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3.9.2007 - ISI Web of Knowledge & PubMed Search Alert |
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Combined effects of thrombosis pathway gene variants
predict cardiovascular events
Auro, K., Alanne, M., Kristiansson, K., Silander, K., Kuulasmaa, K., Salomaa, V., Peltonen, L. and Perola, M. PLoS Genet. 2007; 3(7): e120. Journal Article. IF 7.671 The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5), intercellular adhesion molecule 1 (ICAM1), protein C (PROC), and thrombomodulin (THBD) in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141), we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD) cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%), 54 single nucleotide polymorphisms (SNPs) were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 x THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs-acting either in combination or as single variants--predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level. Bykov, I., Jauhiainen, M., Olkkonen, V. M., Saarikoski, S. T., Ehnholm, C., Junnikkala, S., Vakeva, A., Lindros, K. O. and Meri, S. J Hepatol. 2007; 46(5): 907-14. Journal Article. IF 6.073 BACKGROUND/AIMS: Fatty infiltration initiates alcohol-induced liver changes and complement component C3 affects lipid metabolism. We recently observed that ethanol-induced steatosis seen in normal (C3(+/+)) mice was absent in livers of C3-deficient (C3(-/-)) mice. To understand the underlying molecular mechanisms we analyzed lipid parameters and liver gene expression profiles in these mice. METHODS: A Western-type high-fat diet with ethanol or carbohydrates (control) was fed for 6 weeks to C3(+/+) and C3(-/-) mice. Serum and liver lipid parameters were analyzed and liver mRNA expression patterns studied by micro-array analysis and RT-PCR. RESULTS: In both genotypes ethanol markedly reduced serum cholesterol, apolipoprotein A-I, phospholipid transfer protein activity and hepatic mRNA levels of fatty acid-binding proteins and fatty acid beta-oxidation enzymes. In contrast, exclusively in C3(-/-) mice, ethanol treatment increased serum and liver adiponectin levels but down-regulated transcripts of lipogenic enzymes, adiponectin receptor 2 and adipose differentiation-related protein and up-regulated phospholipase D1. CONCLUSIONS: We propose that these ethanol-induced alterations observed exclusively in C3(-/-) mice contribute to protection against fatty infiltration and subsequent inflammatory processes in the liver of these mice. The results suggest important cross-talk between complement factor C3 and lipid regulators in ethanol-induced steatosis. Correlation of intestinal disaccharidase activities with the C/T-13910 variant and age Enattah, N. S., Kuokkanen, M., Forsblom, C., Natah, S., Oksanen, A., Jarvela, I., Peltonen, L. and Savilahti, E. World J Gastroenterol. 2007; 13(25): 3508-12. Journal Article. AIM: To correlate the C/T(-13910) variant, associated with lactase persistence/non-persistence (adult-type hypolactasia) trait, with intestinal disaccharidase activities in different age groups of the adult population. METHODS: Intestinal biopsies were obtained from 222 adults aged 18 to 83 years undergoing upper gastrointestinal endoscopy because of unspecified abdominal complaints. The biopsies were assayed for lactase, sucrase and maltase activities and genotyped for the C/T(-13910) variant using PCR-minisequencing. RESULTS: There was a significant correlation between lactase activity and the C/T(-13910) variant (P < 0.00001). The mean level of lactase activity among subjects with C/C(-13910) genotype was 6.86 +/- 0.35 U/g, with C/T(-13910) genotype 37.8 +/- 1.4 U/g, and with T/T(-13910) genotype 57.6 +/- 2.4 U/g protein, showing a trimodal distribution of this enzyme activity. Significant differences were also observed in maltase activities among individuals with different C/T(-13910) genotypes (P = 0.005). In contrast, in sucrase activity, no significant differences emerged between the C/T(-13910) genotypes (P = 0.14). There were