Genetic variants and their interactions in the prediction of increased pre-clinical carotid atherosclerosis: the cardiovascular risk in young Finns study.

The relative contribution of genetic risk factors to the progression of subclinical atherosclerosis is poorly understood. It is likely that multiple variants are implicated in the development of atherosclerosis, but the subtle genotypic and phenotypic differences are beyond the reach of the conventional case-control designs and the statistical significance testing procedures being used in most association studies. Our objective here was to investigate whether an alternative approach--in which common disorders are treated as quantitative phenotypes that are continuously distributed over a population--can reveal predictive insights into the early atherosclerosis, as assessed using ultrasound imaging-based quantitative measurement of carotid artery intima-media thickness (IMT). Using our population-based follow-up study of atherosclerosis precursors as a basis for sampling subjects with gradually increasing IMT levels, we searched for such subsets of genetic variants and their interactions that are the most predictive of the various risk classes, rather than using exclusively those variants meeting a stringent level of statistical significance. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the variants, and cross-validation was used to assess how well the predictive models will generalize to other subsets of subjects. By means of our predictive modeling framework with machine learning-based SNP selection, we could improve the prediction of the extreme classes of atherosclerosis risk and progression over a 6-year period (average AUC 0.844 and 0.761), compared to that of using conventional cardiovascular risk factors alone (average AUC 0.741 and 0.629), or when combined with the statistically significant variants (average AUC 0.762 and 0.651). The predictive accuracy remained relatively high in an independent validation set of subjects (average decrease of 0.043). These results demonstrate that the modeling framework can utilize the "gray zone" of genetic variation in the classification of subjects with different degrees of risk of developing atherosclerosis.

Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.

AIMS: The interleukin 18 (IL-18) gene has a single nucleotide promoter region (-137) G-to-C polymorphism (rs187238) which leads to attenuated transcriptional activity of the gene and to lower production of pro-atherogenic IL-18. The C allele of this polymorphism is associated with a lower risk of sudden cardiac death (SCD). We examined the process by which this polymorphism alters the risk of SCD and coronary artery disease (CAD) by analysing the interactions between this polymorphism and environmental factors. METHODS AND RESULTS: TaqMan 5' nuclease assay was used to genotype the study population of the Helsinki Sudden Death Study, comprising medicolegal autopsies of 700 men. According to adjusted logistic regression analysis, there was a significant interaction between IL-18 genotype and hypertension impacting on the risk of SCD due to coronary heart disease (CHD) (P = 0.011) and the severity of autopsy-verified CAD (P = 0.026). Among GG homozygotes, hypertension was a major risk factor for SCD due to CHD [adjusted odds ratio (OR) 3.75 with 95% CI 1.78-7.91, P < 0.001] and hypertension also associated with larger coronary atherosclerotic plaque areas (P = 0.002) and the occurrence of complicated plaques (adjusted OR 8.38 with 95% CI 2.39-29.33, P < 0.001). Among C allele carriers, hypertension was not a significant risk factor for CHD-related SCD or CAD and did not associate with the development of coronary atherosclerotic plaques. According to gene expression analysis of atherosclerotic tissue samples obtained from live patients, hypertension also interacted significantly with IL-18 genotype affecting the expression of IL-18 (P = 0.030) mRNA and interferon-gamma mRNA (P = 0.004). CONCLUSION: Hypertension interacts with IL-18 gene promoter -137 G/C polymorphism, affecting the risk of SCD and the development of coronary atherosclerosis.

Genetic lactase non-persistence, consumption of milk products and intakes of milk nutrients in Finns from childhood to young adulthood.

Previous evidence suggests that the lactase gene C/T- 13910 polymorphism (rs4988235) is associated with avoidance of milk products and lower Ca intake. We examined whether the consumption of milk and milk products and the intakes of milk nutrients differ between the lactase genotypes from childhood to young adulthood. Subjects belong to the Cardiovascular Risk in Young Finns Study where the first cross-sectional surveys were conducted in 1980 (n 3596), with follow-up studies in 1983, 1986, 1989, 1992 and 2001 (n 2620). The same dietary questionnaire was used throughout the follow-up to collect data on habitual consumption of milk and milk products in all subjects, and daily nutrient intakes were assessed with 48 h dietary recalls in 50 % of the subjects. Subjects with the lactase non-persistence (C/C- 13910) genotype consumed less milk since childhood, but the consumption of other milk products did not differ between the genotypes. In adult females, the lactose content of milk products consumed was lower (P = 0.003), and in both sexes low-lactose and milk-free diets were more common in the C/C- 13910 genotype than in the other genotypes. Inadequate Ca intake was most common in females with the C/C- 13910 genotype as early as in childhood (15-63 %), but in males only in adulthood (24 %). In adult females, preference for low-lactose milk and milk products equalised the differences in Ca intake between the genotypes. Thus, in those with the C/C- 13910 genotype, preference for low-lactose milk and milk products may decrease the risk for inadequate Ca intake.

Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy.

Several lines of evidence suggest that catechol-O-methyltransferase (COMT) may be associated with treatment response in depression. We conducted a study on 119 patients with treatment-refractory depression admitted consecutively for electroconvulsive therapy (ECT). The COMT high/high genotype leads to a higher enzyme activity and thus lowers dopaminergic activity in the prefrontal cortex. In the present sample, those homozygous to high-active allele of COMT responded significantly more frequently to ECT.

Serotonin receptor 2A gene and the influence of childhood maternal nurturance on adulthood depressive symptoms.

BACKGROUND: Gene-environment interactions are assumed to be involved in the development of depression. OBJECTIVE: To determine whether the serotonin receptor 2A (HTR2A) gene moderates the association between childhood maternal nurturance and depressive symptoms in adulthood. DESIGN: A 21-year, prospective, longitudinal study with 2 measurements of the independent and dependent variables. SETTING: A population-based sample. PARTICIPANTS: A subsample of 1212 participants of the Cardiovascular Risk in Young Finns study, aged 3 to 18 years at baseline. Main Outcome Measure Depressive symptoms in adulthood. RESULTS: Individuals carrying the T/T or T/C genotype of the T102C polymorphism of the HTR2A gene were responsive to the protective aspects of nurturing mothering, so that in the presence of high maternal nurturance, they expressed low levels of depressive symptoms, while this was not true with the carriers of the C/C genotype. CONCLUSION: The HTR2A gene may be involved in the development of depression by influencing the ability of individuals to use environmental support.

Tryptophan hydroxylase 1 gene haplotypes modify the effect of a hostile childhood environment on adulthood harm avoidance.

We conducted a series of tests to determine whether there is any association between tryptophan hydroxylase 1 (TPH1) and temperament in adulthood. In addition to testing for main effects, we investigated whether TPH1 gene variation modifies the influence of childhood environment on temperament in adulthood. The subjects were 341 healthy adults whose childhood environment was assessed by their mothers in 1980 and who self-rated their temperaments twice, in 1997 and 2001. We found no association between the TPH1 gene and temperament; however, among women, the TPH1 gene modified a relationship between adverse childhood environment and harm avoidance in adulthood. This finding was confirmed in the same sample in another test setting 4 years later. The presence of the A/A haplotype of the TPH1 intron 7 A218A and A779C polymorphism predicted a high level of adulthood harm avoidance in the presence of a hostile childhood environment as defined in terms of emotional rejection, maternal neglect and harsh and inconsistent discipline. In addition, the findings suggest a gene-environment correlation for novelty seeking in men.

Age-dependent association between hepatic lipase gene C-480T polymorphism and the risk of pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.

OBJECTIVE: We investigated the association between hepatic lipase (HL) C-480T polymorphism and the risk of acute myocardial infarction (AMI) as well as pre-hospital sudden cardiac death (SCD). METHODS: Seven hundred sudden or unnatural pre-hospital deaths of middle-aged (33-70 years, mean 53 years) Caucasian Finnish men were subjected to detailed autopsy (Helsinki Sudden Death Study). Genotype data were obtained for 682 men. RESULTS: In logistic regression analysis with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, men with the TT genotype had an increased risk for SCD and AMI compared to CC carriers (OR=3.0, P=0.011; and OR=3.7, P=0.003). There was a significant age-by-genotype interaction (P<0.05) on the risk of SCD. Compared to CC genotype carriers, the association between the TT genotype and SCD was particularly strong (P=0.001) among men <53 years of age, but this association was non-significant among older men. This was mainly due to a strong association between the TT genotype and AMI due to severe coronary disease in the absence of thrombosis. Carriers of the TT genotype were more likely to have severe coronary stenoses (> or =50%) than men with the CT or CC genotype (P=0.019). CONCLUSIONS: The results suggest that HL C-480T polymorphism is a strong age-dependent risk factor of SCD in early middle-aged men.

