A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics.

AIMS: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. METHODS: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88). RESULTS: In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10-12 and P = 3.2 × 10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P = 4.69 × 10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P = 2.6 × 10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P = .01). CONCLUSION: These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

Genome-Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP.

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].

Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics.

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration-time curve (AUC0-∞ ). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0-∞ . A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC0-∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0-∞ in the high exposure group (p = 1.08 × 10-11 ). In addition, the results showed gene-gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC0-∞ (p < 5 × 10-6 ) suggesting an interplay between organic anion transporting polypeptide 1A2 and P-glycoprotein in celiprolol absorption. Taken together, these data indicate that P-glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood-pressure lowering response to celiprolol.

Genomewide Association Study of Simvastatin Pharmacokinetics.

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 × 10-10 ). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 × 10-17 ). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10-13 ) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10-6 ) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10-4 ) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10-6 ), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10-4 ). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10-4 ) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

Prenatal and childhood growth and leisure time physical activity in adult life.

BACKGROUND: Physical activity plays an important role in prevention of chronic diseases. Animal studies have suggested that lifestyle and exercise habits may have a prenatal origin. Our aim was to assess the role of early growth on leisure time physical activity (LTPA) in later life among 57-70-years-old men and women. METHODS: We examined 2003 individuals born in Helsinki, Finland between 1934 and 1944. Of them, 1967 individuals with adequate information on their LTPA in adult life were included in this study. LTPA was assessed by a validated exercise questionnaire (KIHD Study 12 month physical activity history). Subjects' birth and serial growth measurements were obtained from birth, child welfare and school health records. RESULTS: Participants with higher engagement in LTPA showed a more favourable adult anthropometric and body composition profile than those who were less active. LTPA was positively associated with adult social class. Higher weight and length at birth, and weight at 2 years after adult BMI adjustment, predicted higher intensity of total LTPA (P = 0.04, P = 0.01 and P = 0.03), respectively. Higher height at 2, 7 and 11 years predicted higher intensity of conditioning LTPA (P = 0.01, P = 0.04 and P = 0.004). Higher weight and height at 2, 7 and 11 years predicted higher energy expenditure (EE) of total LTPA (P-values being from 0.01 to 0.03). Furthermore, higher height at 2 and 11 years predicted higher EE of conditioning LTPA (P = 0.02 and P = 0.03). CONCLUSION: People who as children were taller and weighed more engage more in leisure time physical activity in late adulthood.

UGT1A3 and Sex Are Major Determinants of Telmisartan Pharmacokinetics-A Comprehensive Pharmacogenomic Study.

To investigate how variability in multiple pharmacokinetic genes associates with telmisartan exposure, we determined telmisartan single-dose (40 mg) pharmacokinetics and sequenced 379 genes in 188 healthy volunteers. Intronic UGT1A variants showed the strongest associations with the area under the plasma concentration-time curve from zero hours to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of telmisartan. These variants were strongly linked with the increased function UGT1A3*2 allele, suggesting that it is the causative allele underlying these associations. In addition, telmisartan plasma concentrations were lower in men than in women. The UGT1A3*2 was associated with a 64% and 63% reduced AUC0-∞ of telmisartan in UGT1A3*2 heterozygous and homozygous men, respectively (P = 1.21 × 10-16 and 5.21 × 10-8 ). In women, UGT1A3*2 heterozygosity and homozygosity were associated with 57% (P = 1.54 × 10-11 ) and 72% (P = 3.31 × 10-15 ) reduced AUC0-∞ , respectively. Furthermore, a candidate gene analysis suggested an association of UGT1A3*3 and the SLCO1B3 c.767G>C missense variant with telmisartan pharmacokinetics. A genotype score, which reflects the effects of sex and genetic variants on telmisartan AUC0-∞ , associated with the effect of telmisartan on diastolic blood pressure. These data indicate that sex and UGT1A3 are major determinants and suggest a role for OATP1B3 in telmisartan pharmacokinetics.

