer concentration, MgCl_{2} concentration, probe design and template DNA concentration. Different HRMA approaches were tested and used to develop a reliable and low-cost SNP genotyping assays for polymorphisms in NOD2/CARD15 gene. Direct HRMA was the fastest and cheapest HRMA approach for L1007fs and R702W polymorphisms, yet for G908R polymorphism sufficient reliability was achieved after introduction of unlabeled probe. In association analysis, we found statistically significant association of L1007fs (p =0.001, OR=3.011, CI95%=1.494-6.071) and G908R (p=2.62 × 10^{-4}, OR=14.117, CI95%= 1.884-105.799) polymorphisms with CD patients. At least one of NOD2/CARD15 polymorphisms was found in 78/354 (22.03% (12.69%) in UC patients and in 26/256 (10.15%) in healthy controls. We have successfully implemented NOD2/CARD15 HRMA assays, which may contribute to the development of genetic profiles for risk prediction of developing CD and for differential diagnosis of CD vs. UC.     

MDR1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia

The human multidrug resistance (MDR1) gene encodes P-glycoprotein, which affects the pharmacokinetics of many drugs. We investigated whether common MDR1 single-nucleotide polymorphisms (C3435T and G2677T) affect predisposition to B-chronic lymphocytic leukemia (B-CLL). Genotyping was performed in 65 patients with CLL and in 70 controls using polymerase chain reaction—restriction fragment length polymorphism. We observed a higher frequency of carriers of 3435CT gene among B-CLL patients as compared to normal individuals (58.5 vs. 22.9 %, p?=?<0.001). The genotype 3435CT was associated with B-CLL [odds ratio = 4.8, 95 % confidence interval = 2.3–10.0]. Moreover, patient and control groups did not differ significantly regarding the MDR1 genotype (G2677T). Furthermore, no correlation was shown between the MDR1 (3435 or 2677) genotypes and clinical and laboratory data of patient group. These data indicate that MDR1 C3435T single-nucleotide polymorphism may carry an increased risk of developing B-CLL.     

Maternal risk for Down syndrome is modulated by genes involved in folate metabolism

Studies have shown that the maternal risk for Down syndrome (DS) may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B_{12} status) concentrations. The polymorphisms transcobalamin II (TCN2) c.776C>G, betaine-homocysteine S-methyltransferase (BHMT) c.742A>G, methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) c.677 C>T and the MTHFR 677C-1298A-1317T haplotype modulate DS risk. The polymorphisms MTHFR c.677C>T and solute carrier family 19 (folate transporter), member 1 (SLC19A1) c.80 A>G modulate folate concentrations, whereas the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) c.66A>G polymorphism affects the MMA concentration. These results are consistent with the modulation of the maternal risk for DS by these polymorphisms.     

Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria

Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9(*)3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.     

Genetic polymorphisms of biotransformation enzymes in patients with Hodgkin's and non-Hodgkin's lymphomas.

Considering the role in the metabolism of chemicals played by biotransformation enzymes, we aimed at determining whether any association exists between genetic polymorphisms in CYP1A1, CYP2E1, epoxide hydrolase (EPHX), glutathione S-transferases (GSTM1/P1/T1) and individual susceptibility to lymphomas. PCR-RFLP-based genotyping assays were used to determine the frequency of polymorphisms in CYP1A1 (3'-flanking region), CYP2E1 (5'-flanking region and intron 6), EPHX (exons 3 and 4), GSTM1 (deletion), GSTP1 (exon 5) and GSTT1 (deletion) in a case-control study comprised of 219 patients with morbus Hodgkin (MH) and non-Hodgkin's lymphomas (NHL) and 455 age- and sex-matched healthy individuals. The distribution of genotypes in CYP2E1-intron 6 was significantly different between the control group and all lymphomas (P = 0.03), patients with NHL (P = 0.024), and especially aggressive diffuse NHL (P = 0.007). Grading of NHL seemed to be associated with this polymorphism as well (P = 0.041). The EPHX-exon 3 genotype distribution was significantly different between control males and males with all lymphomas (P = 0.01) or with NHL (P = 0.019). The Val/Val genotype of GSTP1-exon 5 was prevalent in all MH [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.05-4.14] and this difference was particularly evident in females (OR = 2.97, 95% CI = 1.16-7.61). A significant difference in the distribution of GSTP1-exon 5 genotypes was found between NHL tumors >5 cm and those <5 cm (P = 0.03). The results suggest that genetic polymorphisms of biotransformation enzymes may play a significant role in the development of lymphoid malignancies.     