no statistical differences in lactase (P = 0.84), sucrase (P = 0.18), or maltase activity (P = 0.24) among different age groups. In the majority (> 84%) of the patients with the C/C(-13910) genotype associated with lactase non-persistence, the lactase activity was less than 10 U/g protein. CONCLUSION: Our study demonstrates a statistically significant correlation between the C/T(-13910) genotype and lactase activity and this correlation is not affected by age in adults but the cut-off value of 20 U/g protein used for the diagnosis of lactase non-persistence might be too high. Fan, M., Raitakari, O. T., Kahonen, M., Juonala, M., Hutri-Kahonen, N., Marniemi, J., Rontu, R., Porsti, I., Viikari, J. and Lehtimaki, T. Journal of Hypertension. 2007; 25(7): 1381-1387. Journal Article. IF 4.021 Objective Nicotinamide adenine dinucleotide phosphate ( NADPH) oxidase is a major source of the superoxide anion that contributes to decreased nitric oxide bioavailability in the vasculature. The C242T polymorphism of the CYBA gene that encodes p22phox, a component of NADPH oxidase, has been found to modulate superoxide production. We examined the relationship of the C242T polymorphism with endothelial-dependent brachial artery flow-mediated vasodilatation (FMD) in a population-based sample of young healthy adults. Methods FMD, defined as the increased percentage in brachial artery diameter after reactive hyperemia, was assessed by ultrasound and the C242T polymorphism using a 50 nuclease assay in 2058 subjects aged 24-39 years. Results The mean values of brachial artery FMD were 8.0 +/- 4.4% in all study subjects (n=2058), and 7.8 +/- 4.4, 8.2 +/- 4.5, and 8.7 +/- 4.5% in subjects with the CC (n=1362), CT (n=616), and TT (n=80) genotypes of the C242T CYBA polymorphism, respectively (P=0.02 for trend). The association remained significant (P=0.019) in multivariate analyses adjusted for age, sex, obesity indices, smoking habits, blood pressure, serum glucose, lipids, and C-reactive protein. The relationship between FMD and the C242T polymorphism was stronger (P=0.004) in overweight subjects (body mass index >= 25 kg/m(2), n=895) and ever-smokers (P=0.008, n=1082), whereas no relationship was found in normal-weight subjects and non-smokers (P=0.824 and P=0.438, respectively). Conclusion The C242T polymorphism of the CYBA gene seems to be related to endothelial function in a population-based sample of young healthy adults. Overweight and smoking status may modify this genetic effect. Gunnar, T., Engblom, C. and Ariniemi, K. J Chromatogr A. 2007. Journal Article. IF 3.554 Innovative features and technical improvements in modern bench-top quadrupole gas chromatograph-mass spectrometer (GC-MS) have prepared the way for faster and more cost-effective applications while still maintaining sufficient chromatographic resolution, speed of MS data acquisition and reliability of analytical methodology. In this paper, a short wide-bore capillary column with low film thickness (5mx0.32mm i.d., 0.1mum) was used a pre-fractionating column and only chosen heart-cuts were transferred to the second chromatographic dimension (15mx0.25mm i.d., 0.25mum) by means of a pressure-adjusted continual flow type switching device for quantification of five common amphetamine-type stimulant drugs. The instrumental setting used, in combination with carefully optimized operational fast GC and MS parameters, markedly decreased the retention times of the targeted analytes, e.g., amphetamine 0.891min and methamphetamine 1.037min, and the total chromatographic runtime (1.700min), as well as reducing the need for continuous cleaning of the MS ion source and increasing column life compared with conventional GC-MS approaches. The performance of the instrumental configuration and analytical method was evaluated in validation experiments and the method was also applied to authentic samples. The method demonstrates the potential of fast GC-MS in combination with a gas-phase microfluidic Deans switch device for analysing of (semi)volatile compounds, such as amphetamine-type stimulant (ATS) drugs. This should be particularly useful in modern laboratories aiming at cost-efficient analysis as well as the optimum use of available laboratory capacity and instrumentation. Epidemiological studies of exercise in diabetes prevention Hu, G., Lakka, T. A., Kilpelainen, T. O. and Tuomilehto, J. Appl Physiol Nutr Metab. 