Enantiospecific Pharmacogenomics of Fluvastatin.

The aim of this study was to investigate how variability in multiple genes related to pharmacokinetics affects fluvastatin exposure. We determined fluvastatin enantiomer pharmacokinetics and sequenced 379 pharmacokinetic genes in 200 healthy volunteers. CYP2C9*3 associated with significantly increased area under the plasma concentration-time curve (AUC) of both 3R,5S-fluvastatin and 3S,5R-fluvastatin (by 67% and 94% per variant allele copy, P = 3.77 × 10-9 and P = 3.19 × 10-12 ). In contrast, SLCO1B1 c.521T>C associated with increased AUC of active 3R,5S-fluvastatin only (by 34% per variant allele copy; P = 8.15 × 10-8 ). A candidate gene analysis suggested that CYP2C9*2 also affects the AUC of both fluvastatin enantiomers and that SLCO2B1 single-nucleotide variations may affect the AUC of 3S,5R-fluvastatin. Thus, SLCO transporters have enantiospecific effects on fluvastatin pharmacokinetics in humans. Genotyping of both CYP2C9 and SLCO1B1 may be useful in predicting fluvastatin efficacy and myotoxicity.

CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel.

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P = 0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24 hours after ticagrelor ingestion than the controls (43% vs. 21%; P = 0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.

Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics.

To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC0-∞ ) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10-10 ). UGT1A3*2 was associated with increased AUC0-∞ of montelukast acyl-glucuronide M1 and decreased AUC0-∞ of hydroxymetabolites M5R, M5S, and M6 (P < 10-9 ). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC0-∞ of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC0-∞ of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers.

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects.

Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10-13 ) and 31% (p = 2.5 × 10-8 ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.

Quality of life and metabolic status in mildly depressed patients with type 2 diabetes treated with paroxetine: a double-blind randomised placebo controlled 6-month trial.

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.

Quality of life and metabolic status in mildly depressed women with type 2 diabetes treated with paroxetine: a single-blind randomised placebo controlled trial.

BACKGROUND: Depression is prevalent in people with type 2 diabetes and affects both glycemic control and overall quality of life. The aim of this trial was to evaluate the effect of the antidepressant paroxetine on metabolic control, quality of life and mental well-being in mildly depressed women with type 2 diabetes. METHODS: We randomised 15 mildly depressed women with non-optimally controlled type 2 diabetes to a 10-week single-blind treatment with either paroxetine 20 mg per day or placebo. Primary efficacy measurements were glycemic control and quality of life. Glycosylated hemoglobin A1c (GHbA1c) was used as a measure of glycemic control. Quality of life was evaluated using RAND-36. Mental state was assessed using two clinician-rated scoring instruments, Hamilton's Anxiety Scale (HAM-A) and Montgomery-Asberg's Depression Rating Scale (MADRS), and a patient-rated scoring instrument, Beck's Depression Inventory (BDI). RESULTS: At the end of the study no significant difference between groups in improvement of quality of life was found. A trend towards a superior improvement in glycemic control was found in the paroxetine group (p = 0.08). A superior increase in sex-hormone-binding-globuline (SHBG) levels was evidenced in the paroxetine group (p = 0.01) as a sign of improved insulin sensitivity. There was also a trend for superior efficacy of paroxetine in investigator-rated anxiety and depression. This notion was supported by a trend for superior decrease of serum cortisol levels in the paroxetine group (p = 0.06). CONCLUSION: Paroxetine has a beneficial effect on measures of insulin sensitivity and may improve glycemic control. Larger studies of longer duration are needed to verify the benefits of paroxetine in type 2 diabetes. While waiting for more conclusive evidence it seems sensible to augment standard care of type 2 diabetes with paroxetine even in patients who do not fulfil routine psychiatric criteria for initiation of antidepressant drug treatment.

Developmental origins of physical fitness: the Helsinki Birth Cohort Study.

