Genetic association study and meta-analysis of the HTR2C Cys23Ser polymorphism and migraine

The objectives of this study were to determine if the HTR2C Cys23Ser polymorphism is associated with migraine in a case-control study, and to perform a meta-analysis with present and previous available studies. The HTR2C gene is located at the Xq24-q28 chromosomal band. This band was linked to migraine with aura (MA) in two Australian families. Using the HTR2C Cys23Ser allelic variant, this gene has been ruled out as a migraine gene in 3 out of 4 studies. Only the Japanese study reported a higher risk for MA (OR=6.11; 95% CI=1.70−21.97, p trend<0.01). We performed a case-control study with 335 migraine subjects and 335 sex- and age-matched controls, and a meta-analysis pooling the results of the available data from MA subsets of patients. In the association study we found no significant differences among migraine and MA patients for this polymorphism. In the meta-analysis, under the fixed-effect model, the Ser allele did not confer higher risk for suffering MA (pooled OR=1.1; 99% CI=0.8−1.5, p=0.499). Our study did not confirm the HTR2C Cys23Ser polymorphism as a risk factor for migraine and MA.     

Dopamine (DRD2) and Serotonin (HTR2A, 2C) Receptor Gene Polymorphisms do not influence early response to Risperidone in South Indian Patients with Schizophrenia

Treatment response to antipsychotic drugs is variable and conflicting results have been obtained while studying the influence of DRD2 and HTR2 genetic variants on antipsychotic drug efficacy. To explore further, the present study aimed to assess the influence of DRD2 ‐141 C Ins/Del, Taq1A and HTR2A ‐1438 G/A, 102T/C and HTR2C ‐759 C/T genetic polymorphisms in response to risperidone in patients with schizophrenia. The study was conducted among the n = 320 South Indian patients with schizophrenia who received risperidone treatment (4–8 mg per day) for a minimum of four weeks. Genotyping was done by real‐time PCR. Antipsychotic response was assessed using CGI‐I score in cross‐sectional group, PANSS score in prospective group at baseline and after receiving the risperidone therapy. DRD2 ‐141 C Ins/Del (n = 310, Ins/Ins = 177, Ins/Del+ Del/Del = 133, OR 0.70, 95% CI 0.4–1.2 p 0.2), Taq1A (n = 320, AA = 35, AG = 132, GG = 153, p 0.2), HTR2A ‐1438 G/A (n = 320, AA = 39, AG = 164, GG = 117, p 0.2), HTR2A 102T/C (n = 320, CC = 115, CT = 165, TT = 40, p 0.1) HTR2C ‐759 C/T (females n = 132, CC = 65, CT+TT = 67, OR 1.3, 95% CI 0.6–2.8, p 0.5; males n = 186, C = 120, T = 66, OR 1.2, 95% CI 0.6–2.4, p 0.4) genetic polymorphisms did not show any association with antipsychotic response to risperidone. DRD2 ‐141 C Ins/Del, Taq1A, HTR2A ‐1438 G/A, 102T/C and HTR2C ‐759 C/T genetic variants are not associated with antipsychotic response to risperidone.     

Determinants of antidepressant medication prescribing in elderly residents of aged care homes in Australia: A retrospective study

