OBJECTIVES--To determine whether any of the type II collagen alleles are associated with generalised osteoarthrosis or osteoarthrosis of the finger joints in the genetically isolated Finnish ...population. METHODS--Two patient cohorts with evidence for only primary osteoarthrosis and a cohort of healthy control subjects were selected from the Helsinki University Central Hospital and the Rheumatism Foundation Hospital in Finland. Forty one patients with primary generalised osteoarthrosis, 49 patients with osteoarthrosis of the finger joints, and 48 control subjects were included. Two markers of the type II collagen gene, a PvuII polymorphism and a VNTR polymorphism, were analysed from each subject. RESULTS--Four different alleles of the VNTR marker were observed and the relative risks associated with the different VNTR alleles varied between 0.39 and 1.24 among the patients with generalised osteoarthrosis and between 0.67 and 2.33 among the patients with osteoarthrosis of the finger joints. The PvuII polymorphism detected two different alleles and the associated relative risks were 0.82 and 1.82 for the patients with generalised osteoarthrosis, and 1.04 and 0.96 for the patients with osteoarthrosis of the finger joints. CONCLUSIONS--A major predisposing allele of the type II collagen gene as the causative factor for osteoarthrosis could be excluded in this population. A spectrum of mutations associated with different alleles of this gene could not be excluded, however. Further, these two forms of cartilage disease can be caused by gene defects with reduced penetrance and the effect of such an allele is easily masked under the high frequency of normal alleles.
The frequencies of HLA-D antigens were investigated in 77 Finnish patients who met the ARA criteria of classical or definite rheumatoid arthritis. The control material consisted of healthy blood ...donors. HLA-Dw4 was significantly (p less than 0.01) increased and HLA-Dw2 significantly (p less than 0.01) decreased in the patients. All HLA-Dw4-positive patients belonged to the seropositive group and in comparison with controls HLA-Dw4 antigen was increased highly significantly (p less than 0.001) in the seropositive patients. With respect to HLA-Dw4 antigen, the seropositive and the seronegative group differed significantly (p less than 0.05). All patients had received penicillamine treatment and 75 of them gold treatment before penicillamine. No significant associations were noted between any HLA-D antigen and gold or penicillamine toxicity. The previous gold toxicity seemed to be a significant factor with respect to the subsequent penicillamine toxicity.
The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to ...be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.
Results and side effects were compared in 100 patients with rheumatoid arthritis treated with 600 mg penicillamine daily and 100 patients given 300 mg daily. While haemoglobin rose and erythrocyte ...sedimentation rate dropped in both the 300 mg and the 600 mg cohort, no significant improvement in clinical measure could be demonstrated for the low-dose patients. Medication was discontinued because of side effects in 30 patients on the low dose and 41 patients on the higher dose. Only 8 renal complications were seen among the low-dose patients, vs. 26 in the 600 mg cohort. However, 6 patients on the low dose vs. none on the higher dose dropped out because of inadequate therapeutic effect. Further downward adjustment of currently used daily dose, though desirable because of the relationship between dosage and side effects, seems doomed by unacceptable loss of therapeutic efficacy in most cases.
The effect of diet on blood lipids has been under intensive study during recent decades. However, diet in the context of the hyperapobetalipoproteinemia (hyperapoB) phenotype has received less ...attention. The hyperapoB phenotype is commonly encountered in patients with premature coronary heart disease. It is defined as a combination of an increased concentration of apolipoprotein B (apo B), a normal concentration of LDL cholesterol (LDL-C), and as a result, a low LDL-C/apo B ratio. We studied the associations between diet and blood lipids in a cohort of 534 children and young adults 9 to 24 years old. The ratio of polyunsaturated to saturated fats (P/S ratio) correlated (r=-0.19, P<.001) with the LDL-C/apo B ratio. This association was also found when the model was adjusted with triglycerides (r=-0.24, P<.001). A change in the P/S ratio from 0.10 to 0.60 corresponded to a decrease of 0.12 in the LDL-C/apo B ratio, and in the highest apo B decile, the P/S value was higher in hyperapoB individuals (0.33) than in others (0.28, P=.019). Our results imply that the fatty acid composition of the diet may be one of the environmental factors that influence the hyperapoB phenotype expression.
Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of ...information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK's proposed 'care.data' initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data.
Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in parallel. The separate parallelized analyses are linked by non-disclosive summary statistics and commands transmitted back and forth between the DCs and the AC. This paper describes the technical implementation of DataSHIELD using a modified R statistical environment linked to an Opal database deployed behind the computer firewall of each DC. Analysis is controlled through a standard R environment at the AC.
Based on this Opal/R implementation, DataSHIELD is currently used by the Healthy Obese Project and the Environmental Core Project (BioSHaRE-EU) for the federated analysis of 10 data sets across eight European countries, and this illustrates the opportunities and challenges presented by the DataSHIELD approach.
DataSHIELD facilitates important research in settings where: (i) a co-analysis of individual-level data from several studies is scientifically necessary but governance restrictions prohibit the release or sharing of some of the required data, and/or render data access unacceptably slow; (ii) a research group (e.g. in a developing nation) is particularly vulnerable to loss of intellectual property-the researchers want to fully share the information held in their data with national and international collaborators, but do not wish to hand over the physical data themselves; and (iii) a data set is to be included in an individual-level co-analysis but the physical size of the data precludes direct transfer to a new site for analysis.
Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using ...Mendelian randomization (MR) methods.
The associations of BMI with cardiovascular outcomes coronary heart disease (CHD), heart failure and ischaemic stroke, and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes.
There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD.
Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.
We examined the association of nutritional status as measured by the Mini-Nutritional Assessment Short Form (MNA-SF) with changes in mobility, institutionalization and death after hip fracture.
...Population-based prospective data were collected on 472 out of 693 consecutive hip fracture patients aged 65 years and over between January 2010 and December 2012. Declined vs same or improved mobility level, institutionalization and death during the 4-month follow-up were the outcomes. Age, gender, American Society of Anesthesiologists scores, pre-fracture diagnosis of a memory disorder, mobility level, living arrangements and MNA-SF scores at baseline were the independent variables. Age-adjusted and multivariate logistic regression and Cox proportional hazards models were conducted.
At baseline, 41 (9%) patients were malnourished and 200 (42%) patients at risk of malnutrition according to the MNA-SF. During the follow-up, 90 (19%) had died. In the multivariate Cox proportional hazards model, malnutrition (hazard ratio 2.16; 95% confidence interval (CI) 1.07-4.34) was associated with mortality. In the multivariate binary logistic regression analyses, risk of malnutrition (odds ratios (OR) 2.42; 95% CI 1.25-4.66) and malnutrition (OR 6.10;95% CI 2.01-18.5) predicted institutionalization. Risk of malnutrition (OR 2.03; 95% CI 1.24-3.31) was associated with decline in the mobility level.
Malnutrition or risk of malnutrition as measured by the MNA-SF were independent predictors of negative outcomes after hip fracture. Patients classified as being at risk of malnutrition by the MNA-SF may constitute a patient population with mild-to-moderate malnutrition and may require specific attention when nutritional interventions are designed after hip fracture.
Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive ...responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (
https://clinicaltrials.gov/ct2/show/NCT03276598
; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (
https://clinicaltrials.gov/ct2/show/NCT00338260
; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.
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