2007; 32(3): 583-95. Journal Article. Type 2 diabetes is one of the fastest growing public health problems in both developed and developing countries. It is estimated that the number of people with diabetes in the world will double in coming years, from 171 million in 2000 to 366 million in 2030. Cardiovascular disease accounts for more than 70% of total mortality among patients with type 2 diabetes. The associations of physical activity, physical fitness, and changes in the lifestyle with the risk of type 2 diabetes have been assessed by a number of prospective studies and clinical trials in the past decade. Several studies have also evaluated the joint associations of physical activity, body mass index, and glucose levels with the risk of type 2 diabetes. Prospective studies and clinical trials have shown that moderate or high levels of physical activity or physical fitness and changes in the lifestyle (dietary modification and increase in physical activity) can prevent type 2 diabetes. Our review of the scientific evidence confirms that 30 min/d of moderate- or high-level physical activity is an effective and safe way to prevent type 2 diabetes in all populations. Juonala, M., Viikari, J. S., Alfthan, G., Marniemi, J., Kahonen, M., Taittonen, L., Laitinen, T. and Raitakari, O. T. Circulation. 2007. Journal Article. IF 10.940 BACKGROUND: -Elevated asymmetrical dimethylarginine (ADMA) is a novel risk factor for atherosclerosis that may impair endothelial function by interfering with endothelial nitric oxide synthesis. To gain insight into the effects of ADMA on systemic endothelial function, we examined the association between ADMA and brachial artery flow-mediated dilation (FMD) in a large population of young adults. Methods and Results-Plasma ADMA and brachial FMD, as well as conventional cardiovascular risk factors, were measured in 2096 white adults aged 24 to 39 years. In univariate analysis, ADMA was inversely correlated with FMD (r=-0.07, P=0.003). The inverse association between ADMA and FMD remained significant in a multivariable regression model adjusted for age, sex, conventional cardiovascular risk factors, estimated glomerular filtration rate, and brachial artery baseline diameter (beta+/-SE -1.56+/-0.62%, P=0.01). Conclusions-We conclude that elevated plasma ADMA concentrations are associated with decreased brachial FMD responses in healthy adults. These data provide evidence at the population level that ADMA levels are associated with endothelial function. Incidence of schizophrenia in a nationwide cohort of patients with type 1 diabetes mellitus Juvonen, H., Reunanen, A., Haukka, J., Muhonen, M., Suvisaari, J., Arajarvi, R., Partonen, T. and Lonnqvist, J. Arch Gen Psychiatry. 2007; 64(8): 894-9. Journal Article. IF 13.936 CONTEXT: Patients with schizophrenia have an increased risk of type 2 diabetes mellitus. However, very few studies have dealt with the association of type 1 diabetes and schizophrenia. Preliminary evidence points to a possible inverse association. OBJECTIVE: To investigate the incidence of schizophrenia in a nationwide cohort of patients with type 1 diabetes born in 1950 through 1959 in Finland. DESIGN: A cohort study of individuals born in 1950 through 1959 with a follow-up of 1969 through 1991. SETTING: Finland. PATIENTS: All individuals born in 1950 through 1959 with type 1 diabetes were identified through nationwide registers. The incidence of schizophrenia until 1992 among the total 1950-1959 cohort and in individuals with type 1 diabetes was calculated using information from 3 health care registers. MAIN OUTCOME MEASURE: Incidence of schizophrenia. RESULTS: The incidence of schizophrenia was 0.21 per 10 000 person-years in the group with type 1 diabetes and 0.56 per 10 000 person-years in the group without type 1 diabetes (P < .001). CONCLUSION: The incidence of schizophrenia is decreased in patients with type 1 diabetes. Kaaja, R., Kujala, S., Manhem, K., Katzman, P., Kibarskis, A., Antikainen, R., Yliharsila, H., Erkkola, R. and Tuomilehto, J. International Journal of Clinical Pharmacology and Therapeutics. 