BACKGROUND: Cardiorespiratory fitness (CRF) is a major factor influencing health and disease outcomes including all-cause mortality and cardiovascular disease. Importantly CRF is also modifiable and could therefore have a major public health impact. Early life exposures play a major role in chronic disease development. Our aim was to explore the potential prenatal and childhood origins of CRF in later life. METHODS/PRINCIPAL FINDINGS: This sub-study of the HBCS (Helsinki Birth Cohort Study) includes 606 men and women who underwent a thorough clinical examination and participated in the UKK 2-km walk test, which has been validated against a maximal exercise stress test as a measure of CRF in population studies. Data on body size at birth and growth during infancy and childhood were obtained from hospital, child welfare and school health records. Body size at birth was not associated with adult CRF. A 1 cm increase in height at 2 and 7 years was associated with 0.21 ml/kg/min (95% CI 0.02 to 0.40) and 0.16 ml/kg/min (95% CI 0.03 to 0.28) higher VO2max, respectively. Adjustment for adult lean body mass strengthened these findings. Weight at 2 and 7 years and height at 11 years became positively associated with CRF after adult lean body mass adjustment. However, a 1 kg/m(2) higher BMI at 11 years was associated with -0.57 ml/kg/min (95% CI -0.91 to -0.24) lower adult VO2max, and remained so after adjustment for adult lean body mass. CONCLUSION/SIGNIFICANCE: We did not observe any significant associations between body size at birth and CRF in later life. However, childhood growth was associated with CRF in adulthood. These findings suggest, importantly from a public point of view, that early growth may play a role in predicting adult CRF.

Slower reaction times and impaired learning in young adults with birth weight <1500 g.

OBJECTIVE: Children with very low birth weight (VLBW; <1500 g) perform worse on cognitive tests than do children who are born at term. Whether this difference persists into adulthood has been little studied. We assessed core neurocognitive abilities (processing speed, working memory, attention, and learning capacity) in young adults with VLBW and in term-born control subjects. METHODS: In conjunction with the Helsinki Study of Very Low Birth Weight Adults, 147 VLBW and 171 control subjects who were aged 18 to 27 years and did not have neurosensory impairments performed a computerized test battery (CogState Ltd, Melbourne, Australia). T tests and linear regression models were used. Cohen's d was used to express effect size (ES). RESULTS: VLBW adults had slower reaction times than did control subjects on all 5 tasks: simple reaction time (mean difference: 4.0% [95% confidence interval (CI): 1.1%-7.0%]; ES: 0.30), choice reaction time (mean difference: 3.2% [95% CI: 0.3%-6.2%]; ES: 0.24), working memory (mean difference: 8.4% [95% CI: 3.7%-13.4%]; ES: 0.40), divided attention (mean difference: 7.2% [95% CI: 2.7%-11.9%]; ES: 0.36), and associated learning reaction time (mean difference: 6.4% [95% CI: 1.3%-11.9%]; ES: 0.28). In addition, VLBW adults showed impaired learning abilities on the associated learning task (percentage of correct responses: 85.7 vs 80.2; P < .001; ES: 0.64). The results were little affected by adjustment for confounders. CONCLUSIONS: Nonimpaired VLBW individuals exhibited slower psychomotor speed and lower accuracy on the associated learning task. These results indicate that very preterm birth, even when obvious neurosensory deficits are absent, may have long-term consequences on core neurocognitive abilities.

Impact of glucose metabolism and birth size on cognitive performance in elderly subjects.