Background: Depression is underrecognized and poorly treated among older people living in aged care homes worldwide. Depression has been associated with higher rates of recurrence, disability, and death in older people.Objectives: The primary objective of this study was to assess the determinants of antidepressant medication prescribing among older people living in aged care homes in Australia. A further objective was to investigate the anti-depressant medications in common use, doses of antidepressants, and concurrent pharmacotherapy among people receiving antidepressants.Methods: A random sample of 500 deidentified medication review reports was extracted from a database containing >165,000 Residential Medication Management Review reports. Residents' demographic and clinical characteristics, medical diagnoses, and prescribed medications were systematically extracted from these reports. Logistic regression models were used to determine factors associated with the prescribing of any antidepressant, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and “other” antidepressants (eg, mianserin, mirtazapine, venlafaxine).Results: The mean (SD) age of the residents was 84.0 (9.0) years. Seventy-five percent were female. The prevalence of antidepressant prescribing among these aged care home residents was 33.0%. SSRIs were more commonly prescribed than TCAs, monoamine oxidase inhibitors, and other antidepressants. Antidepressants were more likely to be prescribed in people treated for dementia with mood disorder (odds ratio [OR] = 9.70; 95% CI, 5.26–17.88), depression (OR = 13.28; 95% CI, 6.44–27.36), and Parkinson's disease (OR = 3.56; 95% CI, 1.37–9.23). SSRI prescribing was associated with dementia with mood disorder (OR = 5.85; 95% CI, 3.19–10.72) and depression (OR = 6.44; 95% CI, 3.38–12.26). TCA prescribing was associated with depression (OR = 2.95; 95% CI, 1.18–7.35) and concurrent benzodiazepine use (OR = 2.43; 95% CI, 1.03–5.72). Other antidepressant prescribing was associated with dementia with mood disorder (OR = 6.53; 95% CI, 3.15–13.50) and depression (OR = 5.00; 95% CI, 2.23–11.19).Conclusions: There was preferential prescribing of SSRI antidepressants among these older aged care home residents with depression. Cognitive impairment alone was not significantly associated with antidepressant prescribing; however, these aged care home residents with dementia and mood disorders had an increased likelihood of being treated with antidepressants. The prescribing of TCAs was significantly associated with concurrent benzodiazepine use.     

云南三民族人群IL-18启动子基因多态性与HBV感染的相关性研究

目的分析云南省西双版纳地区基诺族、傣族和哈尼族人群IL-18启动子基因多态性的分布,并对其多态性与HBV感染的相关性进行探讨。方法运用PCR-测序的方法对三民族人群IL-18启动子G-137C、C-607A和G-656T位点进行基因分型,并分析其基因多态性与HBV感染的相关性。结果 （1）基诺族人群G-137C位点基因型和等位基因分布频率与其他两民族相比差异有统计学意义（基诺族vs.傣族：χ2值分别为49.374和37.482,P值均为0.000;基诺族vs.哈尼族：χ2值分别为34.028和26.900,P值均为0.000）。（2）C-607A（G-656T）位点基因型与等位基因分布频率三民族相比均有统计学意义（基诺族vs.傣族：χ2值分别为21.140和16.681,P值均为0.000;基诺族vs.哈尼族：χ2值分别为8.166和5.061,P值分别为0.017和0.024;傣族vs.哈尼族：χ2值分别为8.115和6.140,P值分别为0.017和0.013）。（3）哈尼族人群HBsAg阳性组与HBsAg阴性组G-137C基因型分布频率差异有统计学意义（χ2=9.776,P=0.008）,CC基因型与GG基因型＋GC基因型相比P=0.026,OR=6.194,95%CI=1.310～29.299;GC基因型与CC基因型＋GG基因型相比P=0.036,OR=0.311,95%CI=0.105～0.924。结论 IL-18启动子G-137C、C-607A和G-656T基因型和等位基因分布频率具有民族差异,其多态性对HBV感染易感性的影响也因民族不同有所差异,G-137C多态性与哈尼族HBsAg携带相关。     

Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and olanzapine-induced weight gain among Korean schizophrenic patients

