Huibert Burger

Relation of alleles of the collagen type Iα1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women

BACKGROUNDnOsteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Ialpha1, a bone-matrix protein.nnnMETHODSnWe determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 1778 postmenopausal women using a polymerase-chain-reaction-based assay. We then related the genotypes to bone mineral density and the occurrence of osteoporotic fractures in these women.nnnRESULTSnAs compared with the 1194 women with the SS genotype, the 526 women with the Ss genotype had 2 percent lower bone mineral density at the femoral neck (P=0.003) and the lumbar spine (P=0.02); the 58 women with the ss genotype had reductions of 4 percent at the femoral neck (P= 0.05) and 6 percent at the lumbar spine (P=0.005). These differences increased with age (P=0.01 for modification by age of the effect of COLIA1 on femoral-neck bone density, and P=0.004 for modification of the effect on lumbar-spine bone density). Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures (relative risk per copy of the s allele, 1.5; 95 percent confidence interval, 1.1 to 2.1).nnnCONCLUSIONSnThe COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.

Adjuvant Aspirin Therapy Reduces Symptoms of Schizophrenia Spectrum Disorders: Results From a Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVEnInflammatory processes may play a role in the pathophysiology of schizophrenia. The aim of this study was to determine the efficacy of adjuvant treatment with aspirin (acetylsalicylic acid) in schizophrenia spectrum disorders.nnnMETHODnThis randomized, double-blind, placebo-controlled study was conducted between May 2004 and August 2007. Seventy antipsychotic-treated inpatients and outpatients from 10 psychiatric hospitals in The Netherlands with a DSM-IV-diagnosed schizophrenia spectrum disorder were included. Patients were randomized to adjuvant treatment with aspirin 1000 mg/d or placebo. During a 3-month follow-up, psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). Other assessments included cognitive tests and immune function. The primary efficacy outcome was the change in total PANSS score. Secondary outcomes were changes in the PANSS subscales and cognitive test results.nnnRESULTSnMixed-effect models showed a 4.86-point (95% CI, 0.91 to 8.80) and 1.57-point (95% CI, 0.06 to 3.07) larger decrease in the aspirin group compared to the placebo group on the total and positive PANSS score, respectively. Similar but not statistically significant results were observed for the other PANSS subscale scores. Treatment efficacy on total PANSS score was substantially larger in patients with the more altered immune function (P = .018). Aspirin did not significantly affect cognitive function. No substantial side effects were recorded.nnnCONCLUSIONnAspirin given as adjuvant therapy to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function. Inflammation may constitute a potential new target for antipsychotic drug development.nnnTRIAL REGISTRATIONncontrolled-trials.com Identifier: ISRCTN27745631.

Depressive symptoms in subjects with diagnosed and undiagnosed type 2 diabetes

Objective: To investigate if disturbed glucose homeostasis or known diagnosis of diabetes was associated with depressive symptoms. The reason for the increased prevalence of depression in patients with Type 2 diabetes mellitus (DM2) is unknown. Methods: Within the Utrecht Health Project, an ongoing longitudinal study among inhabitants of a residential area of a large city in The Netherlands, 4747 subjects (age: 39.4 ± 12.5 years) were classified into four mutually exclusive categories: normal fasting plasma glucose (FPG) (<5.6 mmol/l), impaired FPG (≥5.6 and <7.0 mmol/l), undiagnosed DM2 (FPG ≥7.0 mmol/l), and diagnosed DM2. Presence of depressive symptoms was defined as a score of ≥25 on the depression subscale of the Symptom Check List (SCL-90) or self-reported use of antidepressants. Results: Diagnosed DM2 was associated with an increased risk of depressive symptoms (odds ratio (OR) = 1.69; 95% confidence interval (CI) 1.06–2.72) after adjustment for demographic and lifestyle variables. Additional adjustment for number of chronic diseases reduced the OR to 1.36 (95% CI 0.83–2.23). Impaired fasting glucose and undiagnosed DM2 were not associated with depressive symptoms. Conclusions: Our findings suggest that disturbed glucose homeostasis is not associated with depressive symptoms. The increased prevalence of depressive symptoms among patients with diagnosed DM2 suggests that depressive symptoms might be a consequence of the burden of diabetes. The number of chronic diseases seems to explain part of the association between DM2 and depressive symptoms. DM2 = Type 2 diabetes mellitus; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth revision; FPG = fasting plasma glucose; OR = odds ratio; SCID = Structured Clinical Interview for DSM-IV; SCL-90 = Symptom Checklist; SD = standard deviation; SPSS = Statistical Package for the Social Sciences; UHP = Utrecht Health Project.

Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee

OBJECTIVEnTo study the association of the COL2A1 genotype, in relation to the vitamin D receptor (VDR) genotype, with features of radiographic osteoarthritis (ROA) in a population of elderly men and women.nnnMETHODSnIn this cross-sectional study, we analyzed a population-based sample of 851 men and women ages 55-80 years from a large cohort study, the Rotterdam Study. We determined the prevalence of ROA of the knee according to the Kellgren/Lawrence (K/L) score and features of ROA (presence of osteophytes and narrowing of the joint space [JSN]) without considering clinical parameters of the disease. Genotypes were determined at a variable-number tandem repeats marker 1 kb downstream of the COL2A1 gene using a newly developed heteroduplexing method. The VDR genotype was previously determined by a direct molecular haplotyping polymerase chain reaction method to establish the phase of alleles at 3 adjacent restriction fragment length polymorphisms for Bsm I, Apa I, and Taq I.nnnRESULTSnWe found the COL2A1 genotype to be associated with a 2-fold increased risk for JSN, but not with osteophytes or the K/L score. We had previously found the VDR genotype to be associated with osteophytes and the K/L score, but not with JSN. When the COL2A1 genotype was analyzed in combination with the VDR genotype, we found evidence suggesting that the presence of haplotypes of the 2 genes was associated with increased risk for ROA.nnnCONCLUSIONnOur findings demonstrate that both the COL2A1 gene and the VDR gene are involved in ROA, but in separate features. The COL2A1 genotype is associated with JSN, while the VDR genotype is associated with osteophytes.