2007; 45(7): 394-401. Journal Article. IF 1.361 Cardiovascular risk factors are often ineffectively controlled in hypertensive postmenopausal women, and moreover, some antihypertensive drugs may increase particular risk factors such as insulin resistance. In a multicenter, multinational (Finland, Sweden, Lithuania), double-blind, prospectively randomized study hypertensive obese postmenopausal women without hormone therapy (n = 98) were randomly assigned to receive treatment with either the centrally acting agent moxonidine, 0.6 mg/day, or with the peripherally acting atenolol, 50 mg/day, for 8 weeks. In addition to blood pressure measurements, insulin sensitivity was estimated by the quantitative insulin sensitivity check index (QUICKI) and by the insulin sensitivity index (ISI-Matsuda). Subgroup analysis in insulin-resistant women (fasting P-insulin >= 10 mU/1) and blood pressure responders (diastolic blood pressure <= 90 mmHg and/or reduction of blood pressure >= 10 mmHg) were also carried out. Both atenolol and moxonidine led to a significant reduction in diastolic blood pressure of 9.5 mmHg and 6.2 mmHg, respectively. Among insulin-resistant women, an increase in the insulin sensitivity assessed by ISI was improved with moxonidine treatment (p = 0.025). A decrease in insulin sensitivity assessed by QUICKI was observed with atenolol treatment in women with fasting insulin level < 10 mU/1. In patients, in whom blood pressure was reduced, an improvement in insulin sensitivity (ISI) was associated with moxonidine treatment (p = 0.019), but not with atenolol treatment. The centrally acting sympatholytic agent moxonidine did reduce blood pressure somewhat less than atenolol, but it was associated with an improved metabolic profile in terms of decreased insulin resistance both in insulin-resistant postmenopausal women and in women with a significant blood pressure response. Kaukinen, P., Sillanpaa, M., Kotenko, S., Lin, R. T., Hiscott, J., Melen, K. and Julkunen, I. Virology Journal. 2006; 3. Journal Article. Background: Hepatitis C virus (HCV) encodes several proteins that interfere with the host cell antiviral response. Previously, the serine protease NS3/4A was shown to inhibit IFN-beta gene expression by blocking dsRNA-activated retinoic acid-inducible gene I (RIG-I) and Toll-like receptor 3 (TLR3)-mediated signaling pathways. Results: In the present work, we systematically studied the effect of all HCV proteins on IFN gene expression. NS2 and NS3/4A inhibited IFN gene activation. NS3/4A inhibited the Sendai virus-induced expression of multiple IFN (IFN-alpha, IFN-beta and IFN-lambda I/IL-29) and chemokine (CCL5, CXCL8 and CXCL10) gene promoters. NS2 and NS3/4A, but not its proteolytically inactive form NS3/4A-S139A, were found to inhibit promoter activity induced by RIG-I or its adaptor protein Cardif (or IPS-I/MAVS/VISA). Both endogenous and transfected Cardif were proteolytically cleaved by NS3/4A but not by NS2 indicating different mechanisms of inhibition of host cell cytokine production by these HCV encoded proteases. Cardif also strongly colocalized with NS3/4A at the mitochondrial membrane, implicating the mitochondrial membrane as the site for proteolytic cleavage. In many experimental systems, IFN priming dramatically enhances RNA virus-induced IFN gene expression; pretreatment of HEK293 cells with IFN-alpha strongly enhanced RIG-I expression, but failed to protect Cardif from NS3/4A-mediated cleavage and failed to restore Sendai virus-induced IFN-beta gene expression. Conclusion: HCV NS2 and NS3/4A proteins were identified as potent inhibitors of cytokine gene expression suggesting an important role for HCV proteases in counteracting host cell antiviral response. Koistinen, J., Kukkonen, J. V. K., Sormunen, A., Mannila, E., Herve, S. and Vartianinen, T. Chemosphere. 