Background: Weight gain can be an adverse effect of antipsychotics that significantly affects long‐term health and treatment compliance. Many reports have suggested that the 5‐HT2C receptor gene (HTR2C) is related to appetite and eating behaviours associated with body weight change. We hypothesized that there was a relationship between the HTR2C ?759C/T polymorphism and olanzapine‐induced weight gain. Method: Seventy‐nine Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long‐term treatment for at least 3 months. We controlled the use of drugs other than olanzapine except benzodiazepines and anticholinergics. Genotyping for the HTR2C ?759C/T polymorphism was performed on all participants. Result: We found that long‐term treatment with olanzapine resulted in mean gains in weight and BMI of 5·2 kg and 1·93 kg/m², respectively. However, body weight changes from baseline to the study endpoint were not significantly associated with genotypes. The frequency of the T allele did not differ significantly between subjects with weight gains below and above a clinically significant cutoff, defined as 7% relative to baseline (χ² = 0·213, P = 0·445), indicating that the T allele had no protective effect against olanzapine‐induced weight gain. Discussion and conclusion: The findings from this study do not support the presence of a relationship between the –759C/T polymorphism of the HTR2C gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.     

Interleukin‐18 gene 105A/C genetic polymorphism is associated with the susceptibility of Kawasaki disease

Interleukin‐18 (IL‐18)‐656T/G, ‐607A/C, and ‐137C/G promoter polymorphisms had been reported associated with Kawasaki disease (KD). An IL‐18 genetic A/C polymorphism at coding position 105 (rs549908) has been linked with asthma, rheumatoid, and systemic lupus erythematosus. We tested a hypothesis that the IL‐18 105A/C genetic polymorphism confers KD susceptibility. Study participants were Taiwanese KD patients and a healthy control group. Our data indicated that the frequency of C allele was significantly higher in the patient group (13.9%) than in the control group (2.7%; P<0.0001, odds ratio [OR]=5.93; 95% confidence interval [CI]=2.57–13.73). Therefore, persons with the C allele may have higher risk of deve loping KD. In addition, compared with the haplotype frequencies between case and control groups, the KD patients with TACC haplotype appeared to be a significant “at‐risk” haplotype compared with other haplotypes (OR: 4.62, 95% CI: 1.71–12.43; P=0.001). KD patient with the TAGA haplotype appeared to be a significant “protective” haplotype compared with other haplotypes (OR: 0.51, 95% CI:0.29–0.89; P=0.017). Our results suggest that 105A/C polymorphism and the haplotypes in IL‐18 gene are associated with the risk of KD in Taiwanese population. Clin. Lab. Anal. 23:71–76, 2009. © 2009 Wiley‐Liss, Inc.     

A novel genetic variant of BMP2K contributes to high myopia

Loss of eye growth regulation may cause myopia, because modulation of optic globe size is essential for the generation of normal optic power. Evidence has implied variations of BMP2 gene expression mediate ocular development and retinal tissue remodeling. Given BMP2 as a potential regulator involved in myopia development, we investigate whether gene BMP2‐inducible kinase (BMP2K, BIKe), whose expression is up‐regulated during BMP2‐induced osteoblast differentiation, contributes to susceptibility of high myopia. Participants grouped into high myopia had a spherical equivalent greater than ?6.00 D, compared with a control group of spherical equivalent less than ?0.5 D. Genotyping of polymorphisms 1379 G/A (rs2288255) and 3171 C/G (rs12507099), corresponding with 405 Gly/Ser and 1002 Thr/Ser variation in the BMP2K gene were determined by PCR‐restriction fragment length polymorphism and associative study performed by comparing high myopic subjects and healthy controls. The frequency of A allele in the BMP2K gene 1379 G/A polymorphism showed a significant difference between cases and controls (P<0.001, OR=2.99, 95% CI=1.62–5.54) and subjects with either AA or AG genotype show higher risk than GG genotype (P<0.001, OR=3.07, 95% CI=1.59–5.92), while 3171 C/G polymorphism was not significant from this survey. These data suggest that BMP2K gene 1379 G/A variant is strongly correlated with high myopia and may contribute to a genetic risk factor for high degrees of myopic pathogenesis. J. Clin. Lab. Anal. 23:362–367, 2009. © 2009 Wiley‐Liss, Inc.     