CYBA C242T gene polymorphism and flow-mediated vasodilation in a population of young adults: the Cardiovascular Risk in Young Finns Study.

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 5' 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 > or = 25 kg/m, 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.

Epidermal growth factor a61g polymorphism is associated with the age of onset of schizophrenia in male patients.

There is evidence to suggest that dysfunction of dopaminergic neurotransmission in the central nervous system (CNS) plays a role in the etiopathology of schizophrenia. Epidermal growth factor (EGF) gene polymorphism has an impact on EGF production in mononuclear cells, and EGF seems to affect the development of midbrain dopaminergic neurons. The few studies concerning EGF gene polymorphism and schizophrenia have yielded contradictory results. Our aim was to investigate whether EGF gene A61G polymorphism predisposes to schizophrenia, and this polymorphism was therefore studied in 149 schizophrenic patients and in 94 healthy controls using 5' nucleotidase assay (TaqMan). As far as EGF A61G polymorphism was concerned, we detected no significant differences in the allele and genotype frequencies between the patients and the controls. However, the G/G genotype was significantly associated with an earlier age of onset of schizophrenic psychosis in male subjects (P=0.005) as well as in the entire population, but not in female patients (P=0.008 and 0.46, respectively). The average age (+/-SD) of onset of schizophrenia was 20.1+/-3.9 years in male EGF A61G G/G homozygotes and 23.7+/-6.6 (P=0.02) years in other genotypes. In conclusion, EGF gene polymorphism was not associated with the risk of schizophrenia. However, the EGF G/G genotype, which has been suggested to involve abundant production of EGF, was associated with early onset of schizophrenia in male patients.

Tryptophan hydroxylase 1 gene (TPH1) moderates the influence of social support on depressive symptoms in adults.

BACKGROUND: Tryptophan hydroxylases (TPHs) are involved in the biosynthesis of serotonin and are therefore candidate genes for psychiatric disorders, including depression. We examined whether the common 218 A > C and 779 A > C polymorphisms in the tryptophan hydroxylase 1 gene (TPH1) moderated the association between perceived social support and sub-clinical depressive symptoms in adults. METHODS: The subjects were a randomly selected subsample (n=341) of individuals participating in the Cardiovascular Risk in Young Finns study, who had data on social support on one assessment time and depressive symptoms on two assessment times. Social support was assessed on the Perceived Social Support Scale Revised (PSSS-R) and depressive symptoms on a modified version of the Beck's Depression Inventory (BDI). RESULTS: We found that low social support predicted depressive symptoms more strongly in individuals carrying A alleles of the TPH1 than in others. The interaction effect was observed in a cross-sectional analysis and when predicting depressive symptoms over a four-year period. LIMITATIONS: We did not have data on TPH2, which has recently been identified as the primary TPH isomorphism affecting serotonin synthesis in the brain. CONCLUSIONS: TPH1 gene may be involved in the development of depressive symptoms by moderating the impact of depressogenic social influences.

Temperamental activity and epidermal growth factor A61G polymorphism in Finnish adults.

BACKGROUND/AIMS: Epidermal growth factor (EGF) has widespread effects on the developing and mature nervous system. This study examined whether genetic differences in the EGF predict differences in the self-reported level of activity temperament in adults. METHODS: Two hundred and ninety-two men and women from the population-based Cardiovascular Risk in Young Finns Study were genotyped for the functional EGF gene A61G polymorphisms, and their temperamental activity was assessed 3 times in 1992, 1997 and 2001. RESULTS: The EGF gene predicted temperamental activity (the mean of 3 assessments, p = 0.007), with the G/G genotype being associated with the highest level of activity. Additional analyses in separate years indicated that the association was robust across different measurements of activity (p < or = 0.05 in 1992 and 1997, p = 0.008 in 2001). CONCLUSION: These results suggest that polymorphic variation in the EGF A61 gene may be one of the factors underlying the temperament dimension of activity.

Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach.