2007; 68(7): 1382-1391. Journal Article. IF 2.442 The bioaccumulation potential and environmental fate of polychlorinated hydroxydiphenyl ethers (HO-PCDEs; polychlorinated phenoxyphenols, PCPP), the major impurities of chlorophenol formulations and their methoxy analogues (MeO-PCDEs; polychlorinated methoxyanisoles, PCPAs) were investigated. Oligochaete worms (Lumbriculus variegatus) exposed to sediment spiked with a model substance of one HO-hexaCDE (4 '-HO-PCDE 161) or its methoxy analogue (4 '-MeO-PCDE 161) clearly accumulated the test compounds revealing the potential for environmental risk of HO-PCDEs and MeO-PCDEs. The HO-PCDE tested has earlier been reported as an abundant component in a Finnish chlorophenol formulation (Ky-5) and its methoxy analogue is recognized as an abundant MeO-PCDE in sawmill soil contaminated by the formulation. The occurrence of 4 '-HO-PCDE 161 and its methoxy analogue among other HO-PCDEs and MeO-PCDEs in lake mussels (Anodonta piscinalis) incubated in a river contaminated via the manufacture of Ky-5 showed that these compounds are bioavailable and transported in the aquatic environment. Mussel comparison with sediment data pointed to a higher accumulation potential for MeO-PCDEs than for HO-PCDEs. The finding of HO-PCDEs in groundwater samples collected from a groundwater reservoir, which had been contaminated by chlorophenols, points to potential of HO-PCDEs for transport with water in soil. (c) 2007 Elsevier Ltd. All rights reserved. Lam, P. P. L., Hyvarinen, K., Kauppi, M., Cosen-Binker, L., Laitinen, S., Keranen, S., Gaisano, H. Y. and Olkkonen, V. M. Molecular Biology of the Cell. 2007; 18(7): 2473-2480. Journal Article. IF 6.562 We identified in a yeast two-hybrid screen the EF-hand Ca2+-binding protein Cab45 as an interaction partner of Munc18b. Although the full-length Cab45 resides in Golgi lumen, we characterize a cytosolic splice variant, Cab45b, expressed in pancreatic acini. Cab45b is shown to bind Ca-45(2+), and, of its three EF-hand motifs, EF-hand 2 is demonstrated to be crucial for the ion binding. Cab45b is shown to interact with Munc18b in an in vitro assay, and this interaction is enhanced in the presence of Ca2+. In this assay, Cab45b also binds the Munc18a isoform in a Ca2+-dependent manner. The endogenous Cab45b in rat acini coimmunoprecipitates with Munc18b, syntaxin 2, and syntaxin 3, soluble N-ethylmaleimide-sensitive factor attachment protein receptors with key roles in the Ca2+-triggered zymogen secretion. Furthermore, we show that Munc18b bound to syntaxin 3 recruits Cab45b onto the plasma membrane. Importantly, antibodies against Cab45b are shown to inhibit in a specific and dose-dependent manner the Ca2+-induced amylase release from streptolysin-O-permeabilized acini. The present study identifies Cab45b as a novel protein factor involved in the exocytosis of zymogens by pancreatic acini. Lundqvist, E., Kaprio, J., Verkasalo, P. K., Pukkala, E., Koskenvuo, M., Soderberg, K. C. and Feychting, M. International Journal of Cancer. 2007; 121(4): 810-818. Journal Article. IF 4.693 Associations between anthropometric measures and cancer have been studied previously, but relatively few studies have had the opportunity to control for genetic and early shared environmental factors. In this study, we analyzed 2 twin cohorts from Sweden born 1886-1925 (n=21,870) and 1926-1958 (n=30,279) and I from Finland born 1880-1958 (n=25,882) including in total 78,031 twins, and studied the association between BMI and height and risk of prostate, breast, ovarian, corpus uteri, colon and rectal cancer. The cohorts were both analyzed through a co-twin control method and as traditional cohorts. In co-twin control analyses, older obese (BMI >= 30 kg/M-2) subjects (median age 56 years at baseline) were at higher risk of cancer of the corpus uteri (OR 3.0; 95% CI 0.9-10.6), colon (OR=1.9; 95% CI 0.8-4.5) and breast (OR=2.5; 