Association between the G1246A polymorphism of the <Emphasis Type="Italic">hypocretin receptor 2 gene</Emphasis> and cluster headache: a meta-analysis

The objective of this study was to investigate the association between polymorphisms of the hypocretin receptor 2 gene (HCRTR2) and the risk of cluster headache (CH). The study is a meta-analysis of published case-control studies investigating the association between polymorphisms of the HCRTR2 gene and CH. Pooled odds ratios (OR) were estimated using both random (RE) and fixed effects (FE) models. Three studies, performed in five different European countries, with 593 cases and 599 controls, were included in the study. Allele G of the G1246A HCRTR2 polymorphism was significantly associated with CH (FE OR 1.58, CI 95% 1.27–1.95; RE OR 1.55 (1.14–2.12)). Carriers of the GG genotype showed a higher disease risk compared to the remaining genotypes (FE OR 1.75, CI 95% 1.37–2.25; RE OR 1.69, CI 95% 1.11–2.58). Our data confirm that the G1246A polymorphism of the HCRTR2 gene may modulate the genetic risk for CH.     

A single-nucleotide polymorphism in the TP53 and MDM-2 gene modifies breast cancer risk in an ethnic Arab population

Breast cancer is the most common oncological disease in women worldwide. Genetic predisposition to breast cancer can be associated with single‐nucleotide polymorphisms (SNPs), which are observed in many women. Such gene polymorphisms, in combination with nutritional and environmental factors, can affect breast cancer development. The tumor suppressor TP53 and its negative regulator MDM2 play crucial roles in carcinogenesis. Previous case–control studies have revealed that TP53 72Arg > Pro and MDM2 309T > G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and breast cancer susceptibility in the Saudi population has not been explored. In this study, we performed a case–control study of patients with breast cancer and healthy controls in a Saudi population using TaqMan‐based real‐time PCR. We found an increased breast cancer risk associated with the MDM2 GG [odds ratio (OR) = 2.79, 95% confidence interval (CI) = 2.04–3.92] and TG [OR = 1.43, 95% CI = 1.12–2.02] genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 2.19, 95% CI = 1.54–3.06) compared with the Arg/Arg genotype. The gene–gene interaction of MDM2 and TP53 polymorphisms increased breast cancer risk in a multiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 7.71, 95% CI = 3.49–17.54). These findings suggest that polymorphisms of MDM2 and TP53 genes may be a genetic modifier for developing breast cancer in this ethnic population in the Arab world.     

Endothelin-converting enzyme-1b C-338A polymorphism is associated with the increased risk of coronary artery disease in Chinese population

BACKGROUND: Endothelin-converting enzyme-1 (ECE-1), the key enzyme responsible for endothelin-1 generation, has been linked to coronary artery disease (CAD). Recently, a genetic polymorphism (ECE-1b C-338A) located in ECE-1 gene promoter was identified. However, it is unclear whether this polymorphism is associated with the risk of CAD. METHODS: We conducted a study with CAD patients and controls matched by age and sex to examine the prevalence of ECE-1b C-338A polymorphism in CAD. RESULTS: The frequencies of ECE-1b-338CC, CA, and AA genotypes in cases (40.1%, 42.2%, and 17.7%) were significantly different from those of controls (50.6%, 40.5%, and 8.9%, chi2=9.989, P=0.007). Subjects with the variant genotypes (CA+ AA) had a 58% increased risk of CAD relative to CC carriers (adjusted OR=1.58, 95% CI=1.07-2.32). Furthermore, the adjusted OR of AA genotype for CAD was 2.33 (95% CI=1.25-4.35). In stratified analyses, the A allele was significantly associated with increased risk of CAD in female (adjusted OR=2.86, 95% CI=1.40-5.84) and subjects with age >or= 64 y (adjusted OR=2.96, 95% CI=1.73-5.08). Moreover, the frequency of patients with variant genotypes increased gradually from single- to triple-vessel disease although without statistical significance (P=0.069 for trend). CONCLUSION: Our results suggested that ECE-1b-338C to A variant might be associated with increased risk of CAD in Chinese population.     