BACKGROUND: Schizophrenia is a common psychiatric disease affecting about 1% of population. One major problem in the treatment is finding the right the drug for the right patients. However, pharmacogenetic results in psychiatry can seldom be replicated. METHODS: We selected three candidate genes associated with serotonergic neurotransmission for the study: serotonin 2A (5-HT2A) receptor gene, tryptophan hydroxylase 1 (TPH1) gene, and G-protein beta-3 subunit (GNB3) gene. We recruited 94 schizophrenia patients representing extremes in treatment response to typical neuroleptics: 43 were good responders and 51 were poor responders. The control group consisted of 392 healthy blood donors. RESULTS: We do, in part, replicate the association between 5-HT2A T102C polymorphism and response to typical neuroleptics. In female patients, C/C genotype was significantly more common in non-responders than in responders [OR = 6.04 (95% Cl 1.67-21.93), p = 0.005] or in the control population [OR = 4.16 (95% CI 1.46-11.84), p = 0.005]. TPH1 A779C C/A genotype was inversely associated with good treatment response when compared with non-responders [OR = 0.59 (95% Cl 0.36-0.98), p = 0.030] or with the controls [OR = 0.44 (95% CI 0.23-0.86, p = 0.016], and GNB3 C825T C/T genotype showed a trend-like positive association among the male patients with a good response compared with non-responders [OR = 3.48 (95% Cl 0.92-13.25), p = 0.061], and a clearer association when compared with the controls [OR = 4.95 (95% CI 1.56-15.70), p = 0.004]. CONCLUSION: More findings on the consequences of functional polymorphisms for the role of serotonin in the development of brain and serotonergic neurotransmission are needed before more detailed hypotheses regarding susceptibility and outcome in schizophrenia can be formulated. The present results may highlight some of the biological mechanisms in different courses of schizophrenia between men and women.

Blood leukocyte count is a risk factor for intima-media thickening and subclinical carotid atherosclerosis in middle-aged men.

Leukocytosis is known to predict future cardiovascular events even in subjects without coronary heart disease (CHD), but its association with early atherosclerotic changes has remained less certain. The aim of the present study was to investigate how the blood leukocyte count compares with several other risk factors for CHD in determining carotid artery intima-media thickness (IMT) and subclinical carotid atherosclerosis in a population sample. Both carotid arteries were investigated with high-resolution B-mode ultrasound in a community-based sample of 219 randomly selected men aged 50-59 years to calculate the mean maximum IMT (MMax IMT) of 12 standard sites. Risk factor assessment included several traditional biochemical risk factors, blood pressure, maximal oxygen consumption and work load on ergometry, life-style habits and hematologic parameters. As genetic determinants, apolipoprotein E and A-IV polymorphisms were studied. According to multivariate regression analysis, age (P<0.0001), blood leukocyte count (P<0.0001) and systolic blood pressure (P<0.042) were the only significant predictors of MMax IMT. MMax IMT increased linearly from the lowest tertile of blood leukocyte count (1.14+/-0.20mm) to the second (1.18+/-0.25 mm) and to the highest tertile (1.25+/-0.27 mm, P=0.019). This difference remained significant after adjustment with age, systolic blood pressure and smoking (P=0.032). Leukocytes seem to have an independent role in the early arterial damage and they may reflect subclinical disease. This implies that leukocyte count is undervalued in the diagnostics and prognostics of carotid atherosclerosis.

Genetic variant of the SREBF-1 gene is significantly related to cholesterol synthesis in man.

Sterol regulatory element binding proteins-1 and -2 (SREBPs) are transcription factors controlling lipid homeostasis in human cells. The G-allele carriers of the SREBF-1 gene C-G polymorphism in exon 18c and coding for glycine at the protein level (G952G) have shown to associate more frequently with obesity and type 2 diabetes than the C-allele carriers. However, the C-allele has suggested to be linked to dyslipidemia. Thus, our aim was to study effect of the SREBF-1 gene polymorphism (G952G) on sterol metabolism in man. Ninety-five subjects with moderate hypercholesterolemia participated in this study and 14 homozygous CC carriers of the SREBF-1 (G952G) gene were found. Plasma lathosterol concentration and lathosterol-to-cholesterol ratio, markers of endogenous cholesterol synthesis, were significantly higher in CC homozygous subject compared to others. Similarly muscle cholesterol (p=0.045) and lathosterol (p=0.054) concentrations were elevated in the CC homozygotes supporting the view that endogenous cholesterol synthesis rate is SREBF-1 genotype-dependent.

The influence of hepatic lipase C-480T polymorphism on coronary flow reserve in young men is independent of the plasma cholesterol level.