95% CI 1.3-4.2). For younger obese women (median age 30 years at baseline), an inverse tendency was observed for breast cancer (OR=0.6; 95% CI 0.3-1.5, p for trend =0.05). The tallest women had an increased risk of breast (OR=1.8; 95% CI 1.3-2.7) and ovarian cancer (OR=1.7; 95% CI 0.83.5). No consistent associations were found for prostate cancer either for BMI or height. There are some suggestions in our study that uncontrolled genetic or early shared environmental factors may affect risk estimates in studies of anthropometric measures and cancer risk, but do not explain observations of increased cancer risks related to BMI or height. (c) 2007 Wiley-Liss, Inc. Paile-Hyvarinen, M., Wahlbeck, K. and Eriksson, J. G. BMC Fam Pract. 2007; 8: 34. Journal Article. IF 1.558 BACKGROUND: Depression is prevalent in people with type 2 diabetes and affects both glycaemic control and overall quality of life. The aim of this investigator-initiated trial was to evaluate the effect of the antidepressant paroxetine on quality of life, metabolic control, and mental well-being in mildly depressed diabetics aged 50-70 years. METHODS: We randomised 49 mildly depressed primary care outpatients with non-optimally controlled diabetes to a 6-month double-blind treatment with either paroxetine 20 mg per day or matching placebo. Primary efficacy measurements were quality of life and glycaemic control. The primary global outcome of the study was defined as a 10 points improvement in the SF-36 quality of life score. The primary metabolic outcome of the study was defined as a 0.8%-units decrease in glycosylated haemoglobin A1c(GHbA1c). Psychiatric symptoms were assessed with the Hospital Anxiety and Depression Scale. RESULTS: Six patients withdrew their consent before starting medication and six dropped out later in the study. We performed analysis of covariance with the baseline value as a covariate. Quality of life and glycaemic control as well as symptoms of depression and anxiety improved in both groups over the 6-month study period. After three months of treatment we found a statistically significant difference between the two treatment groups in GHbA1c (mean difference = 0.59%-units, p = 0.018) and in SF-36 score (mean difference = 11.0 points, p = 0.039). However, at the end of the study, no statistically significant differences between the treatment groups were observed. No severe adverse events occurred. CONCLUSION: This pragmatic study of primary care patients did not confirm earlier preliminary findings indicating a beneficial effect of paroxetine on glycaemic control. The study indicates that in pragmatic circumstances any possible benefit from administration of paroxetine in diabetic patients with sub-threshold depression is likely to be modest and of short duration. Routine antidepressant prescription for patients with diabetes and sub-threshold depressive symptoms is not indicated. TRIAL REGISTRATION: Current controlled trials ISRCTN55819922. Palosuo, T., Reinikka-Railo, H., Kautiainen, H., Alenius, H., Kalkkinen, N., Kulomaa, M., Reunala, T. and Turjanmaa, K. Allergy. 2007; 62(7): 781-786. Journal Article. IF 5.334 Background: Assessment of allergenic potential of medical devices made of natural rubber latex (NRL) requires the measurement of concentrations of specific allergenic proteins or polypeptides eluting from rubber. Methods: Four NRL allergens (Hev b 1, 3, 5, and 6.02) were quantified in all medical glove brands marketed in Finland in 1999, 2001, and 2003 (n = 208) by a capture enzyme immunoassay. The results were compared with those obtained from previous nationwide market surveys, using a skin prick test-validated human IgE-based ELISA-inhibition method. Results: A high overall correlation (r = 0.87, 95% CI 0.83-0.90) emerged between the sum values of the four allergens(mu g/g glove) and IgE-ELISA inhibition (allergen units, AU/ml, 1 : 5 diluted glove extract). The sum of four allergens when set at 0.15 mu g/g discriminated 'low allergenic' (< 10 AU/ml) from 'moderate- to high-allergenic' ( >= 10 AU/ml) gloves at