CYP2E1, GSTM1 and GSTT1 genetic polymorphisms and susceptibility to antituberculosis drug-induced hepatotoxicity: a nested case-control study

What is Known and Objective: The pathogenic mechanism of antituberculosis drug‐induced hepatotoxicity (ATDH) is thought to involve drug‐metabolizing enzymes including N‐acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S‐transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital‐based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case–control study nested in a population‐based prospective antituberculosis treatment cohort. Methods: A total of 4304 patients with smear‐positive tuberculosis (TB) who received standard short‐course chemotherapy were monitored for 6–9 months. Incidence density sampling method was adopted to select controls and 4 : 1 matched with each ATDH cases by age (±5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR–RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P‐values. Results and Discussion: A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0·99, 95% CI:0·62–1·59; OR = 1·13, 95% CI: 0·40–3·20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1·22, 95% CI: 0·76–1·96; OR = 0·96, 95% CI: 0·60–1·52, respectively) compared with non‐null genotypes. What is new and Conclusion: This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case–control population‐based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population.     

The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients

Background. Bleeding is a serious adverse drug reaction associated with warfarin therapy, often induced by interacting co-medication.

Methods. We investigated the frequency and clinical consequences of warfarin drug interactions utilizing medical records of 6,772 warfarin-treated in-patients of Turku University Hospital.

Results. A total of 48% of warfarin-treated in-patients were exposed to interacting co-medication. Adjusted odds ratio (OR) for bleeding was highest for cytochrome P450 2C9 (CYP2C9) inhibitors (OR 3.6; 95% confidence interval (CI) 2.4–5.6). Non-selective non-steroidal anti-inflammatory drugs (NSAID) and coxibs were associated with a bleeding risk of a similar magnitude (OR 2.6; 95% CI 1.6–4.2 and OR 3.1; 95% CI 1.4–6.7, respectively). Selective serotonin re-uptake inhibitors (SSRI) were associated with a remarkably higher bleeding risk than non-SSRIs (OR 2.6; 95% CI 1.5–4.3 and OR 1.2; 95% CI 0.3–4.3, respectively). Odds ratio for bleeding in the platelet aggregation inhibitor group was 1.6 (95% CI 0.8–3.1).

Conclusion. We conclude that co-medication in warfarin-treated in-patients is common and should be carefully evaluated to decrease the bleeding risk associated with warfarin therapy.     

鼠双微粒体2基因rs1625525和rs1196336位点基因多态性与乳腺癌遗传易感性的相关性研究

目的 探讨鼠双微粒体2(murine double minute 2,MDM2)基因rs1625525,rs1196336两个位点多态性与乳腺癌遗传易感性的关系。方法 选取2021年1月～12月中国人民解放军联勤保障部队第九二三医院收治的乳腺癌患者176例,乳腺良性瘤患者156例,同期女性健康体检者203例作为研究对象,采用多重SNaPshot技术检测MDM2基因rs1625525A/G和rs1196336A/T两个位点的基因多态性,比较各组两位点基因型和等位基因频率,分析两个位点多态性与乳腺癌遗传易感性的关系。结果 MDM2基因rs1625525位点的AA,AG和GG基因型在乳腺癌组的基因型频率分别为48.9%,39.2%和11.9%,在对照组的基因型频率分别为50.7%,44.3%和5.0%。三种基因型在对照组与乳腺癌组分布频率差异有统计学意义(χ²=6.314,P<0.05), GG基因型和隐性模型可能增加乳腺癌的患病风险(OR=2.522,95%CI:1.115～5.708,P=0.026;OR=2.699,95%CI:1.221～5.966,P=0...     