BACKGROUND: The hepatic lipase (HL) gene C-480T promoter polymorphism affects gene transcription and enzyme activity and leads to CC, CT, and TT genotypes. Recently, HL expression was detected in macrophages. It has been postulated that HL might have a direct role in the pathogenesis of atherosclerosis without changes in the plasma profile. We hypothesized that the difference of plasma cholesterol level may not influence the effect of HL genotype on coronary reactivity. METHODS: A total of 108 young men (aged 34+/-5 years) were genotyped and divided into three groups. These groups contained 45, 49 and 14 men having either normal (4.9+/-1.2 mmol/L), mildly (5.5+/-0.8 mmol/L) or severely (7.8+/-1.9 mmol/L, subjects with familial hypercholesterolemia) elevated mean plasma cholesterol level, respectively. Myocardial blood flow (MBF) was measured at rest and during adenosine or dipyridamole-induced hyperemia with positron emission tomography using [(15)O] H(2)O. RESULTS: The effect of HL genotype on the indices of MBF was parallel within all cholesterol groups and therefore they were combined. In all subjects, basal flow did not differ between the genotypes. However, men with CC genotype had a significantly higher hyperemic blood flow (3.86+/-1.26 mLg(-1)min(-1) versus 3.20+/-1.38 mLg(-1)min(-1), p=0.007), higher coronary flow reserve (CFR, 4.80+/-1.77 versus 3.77+/-1.43, p=0.001) and lower coronary resistance during hyperemia (25.63+/-9.98 mmHg min g mL(-1) versus 35.00+/-23.95 mmHg min g mL(-1), p=0.003) than T allele carriers. In multivariate regression analysis, after adjustment for age, body mass index, serum lipids, blood pressure, adenosine or dipyridamole administration, and study group, HL polymorphism was an independent predictor of blood flow during hyperemia (p=0.016), coronary resistance (p=0.014), and CFR (p=0.005), respectively. CONCLUSIONS: The HL C-480 T polymorphism is associated with CFR, which is an early indicator of atherosclerosis, independently of the level of plasma cholesterol in young men.

The p22phox C242T gene polymorphism is associated with a reduced risk of angiographically verified coronary artery disease in a high-risk Finnish Caucasian population. The Finnish Cardiovascular Study.

BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a major source of the superoxide anion, which may play an important role in the development of atherosclerosis and coronary artery disease (CAD). The p22phox, a component of the NADPH oxidase, is essential for the activation of this enzyme, and intensive expression of the p22phox has been reported in human atherosclerotic arteries. However, studies on the association of the C242T polymorphism in the p22phox gene with CAD have produced conflicting results, and the relation of this polymorphism with CAD is not well known in a population with acquired risk factors enhancing the NADPH-dependent superoxide production. METHODS: As part of the Finnish Cardiovascular Study, a case-control study was conducted with 402 high-risk Finnish Caucasian patients undergoing coronary angiography. Genotyping was performed using the 5' nuclease TaqMan assay. RESULTS: The prevalence of the T allele (TT + TC genotypes) was significantly lower among angiographically verified CAD patients (n = 250) than among control subjects (n = 152, P = .013). In contrast to subjects with the CC genotype, the T allele was found protective against CAD (odds ratio = 0.531, 95% CI 0.331-0.852, P = .009), and the results remained significant after adjustment for other significant coronary risk factors. CONCLUSIONS: The T allele in the C242Tpolymorphism of the p22phox gene had a protective effect against the development of CAD despite the exposure of study subjects to risk factors related to excessive NADPH-dependent superoxide production.

Effects of polymorphisms in beta1-adrenoceptor and alpha-subunit of G protein on heart rate and blood pressure during exercise test. The Finnish Cardiovascular Study.