Long-term oral contraceptive use increases breast cancer risk in women over 55 years of age: the DOM cohort.

The role of past oral contraceptive use in the development of breast cancer is unclear, particularly in postmenopausal women. The authors investigated this relationship among pre‐ and postmenopausal middle‐aged women in a nested case‐control study within the population‐based DOM cohort, Utrecht, the Netherlands. Among a total population of 12,184 women followed up for an average of 7.5 years, 309 breast cancer cases aged 42 to 63 years, diagnosed from November 1982 through May 1996, and 610 controls were examined. Overall, duration of oral contraceptive use was not clearly related to breast cancer. In women older than 55 years, however, oral contraceptive use for more than 10 years was associated with a 2‐fold increased risk of breast cancer (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1–4.0). We conclude that long duration of oral contraceptive use increases the risk of breast cancer in women over 55 years of age but not in younger women. Int. J. Cancer 87:591–594, 2000.

Pharmacogenetics of glucose-lowering drug treatment - A Systematic review

Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication.A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs.Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides.Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A1c (HbA1c) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers.Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.

Long-term response to successful acute pharmacological treatment of psychotic depression.

BACKGROUNDnData about follow-up after acute pharmacological treatment of psychotic depression are scarce.nnnMETHODSnA 4 month open follow-up was done, preferentially with same medication as during acute treatment, of patients (n=59) with DSM-IV-TR major depressive disorder with psychotic features, aged 18 to 65 years, who had completed as responders an acute double-blind 7 week trial with imipramine, venlafaxine or venlafaxine plus quetiapine. Main outcome measures were Hamilton Rating Scale for Depression and Clinical Global Impression Scale.nnnRESULTSnSix patients dropped out during the 4 month follow-up. Almost all patients (86.4%; 51/59) remained responder while remission rate increased from 59.3% (35/59) to 86.8% (46/53), independent of treatment. Relapse rate was low (3.8%; 2/53). Tolerability was good. Weight increased with all treatments.nnnLIMITATIONSnLimitations were the limited sample size and consequent limited statistical power. The treatment during follow-up was not double-blind.nnnCONCLUSIONSnContinuation treatment with the same medication that was effective in the acute treatment trial, remained effective during the 4 month follow-up in many patients leading to further improvement, and was well tolerated.

Non-steroidal anti-inflammatory drugs and the risk of psychosis

The objective of the current research was to examine the relation between non-steroidal anti-inflammatory drugs (NSAID) use and risk of psychosis. To this end we performed a longitudinal case-control study using prescription data from a Dutch health insurance company. Men aged 25 years or over and women aged 30 years or over were excluded to prevent inclusion of non-incident cases. This resulted in eighty-two cases and 359 randomly selected controls from the same population. The overall relative risk of incident antipsychotic use for NSAID users, adjusted for age and prescription frequency, was 0.80 (95% CI: 0.48-1.33). After stratification for gender the risk of psychosis was significantly lower (59%) in male NSAID users only. The relative risks for male and female subjects were 0.41 (95% CI: 0.17-0.97) and 1.31 (95% CI: 0.65-2.64), respectively. These results suggest that in men NSAIDs may lower the risk of psychosis.

Acetylsalicylic acid as an adjuvant therapy for schizophrenia

BackgroundFindings from both epidemiological and basic research point to the possibility that NSAIDS impede the deterioration in schizophrenia.MethodsTo study the efficacy of acetylsalicylic acid we will perform a randomized placebo controlled double-blind add-on trial of 80 inpatients and outpatients with schizophrenia, schizophreniform or schizoaffective disorder. Patients will be 1:1 randomized to either 3 months 1000 mg acetylsalicylic acid per day or 3 months placebo, in addition to their regular antipsychotic treatment. All patients will receive pantoprazole treatment for gastroprotection. The outcomes of this study are 3-month change in psychotic and negative symptom severity, cognitive function, and several immunological parameters.This trial may (1) yield a new (adjuvant) therapy for schizophrenia and (2) add to the knowledge on the pathogenesis of this major psychiatric disorder.

Cyclical etidronate use is not associated with symptoms of peptic ulcer disease

AbstractObjective: To investigate whether the alkylbisphosphonate etidronate is associated with an increased risk of gastrointestinal symptoms.nn Methods: We conducted an observational follow-up study on a possible relationship between etidronate use and the risk of gastrointestinal symptoms in a cohort of 2754 women over 50u2009years of age. The study was performed with data on drug prescriptions obtained from the PHARMO database in the Netherlands. Women were included when they used either cyclical etidronate (n=1050) or estrogen (n=1704) for at least 14u2009days. They were followed-up for incident use of antiulcer drugs while on exposure medication.nn Results: The mean ages were 72u2009years and 59u2009years in the etidronate and estrogen groups, respectively. In total, there were 95 women with incident prescriptions for gastrointestinal events after a median duration of follow-up of 2.7u2009months (range 0.1–19.4u2009months). The crude relative risk of a gastrointestinal event for etidronate compared with estrogen use was 1.2 [95% confidence interval (95% CI) 0.8–1.8]. Adjusted for baseline age, use of corticosteroids, salicylates and nonsteroidal anti-inflammatory drugs, the relative risk reversed to 0.6 (95% CI 0.4–1.2).nn Conclusion: The use of cyclical etidronate is not associated with an elevated risk of symptoms of peptic ulcer disease.