No association between bipolar disorder risk polymorphisms in ANK3 and CACNA1C and common migraine

(Headache 2011;51:713‐725) Background.— Migraine and bipolar disorder are characterized by a high level of co‐morbidity, and a common familial–genetic basis has recently been hypothesized for the 2 disorders. Genome‐wide association studies have reported strong evidence of association between the polymorphisms rs10994336[T] in the ANK3 gene and rs1006737[A] in the CACNA1C gene and risk of bipolar disorder. Objective.— The aim of this study was to evaluate the hypothesis of a genetic linkage between migraine and bipolar disorder by investigating the familial transmission of the 2 bipolar disorder risk polymorphisms, in a sample of family trios with probands with childhood migraine, and unrelated controls. Methods.— Our sample comprised 192 family trios, each with a proband with childhood migraine (137 migraine without aura, 44 migraine with aura) and 228 unrelated controls. The markers rs10994336 and rs1006737 were genotyped using a TaqMan single nucleotide polymorphism Genotyping Assay. The transmission disequilibrium test analysis for the family trios and the case–control analysis were performed using the program UNPHASED. Results.— The allelic and genotypic transmission disequilibrium test analysis did not show any evidence of transmission distortion of the 2 markers in both migraine overall (rs10994336: OR = 1.61, P = .11; rs1006737: OR = 1.12, P = .49) and in the migraine without aura and migraine with aura subgroups. Likewise, the case–control analysis of alleles and genotypes frequencies did not show any evidence of association. Conclusion.— In the present study, we did not find evidence for association between the bipolar disorder risk polymorphisms rs10994336 in the ANK3 gene and rs1006737 in the CACNA1C gene in migraine. However, as these are variants that have a small effect on the risk of bipolar disorder (OR < 1.5), we cannot exclude a similar small effect on migraine susceptibility with the present sample size.     

The role of thrombin activatable fibrinolysis inhibitor in arterial thrombosis at a young age: the ATTAC study1

Summary. Background and objectives: Thrombin activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis and may therefore contribute to the pathophysiology of arterial thrombosis. The aim of the present study was to elucidate the pathogenetic role of TAFI levels and genotypes in young patients with arterial thrombosis. Patients and methods: In a case–control study, 327 young patients with a recent first‐ever event of coronary heart disease (CHD subgroup) or cerebrovascular disease (ischemic stroke subgroup) and 332 healthy young controls were included. TAFI levels [intact TAFI, activation peptide (TAFI‐AP) and (in)activated TAFI (TAFIa(i)] and TAFI activity were measured and genetic variations in the TAFI gene (?438G/A, 505G/A and 1040C/T) were determined. Results: In the total group of patients, TAFIa(i) levels were higher (145.1 ± 37.5%) than in controls (137.5 ± 31.3%, P = 0.02). Plasma levels of intact TAFI, TAFI‐AP and TAFI activity were similar in patients and controls. In the CHD subgroup (n = 218), intact TAFI levels were higher (109.4 ± 23.0%) than in controls (102.8 ± 20.7%, P = 0.02). In 325Ile/Ile homozygotes, lower TAFI levels and a decreased risk of arterial thrombosis were observed (OR 0.58, 95% CI 0.34–0.99) compared with patients with the common 325Thr/Thr genotype. This association was most evident in CHD patients (OR 0.48, 95% CI 0.26–0.90). Haplotype analyses supported a role for the Thr325Ile polymorphism. Conclusions: TAFIa(i) levels were higher in patients with cardiovascular disease. Furthermore, the TAFI 325Thr/Ile polymorphism was associated with lower TAFI levels and with the risk of cardiovascular disease in young patients, especially in CHD.     