Absence of kl-vs variant of klotho gene in Iranian cardiac patients (comparison to the world populations)

Objective: Klotho has an important role in development of coronary artery (CAD) disease. A functional variant of klotho gene (kl-vs) has been found as an independent risk factor for early-onset occult coronary artery disease (CAD) in previous studies. The Frequency of this variant was not known in Iranian population. We have examined the allele frequency of the kl-vs variant in a case-control study in an Iranian population. Methods and results: Genotyping for kl-vs variant was carried out in N=107 individuals including N=54 cases and N=53 control who all underwent coronary angiogram for CAD evaluation. Patients with >50% stenosis in vessels considered as case groups (or CAD^{+}) and patients with normal vessels (or CAD^{-}) as controls. The frequency of kl-vs variant was determined in these patients using PCR-RFLP technique. None of the individual was carrying the kl-vs mutation in our samples. The frequency of kl-vs mutation was significantly different from previous studies in different populations. Conclusion: The kl-vs variant seems to be scare found in the Iranian population in comparison to other populations reported previously. Klotho gene might be a candidate gene of atherosclerosis in some populations but not in Iranian population. Further studies are required to examine the frequency of kl-vs variant in other populations from the Middle East.     

CYP1B1基因多态性与子宫内膜异位症易感性的相关研究

目的 研究CYP1B1基因第2外显子119(G-T)、第3外显子432(C-G)多态性与子宫内膜异位症(endometriosis,Ems)易感性的关系.方法 采用等位基因特异性聚合酶链反应对55例Ems患者和45例对照组进行CYP1B1基因第2外显子119(G-T)、第3外显子432(C-G)突变分析,探讨Ems的发生与CYP1B1基因多态性之间的相关性.结果 CYP1B1基因密码子119中等位基因G、T在Ems组和对照组分布的差异有统计学意义(P＜0.05),其中等位基因T使Ems发病风险提高2.061倍;CYP1B1基因密码子119G/T各基因型分布两组间差异有统计学意义(P＜0.05),纯合突变(T/T)基因型、杂合突变(G/T)基因型与野生型(G/G)基因型相比,患Ems的危险度分别为2.625倍和3.214倍.以CYP1B1联合野生型GG和CC个体的OR值为1相比,CYP1B基因密码子119杂合型突变(Ala/Ser)合并密码子432野生型个体的OR值为2.976,95%CI:1.129～7.848,P＜0.05.结论 CYP1B1基因第2外显子119(G-T)突变等位基因与Ems的发生有一定关系,突变基因型增加了Ems的发病风险;CYP1B1基因第2外显子杂合型突变(Ala/Ser)联合密码子432野生型能增加Ems的发病风险.     

Polymorphisms in genes that regulate cyclosporine metabolism affect cyclosporine blood levels and clinical outcomes in patients who receive allogeneic hematopoietic stem cell transplantation

In patients who received allogeneic hematopoietic stem cell transplantation (HSCT), we investigated the correlations between single nucleotide polymorphisms (SNPs) in genes that regulate cyclosporine metabolism and clinical outcomes. All patients received sibling-matched HSCT. DNA samples of patients and donors were analyzed for 4 SNPs: MDR1 +1236C>T (rs1128503), +2677G>T>A (rs2032582), +3435C>T (rs1045642), and CYP3A5 +6986G>A (rs776746). A total of 156 patients (median age 40 years) were analyzed. Nineteen patients received HSCT for nonmalignant disease. The CYP3A5 +6986AA genotype was associated with a high cyclosporine blood level after transplantation. However, this genotype was not related to any particular clinical outcome. In contrast, the MDR1 +1236C>T SNP was correlated with specific clinical outcomes. When neither the donor nor the recipient had the CC genotype of MDR1 +1236, patients had lower creatinine levels (P < .001) and less transplantation-related mortality (TRM) (P = .012). These patients also showed longer overall survival (OS) in both univariate (P = .003) and multivariate (P = .003) analyses. Although the CYP3A5 +6986AA genotype was correlated with a high blood cyclosporine concentration, lack of the MDR1 +1236CC genotype in both the donor and recipient was correlated with less TRM and a longer OS in patients who received allogeneic HSCT.     