We tested whether the Arg389Gly and Ser49Gly polymorphisms of the beta1-adrenergic receptor gene ADRB1 and the T393C polymorphism of the G protein alpha-subunit gene GNAS1 modulate heart rate (HR) and blood pressure responses during an exercise stress test. The study population comprised 890 participants (563 men and 327 women, mean age 58.1 +/- 12.6 yr) of the Finnish Cardiovascular Study. Their HR, systolic (SAP), and diastolic arterial pressures (DAP) at rest, during exercise, and 4 min after the test were measured and analyzed by repeated-measurement ANOVA (RANOVA). Genotypes were detected by TaqMan 5' nuclease assay. In all subjects, and in men and women separately, the T393C of GNAS1 was the only polymorphism with genotype x time interaction in HR over the three study phases (P = 0.04, RANOVA). None of the polymorphisms presented genotype x time interaction in SAP or DAP responses (P > 0.10, RANOVA). In all subjects at rest, the Ser49Gly polymorphism of ADRB1 tended (P = 0.06, ANOVA) to differentiate HR. Arg389Gly polymorphism of ADRB1 affected maximal SAP during exercise (P = 0.04, ANOVA) and the change in SAP from rest to maximal (P = 0.03, ANOVA). Arg389 homozygotes, particularly men, were less likely to have ventricular extrasystoles during the exercise (odds ratio = 0.68, 95% confidence interval = 0.51-0.91, P = 0.009, and odds ratio = 0.60, 95% confidence interval = 0.42-0.86, P = 0.006, respectively) than did Gly389 carriers. In conclusion, polymorphisms examined appear to have modulatory effects on hemodynamics in a clinical exercise test setting. However, the effects in absolute numbers were minor and clinically possibly insignificant.

Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia.

The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.

Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes.

BACKGROUND: Endothelial dysfunction may play a pathophysiological role in the development of atherosclerosis in subjects with type 1 diabetes. We examined whether alterations in vascular endothelial function exist in children with type 1 diabetes and tested the hypothesis that endothelial dysfunction is associated with early structural atherosclerotic vascular changes in these children. METHODS AND RESULTS: Noninvasive ultrasound was used to measure brachial artery flow-mediated dilation (FMD) responses and carotid artery intima-media thickness (IMT) in 75 children (mean age 11+/-2 years), 45 with type 1 diabetes (diabetes duration 4.4+/-2.9 years) and 30 healthy control children. Children with diabetes had lower peak FMD response (4.4+/-3.4% versus 8.7+/-3.6%, P<0.001) and increased IMT (P<0.001) compared with controls. Sixteen children with diabetes (36%) had endothelial dysfunction defined as total FMD response in the lowest decile for normal children. These children had increased carotid IMT (0.58+/-0.05 versus 0.54+/-0.04 mm, P=0.01) and higher LDL cholesterol concentration (2.63+/-0.76 versus 2.16+/-0.60 mmol/L, P=0.03) compared with diabetic children without endothelial dysfunction. Multivariate correlates of increased IMT included diabetes group (P=0.03), low FMD (P=0.03), and high LDL cholesterol (P=0.08). CONCLUSIONS: Impaired FMD response is a common manifestation in children with type 1 diabetes and is associated with increased carotid artery IMT. These data suggest that endothelial dysfunction in children with type 1 diabetes may predispose them to the development of early atherosclerosis.

Interleukin-6 modulates plasma cholesterol and C-reactive protein concentrations in nonagenarians.

OBJECTIVES: To establish whether the relationship between interleukin-6 (IL-6) and plasma lipid and C-reactive protein (CRP) concentrations is different in Finnish nonagenarians than in middle-aged subjects with lower inflammatory status. DESIGN: Cross-sectional. SETTING: Observational cohort study concentrating on the oldest old. PARTICIPANTS: Nonagenarians (n=291, mean age+/-standard deviation 90+/-1; 68 men, 223 women) who lived in the Tampere municipality in southern Finland and a middle-aged control population from the same area (n=227, aged 44+/-8). MEASUREMENTS: Plasma high sensitive CRP and lipid concentrations were analyzed using an automatic analyzer and IL-6 levels using enzyme-linked immunosorbent assay. RESULTS: Plasma concentrations of IL-6 (4.39+/-5.25 vs 1.88+/-1.98 pg/mL) and CRP (3.54+/-4.98 vs 1.53+/-1.91 mg/L) were significantly higher in nonagenarians than in middle-aged subjects (P<.001). In nonagenarians, plasma CRP levels increased (P<.001) and plasma total cholesterol (P=.006), low-density lipoprotein cholesterol (P=.02), and high-density lipoprotein cholesterol (P=.002) levels decreased according to IL-6 quartiles. In middle-aged subjects, similar associations were not found. CONCLUSION: The relationship between IL-6 and plasma CRP and cholesterol levels in nonagenarians with enhanced systemic inflammation differs from that of middle-aged subjects.