The PAI‐1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women

Summary. Background: Plasminogen activator inhibitor type 1 (PAI‐1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial. Objective: We aimed to assess the impact of the 4G PAI‐1 polymorphism on pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. Patients/methods: This study represents a secondary investigation of a prior prospective cohort study investigating the association between inherited thrombophilias and adverse pregnancy events in Australian women. Healthy nulliparous women were recruited to this study prior to 22 weeks gestation. Genotyping for the 4G/5G PAI‐1 gene was performed using Taqman assays in an ABI prism 7700 Sequencer several years after the pregnancy was completed. Pregnancy outcome data were extracted from the medical record. The primary outcome was a composite comprising development of severe pre‐eclampsia, fetal growth restriction, major placental abruption, stillbirth or neonatal death. Results: Pregnancy outcome data were available in 1733 women who were successfully genotyped for this polymorphism. The primary composite outcome was experienced by 139 women (8% of the cohort). Four hundred and fifty‐nine women (26.5%) were homozygous for the 4G deletion polymorphism, while 890 (51.4%) were heterozygous. Neither homozygosity nor heterozygosity for the PAI‐1 4G polymorphism was associated with the primary composite outcome (homozygous OR = 1.30, 95% CI = 0.81–2.09, P = 0.28, heterozygous OR = 0.84, 95% CI = 0.53–1.31, P = 0.44) or with the individual pregnancy complications. Conclusion: The PAI‐1 4G polymorphism is not associated with an increase in the risk of serious adverse pregnancy events in asymptomatic nulliparous women.     

Relative Toxicity of Selective Serotonin Reuptake Inhibitors (SSRIs) in Overdose

Background: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. Objective: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. Methods: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc > 440 msec. Results: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5–21.3) and 30 of 469 (6.4%; 95% CI 4.3–9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p = 0.0002); citalopram (450 IQR: 436–484) was individually different to fluoxetine (p = 0.045), fluvoxamine (p = 0.022), paroxetine (p = 0.0002), and sertraline (p = 0.001). The proportion of citalopram overdoses with a QTc > 440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32–11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p = 0.026); citalopram (400 IQR: 380–440) was individually different from sertraline (p = 0.023). Conclusions: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.     

Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy

Background and aims. The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO‐production can be affected by polymorphisms in the endothelial NO‐synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients.

Patients and methods. A total of 1510 Finnish and Swedish T1D patients were included in a cross‐sectional case‐control study. Incipient DN was defined as an albumin excretion rate (AER) of 20–200?µg/min (n = 336). Overt DN = AER>200?µg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration ?20 years, AER<20?µg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27?bp repeat (NOS4ab) and Glu298Asp (rs1799983).

Results. Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu‐allele of the Glu298Asp‐polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12–1.91). The variables smoking (OR = 2.13; 95% CI = 1.63–2.78), male sex (OR = 1.61; 95% CI = 1.23–2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02–1.03), systolic (OR = 1.05; 95% CI = 1.04–1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02–1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a‐allele was not associated with DN.

Conclusions. The Glu/Glu‐genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.     

Association of GSTT1, GSTM1 and CYP1A1 polymorphisms with susceptibility to systemic lupus erythematosus in the Chinese population

BackgroundGSTT1, GSTM1, CYP1A1 are enzymes responsible for the detoxification of the toxicant which may be involved in the development of systemic lupus erythematosus (SLE). We examined the relationship between the risk of SLE and the polymorphisms of these genes in the Chinese population.MethodsSamples from 298 SLE patients and 284 healthy controls were collected. Polymerase chain reaction-restriction fragments length polymorphism (PCR–RFLP) was used to analyze the genotypes of CYP1A1 m2 and m4, while multiplex PCR was used to analyze the genotypes of GSTT1 and GSTM1.ResultsStatistically significant difference was observed in genotypes for GSTM1 (p = 0.003, OR 1.66 [95% CI 1.19–2.32]), but not for GSTT1 (p = 0.119, OR 0.77 [95% CI 0.56–1.07]), in the SLE patients as compared with the controls. Combinational analysis for double-null deletion of both GSTT1 and GSTM1 showed no significant difference (p = 0.863, OR 1.03 [95% CI 0.70–1.52]). Significant difference was observed in the genotype frequencies (p = 0.013), but not in the allele frequencies (p = 0.444, OR 0.90 [95% CI 0.70–1.17]), of CYP1A1 m2. All candidates have a wild-type genotype for CYP1A1 m4.ConclusionsPolymorphisms of GSTM1 are associated with SLE in the Chinese population.