Impact of glutathione S-transferase M1 and T1 gene polymorphisms on the smoking-related coronary artery disease

Glutathione S-transferase (GST) plays a key role in the detoxification of xenobiotic atherogen generated by smoking. To analyze the effect of GSTM1/T1 gene polymorphisms on the development of smoking-related coronary artery disease (CAD), 775 Korean patients who underwent coronary angiography were enrolled. The subjects were classified by luminal diameter stenosis into group A (>50%), B (20-50%), or C (<20%). GSTM1 and GSTT1 gene polymorphisms were analyzed using multiplex polymerase chain reaction (PCR) for GSTM1/T1 genes and CYP1A1 gene for internal control. Of 775 subjects, 403 patients belonged to group A. They had higher risk factors for CAD than group B (N=260) and group C (N=112). The genotype frequencies of null GSTM1 and GSTT1 showed no significant differences among 3 groups. Considering the effect of GSTM1 gene polymorphisms on the smoking-related CAD, smokers with GSTM1 null genotype had more increased risk for CAD than non-smoker with GSTM1 positive genotype (odds ratios [OR], 2.07, confidence interval [CI], 1.06-4.07). Also the effect of GSTT1 gene polymorphism on smoking-related CAD showed the same tendency as GSTM1 gene (OR, 2.00, CI, 1.05-3.84). This effect of GSTM1/T1 null genotype on smoking-related CAD was augmented when both gene polymorphisms were considered simultaneously (OR, 2.76, CI, 1.17-6.52). We concluded that GSTM1/T1 null genotype contributed to the pathogenesis of smoking-related CAD to some degree.     

武汉地区原发性高血压代谢综合征与CYP11B2-344T/C基因多态性关系的探讨

目的:探讨武汉地区原发性高血压(EH)代谢综合征(MS)与醛固酮合成酶(CYP11B2)基因-344C/T多态性的关系。方法:701例武汉地区汉族人群分为3组,其中血压正常对照组303例,EH伴MS组189例,EH不伴MS组209例。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测3组人群CYP11B2-344T/C基因多态性。结果:(1)EH不伴MS组CYP11B2基因CC+TC基因型频率明显高于血压正常对照组。(2)CYP11B2TT基因型EH伴MS组的血压水平明显高于其它基因型。结论:EH不伴MS与CYP11B2基因多态性相关;EH伴MS患者血压水平与CYP11B2基因TT基因型明显相关。     

变性高效液相色谱法检测中国汉族人SCN1A外显子16T1067A基因多态性

目的 建立检测SCN1A外显子16 T1067A单核苷酸多态性(SNP)的变性高效液相色谱(DHPLC)方法,并检测中国汉族人SCN1A外显子16 T1067A基因多态性.方法 设计针对SCN1A编码区引物,应用DHPLC技术检测其序列多态性,并检测127例中国汉族人SCN1A外显子16 T1067A基凶多态性.结果 127例汉族人中,SCNIA T1067A AA、AG、GG表型频率分别为0.8031、0.1969、0,SCNIA T1067A A、SCN1A T1067A G基因频率分别为0.9016、0.0984.结论 DHPLC简便、快速、准确.适合于大规模的人群调查.SCN1A外显子16 T1067A基因多态性在不同种族间分布存在着明显的差异.     

温州地区汉族正常人群CYP1A2基因多态性分布特征

目的检测CYP1A2基因多态性在温州地区汉族正常人群的分布特征。方法采用聚合酶链反应（PCR）产物直接测序法检测108例随机血液样本DNA中CYP1A2基因序列单核苷酸多态性位点（SNP）的分布。对检测到的3个多态位点2159G〉A、3613T〉C、5347C〉T,进一步采用PCR技术分析472例正常人位点的基因型频率和等位基因频率。结果 （1）2159 G〉A位点：G和A等位基因的频率分别为93.8%,6.2%,GG、GA、AA基因型频率分别为87.7%、12.1%、0.2%（χ2=0.325,P〉0.05）;（2）3613 T〉C位点：T和C等位基因的频率分别为97.9%、2.3%,TT、TC、CC基因型频率分别为95.3%、4.4%、0.3%（χ2=0.298,P〉0.05）;（3）5347 C〉T位点：C和T等位基因的频率分别为87.9%、12.1%。CC、CT、TT基因型分布频率分别为77.8%、20.3%、1.9%（χ2=0.742,P〉0.05）;（4）2159 G〉A、5347 C〉T组成的单倍型频率为3.2%。结论温州地区汉族正常人群CYP1A2基因存在2159G〉A、3613T〉C、5347C〉T多态位点。     

Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss

The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40-1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53-1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71-1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68-2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.     

Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphism in postmenopausal women: correlation to bone mineral density and susceptibility to osteoporosis

OBJECTIVE: Osteoporosis is a common disorder with a strong genetic component. Our aim was to investigate the correlations of the interleukin-1beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1Ra) gene polymorphisms with bone mineral density (BMD) and their relationship to osteoporosis. METHODS: The IL-1beta (promoter and exon 5) and IL-1Ra (intron 2) gene polymorphisms were determined using polymerase chain reaction. BMD of the lumbar spine and proximal femur were measured using dual-energy X-ray absorptiometry. RESULTS: The prevalence of each genotype of the interleukin-1 related genes in the study population was: (1) 14% C/C, 71.5% C/T, and 14.5% T/T in IL-1beta promoter; (2) 95.3% E1/E1 and 4.7% E1/E2 in IL-1beta exon 5; (3) 92.4% I/I, 6.4% I/II, and 1.2% II/II in IL-1Ra intron 2. After adjustment for potential confounding factors such as age, height, weight, years since menopause, and daily calcium intake, subjects with genotype E1/E2 (n=8) in IL-1beta exon 5 had lower BMD values and a significantly greater risk for osteoporosis (OR 10.6, 95% CI 1.3-83.8) at the lumbar spine when compared with subjects with genotype E1/E1 (n=164) in IL-1beta exon 5. CONCLUSION: The Taq I IL-1beta exon 5 gene polymorphism is associated with reduced BMD and predisposes women to osteoporosis at the lumbar spine, but our results should be interpreted with caution because of the small number of subjects with the unfavorable E1/E2 genotype.     

Linkage disequilibrium at the cystathionine β synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine

Cystathionine β synthase (CBS) is a key enzyme in homocysteine metabolism. We have examined four apparently non-functional polymorphisms in the CBS gene and have determined their frequency, degree of linkage disequilibrium and association with plasma homocysteine levels. The polymorphisms are a 68 bp insertion in exon 8, C699T in exon 8, C1080T in exon 11 and C1985T in the 3′ untranslated region. 785 individuals participating in the European Atherosclerosis Research Study II (EARSII), from 11 countries across Europe were genotyped for these polymorphisms. The 68bp insertion had the highest frequency in the UK and in the Middle region, with a lower frequency in the Baltic and the South (p=0.01), and the exon 11 polymorphism had the highest frequencies of the rare allele in the Baltic (p<0.05). There was a high degree of linkage disequilibrium between the polymorphisms (p<0.001 overall), except between C699T and the C1985T, with three common haplotypes accounting for nearly 80% of chromosomes. Examination of the association between these polymorphisms and plasma homocysteine levels revealed that the carriers of the rare alleles of the C699T, C1080T and C1985T polymorphisms had lower plasma homocysteine concentrations than those homozygous for the common alleles, although these differences were not statistically significant. The thermolabile valine variant caused by a substitution of a C for a T at nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) has previously been shown to have profound effects on plasma levels of homocysteine in this sample, but the homocysteine-raising effect associated with this thermolabile variant was not seen in carriers of the 68 bp insertion, with this interaction being statistically significant (p<0.001). These data demonstrate that variation in the CBS gene as detected with these four polymorphisms, had no statistically significant effect on plasma homocysteine levels in these healthy young men. However, the presence of the 68 bp insertion, which is found in approximately 7.5% of individuals in the populations of Europe sampled, abolishes the raising effect of thermolabile MTHFR Val/Val genotype, and may be of importance in the situation of high homocysteine.     

Odd-even effects in polymeric liquid crystals

Semiflexible mesophasic polymers of the general formula \documentclass{article}\pagestyle{empty}\begin{document}$ \rlap{--} [{\rm OOC(CH}_{\rm 2} {\rm )}_{n - 2} - {\rm COO} - {\rm R}^1 \rlap{--} ]_{\rm X} ,n = 9,11,13,\rlap{--} [{\rm OOC(CH}_{\rm 2} )_{n - 2} - {\rm COO} - {\rm R}^2 \rlap{--} ]_{\rm X} ,n = 9,11,13,14, $\end{document} and \documentclass{article}\pagestyle{empty}\begin{document}$ \rlap{--} [{\rm OOCO} - {\rm (CH}_{\rm 2} {\rm )}_{n - 4} - {\rm OCOO} - {\rm R}^2 \rlap{--} ]_{\rm X} ,n = 9,11,13, $\end{document} where \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm R}^{\rm 1} = - {\rm C}_{\rm 6} {\rm H}_{\rm 5} - {\rm C}({\rm CH}_3 ) = {\rm CH} - {\rm C}_6 {\rm H}_5 - $\end{document} and \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm R}^{\rm 2} = {\rm C}_{\rm 6} {\rm H}_{\rm 5} - {\rm C}({\rm CH}_3 ) = {\rm N} - {\rm N} = ({\rm CH}_3 ){\rm C} - {\rm C}_6 {\rm H}_5 - $\end{document} are prepared and their solid and liquid crystalline behaviour examined and compared to that of the corresponding homologues with n even. Evidence is given of relevant odd-even effects in the thermodynamic parameters of the clearing transition. The conclusion is drawn in favour of an anisotropic structuration also of the flexible parts of the polymer chain in the liquid crystal phase.