AIMS: We aimed to investigate the impact of diabetes and impaired glucose tolerance on cognitive performance and to explore the association between birth weight and cognitive performance among diabetic subjects. METHODS: We performed a standard oral glucose tolerance test and a computerised test for assessment of cognitive performance (CogState) in 1243 subjects; 173 of them had type 2 diabetes. At the time of cognitive testing the mean age of the subjects was 64 years. Subjects with type 1 diabetes or a history of stroke were excluded. RESULTS: Subjects with known diabetes performed significantly poorer in cognitive tasks measuring visual attention, working memory and episodic learning than subjects with normal glucose tolerance. Subjects with newly diagnosed diabetes or milder impairments in glucose regulation did not differ from the normoglycaemic group. A low birth weight enhanced the association between diabetes and poor performance in the working memory and episodic learning tasks. CONCLUSIONS: Poorer cognitive performance was associated with known type 2 diabetes but not with newly diagnosed diabetes or milder impairments in glucose regulation. Low birth weight was found to be an additional vulnerability factor enhancing cognitive decline in diabetic subjects.

Intellectual ability in early adulthood and type 2 diabetes in later life.

The aim of this study is to assess whether intellectual ability in young adult men predicts the development of type 2 diabetes in later life. 641 men participating in the Helsinki Birth Cohort Study were administered a 2-h (75 g) oral glucose tolerance test at a mean age of 61 years. Intellectual ability was assessed during compulsory military service at a mean age of 20 years. Associations were explored using linear and logistic regression models. Intellectual ability in young adulthood did not predict glucose tolerance at age 61 years. However, educational attainment was associated with the prevalence of type 2 diabetes, independently of early intellectual ability. Men with the highest educational attainment were less likely to have type 2 diabetes than men with the lowest educational attainment (OR = 0.50, 95% CI 0.28-0.91). While education seems to protect from type 2 diabetes, we could not detect a connection between early intellectual ability and impairment in glucose regulation in later adulthood.

Role of socioeconomic indicators on development of obesity from a life course perspective.

AIMS: Development of obesity is modified by several factors, including socioeconomic ones. We studied the importance of socioeconomic indicators on the development of obesity from a life course perspective. METHODS: 2003 people born 1934-1944 in Helsinki, Finland, participated in clinical examinations in 2001-2004. Obesity was defined as body mass index (BMI) >30 kg/m(2). RESULTS: Prevalence of obesity was 22.3% in men and 27.2% in women. Lower educational attainment and lower adult social class were associated with higher BMI in both men (P = .03 and P < .01) and women (P < .001 and P = .01). Childhood social class was inversely associated with BMI only in men (P < .001); lower household income was associated with higher BMI in women only (P < .001). Those men belonging to the lowest childhood social class had higher risk of being obese than those of the highest childhood social class (OR 1.8 (95% CI: 1.0-3.1)). Household income was the strongest predictor of obesity among women. CONCLUSION: Overweight and obesity are inversely associated with socioeconomic status. Men seem to be more susceptible to adverse childhood socioeconomic circumstances than women, while adult socioeconomic indicators were more strongly associated with obesity in women.

Depression and its association with diabetes, cardiovascular disease, and birth weight.

BACKGROUND: Diabetes increases the risk for depression. AIM: To study the independent effects of diabetes mellitus (DM) and cardiovascular disease (CVD) on the prevalence of depression and to examine low birth weight as a possible common explanatory factor. METHODS: 2003 subjects from the Helsinki Birth Cohort Study underwent a 75-g oral glucose tolerance test and filled out the Beck Depression Inventory. RESULTS: Depressive symptoms were more prevalent among subjects with diabetes (23.5%) than among those with normal glucose tolerance (16.6%) (P < 0.001). A history of CVD also markedly increased the odds of having depressive symptoms (odds ratio (OR) = 2.38, 95% confidence interval (CI) = 1.70-3.32, P < 0.001). The association between DM and depressive symptoms was, however, rendered non-significant when adjusting for the presence of CVD. Being born with a low birth weight doubled the risk for having depressive symptoms (OR = 2.64, 95% CI = 1.42-4.91, P = 0.002) and magnified the association between CVD/DM and depression. CONCLUSION: Diabetes has only a minor independent effect on concurrent occurrence of depressive symptoms, while cardiovascular disease seems to be a more important underlying factor. The association between disease and depression is in particular characteristic to individuals born with a low birth weight.