a sensitivity of 0.93 (95% CI 0.85-0.98) and specificity of 0.90 (95% CI 0.83-0.94). When the sum was below the detection limit (0.03 mu g/g) all gloves belonged to the previously defined low-allergen category. Conclusions: By comparing the sum concentration of four selected NRL allergens with results obtained in human IgE-ELISA inhibition, it was possible set a cut-off level (0.15 mu g/g) below which virtually all gloves contain low or insignificant amounts of allergens, and can be considered as low allergenic. At different cut-off-points, one could calculate the likelihood of a given glove to belong to the previously defined low, moderate or high allergen categories. Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci Perola, M., Sammalisto, S., Hiekkalinna, T., Martin, N. G., Visscher, P. M., Montgomery, G. W., Benyamin, B., Harris, J. R., Boomsma, D., Willemsen, G., Hottenga, J. J., Christensen, K., Kyvik, K. O., Sorensen, T. I., Pedersen, N. L., Magnusson, P. K., Spector, T. D., Widen, E., Silventoinen, K., Kaprio, J., Palotie, A. and Peltonen, L. PLoS Genet. 2007; 3(6): e97. Journal Article. IF 7.671 Twin cohorts provide a unique advantage for investigations of the role of genetics and environment in the etiology of variation in common complex traits by reducing the variance due to environment, age, and cohort differences. The GenomEUtwin (http://www.genomeutwin.org) consortium consists of eight twin cohorts (Australian, Danish, Dutch, Finnish, Italian, Norwegian, Swedish, and United Kingdom) with the total resource of hundreds of thousands of twin pairs. We performed quantitative trait locus (QTL) analysis of one of the most heritable human complex traits, adult stature (body height) using genome-wide scans performed for 3,817 families (8,450 individuals) derived from twin cohorts from Australia, Denmark, Finland, Netherlands, Sweden, and United Kingdom with an approximate ten-centimorgan microsatellite marker map. The marker maps for different studies differed and they were combined and related to the sequence positions using software developed by us, which is publicly available ( https://apps.bioinfo.helsinki.fi/software/cartographer.aspx). Variance component linkage analysis was performed with age, sex, and country of origin as covariates. The covariate adjusted heritability was 81% for stature in the pooled dataset. We found evidence for a major QTL for human stature on 8q21.3 (multipoint logarithm of the odds 3.28), and suggestive evidence for loci on Chromosomes X, 7, and 20. Some evidence of sex heterogeneity was found, however, no obvious female-specific QTLs emerged. Several cohorts contributed to the identified loci, suggesting an evolutionarily old genetic variant having effects on stature in European-based populations. To facilitate the genetic studies of stature we have also set up a website that lists all stature genome scans published and their most significant loci (http://www.genomeutwin.org/stature_gene_map.htm). Ranta, K., Kaltiala-Heino, R., Rantanen, P., Tuomisto, M. T. and Marttunen, M. European Psychiatry. 2007; 22(4): 244-251. Journal Article. IF 1.463 Social phobia (SP) has onset during early adolescence, and is associated with significant impairment in social and educational functioning of adolescents. Therefore, valid and easy-to-use tools for screening and identification of SP among adolescent community populations are needed. We investigated both construct and discriminative validity, and screening properties of the 17-item Social Phobia Inventory (SPIN) relative to SP diagnoses based on a semi-structured clinical interview (K-SADS-PL), in a sample of 752 12 to 17-year-old Finnish students from general population. The SPIN demonstrated good properties to differentiate adolescents with SP and those with sub-clinical SP symptoms (SSP), from adolescents without SP. The SPIN also differentiated adolescents with SP from those with depressive and disruptive disorders. In this sample 27% of participants scored above the previously suggested SPIN cut-off (15 points) for adolescent SP We suggest using a somewhat higher cut-off score, 24 points, when using the SPIN as a screen for SP in general adolescent populations. This cut-off score resulted in a sensitivity of 81.2%, a specificity of 85. 1%, a positive predictive value of 26.9%, and a negative predictive value of 98.6% in relation to the SP diagnosis in our sample. To screen for both SP and SSP, 19 points as a cut-off score produced satisfactory diagnostic efficiency statistics. The SPIN appears to have good properties for screening and identification of adolescent SP. (c) 2006 Elsevier Masson SAS. All rights reserved. No association between common variants in glyoxalase 1 and autism spectrum disorders Rehnstrom, K., Ylisaukko-Oja, T., Vanhala, R., von Wendt, L., Peltonen, L. and Hovatta, I. Am J Med Genet B Neuropsychiatr Genet. 2007. Journal Article. The autism spectrum disorders (ASDs) are complex diseases with a strong genetic component. Numerous candidate gene studies have tested association between various functional and positional candidate genes and autism, but no common variation predisposing for autism has been identified to date. It has been previously proposed, that glyoxalase 1 (GLO1) might be involved in the pathogenesis of autism as GLO1 protein polarity was significantly changed in the brains of autism patients compared to controls. GLO1 harbors a functional polymorphism that affects the polarity and the enzymatic activity of the protein. In the same study, this polymorphism showed a suggestive association to autism. To investigate whether common variants in GLO1 predispose to autism in the Finnish population, we have genotyped six polymorphisms in GLO1 in families with more than 230 individuals affected with ASDs and carried out both linkage and association analyses. We did not observe significant linkage or association between any SNP and ASDs. Therefore, we suggest that common variants in GLO1 are not significant susceptibility factors for ASDs in the Finnish population. (c) 2007 Wiley-Liss, Inc. Stenholm, S., Sainio, P., Rantanen, T., Alanen, E. and Koskinen, S. Aging Clin Exp Res. 2007; 19(4): 277-83. Journal Article. IF 1.068 BACKGROUND AND AIMS: Obesity among older persons is rapidly increasing, thus affecting their mobility negatively. The aim of this study was to examine the association of high body mass index (BMI) with walking limitation, and the effect of obesity-related diseases on this association. METHODS: In a representative sample of the Finnish population of 55 years and older (2055 women and 1337 men), maximal walking speed, chronic diseases, and BMI were ascertained in a health examination. Walking limitation was defined as maximal walking speed of less than 1.2 m/s or difficulty in walking 500 meters. To analyze the effects of chronic conditions, smoking, marital status, and education on BMI class differences in walking limitation, covariates were sequentially adjusted in logistic regression analyses. RESULTS: In women, an increasing gradient in the age-adjusted risk of walking limitation was observed with higher BMI: overweight (OR 1.47, 95% CI 1.10-1.96), obese (OR 2.77, 95% CI 2.01-3.82), and severely obese (OR 5.80, 95% CI 3.52-9.54). In men, the risk was significantly increased among the obese (OR 1.63, 95% CI 1.04-2.55) and severely obese (OR 4.33, 95% CI 2.20- 8.53). After adjustment of multiple covariates, the association remained significant among the obese (OR 1.99, 95% CI 1.38-2.86) and severely obese women (OR 3.64, 95% CI 2.12-6.26), as well as severely obese men (OR 2.78, 95% CI 1.30-5.95). Knee osteoarthritis in women and diabetes in men contributed most to the excess risk of walking limitation among obese persons, 18 and 32% respectively. CONCLUSIONS: Obesity increases the risk of walking limitation, independent of obesity-related diseases, smoking, marital status, and education, especially in older women. The results of this study emphasize the importance of maintaining normal body weight, in order to prevent obesity-related health risks and loss of functioning in older age. |