Britt-Marie Loo

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Associations of Dyslipidemias From Childhood to Adulthood With Carotid Intima-Media Thickness, Elasticity, and Brachial Flow-Mediated Dilatation in Adulthood: The Cardiovascular Risk in Young Finns Study

Background—Dyslipidemias are the major cause for atherosclerosis. They may act synergistically with nonlipid risk factors to increase atherogenesis. In the present study, we examined the effects of dyslipidemias from childhood to adulthood and their interaction with nonlipid risk factors on markers of subclinical atherosclerosis. Methods and Results—Study subjects were participants of the longitudinal Cardiovascular Risk in Young Finns Study started in 1980 (n=2265, age 3 to 18 years). To phenotype type IIa, IIb, and IV dyslipidemias and hypoHDL-cholesterolemia, we calculated age and sex-specific z scores for lipid values for each subject in 1980, 1983, 1986, and 2001. Subjects with mean z score over 90th percentile for LDL-cholesterol or triglycerides were considered having type IIa or IV dyslipidemia. Subjects with mean z score over 90th percentile for LDL-cholesterol and triglycerides had type IIb dyslipidemia, and those with mean z score below 10th percentile for HDL-cholesterol had hypoHDL-cholesterolemia. Compared to controls, subjects with type IIb dyslipidemia had increased carotid IMT (P<0.01). This difference remained significant when adjusted with other risk factors (P<0.05). Carotid IMT also increased significantly more with increasing number of nonlipid risk factors (P<0.001) or presence of the metabolic syndrome (P<0.05) in subjects with type IIb than in controls. Subjects with type IIb or type IV dyslipidemia had decreased carotid elasticity (P<0.05), but these differences became nonsignificant (P>0.3) when adjusted with blood pressure. Conclusions—Our findings suggest that type IIb dyslipidemia has deleterious effects on vasculature already since childhood. Subjects with type IIb dyslipidemia are more vulnerable to the effects of cardiovascular risk factors and metabolic syndrome.

Inflammation in psychotic disorders: a population-based study.

We investigated inflammatory markers in psychotic disorders and their association with metabolic comorbidity, antipsychotic medication, smoking, alcohol use, physical condition, and mood. From the population-based Finnish Health 2000 study, we identified all persons with schizophrenia (n=45), other nonaffective psychosis (ONAP) (n=57), affective psychosis (n=37) and chose controls matched by age, sex, and region of residence. We found that persons with schizophrenia had significantly higher sIL-2Rα, IL-1RA and C-reactive protein (CRP), persons with ONAP significantly higher IL-1RA and CRP and persons with affective psychosis almost significantly higher TNF-α compared to their matched controls. Current antipsychotic use was associated with elevated IL-1RA and CRP. After taking metabolic and lifestyle-related variables that associated with inflammatory markers into account, only antipsychotic medication remained associated with elevated IL-1RA and TNF-α which are markers related to the activation of innate immune system. CRP was influenced by both antipsychotic medication and nonaffective psychosis. sIL-2Rα, a marker of T-cell activation, was associated with depressive symptoms, schizophrenia, and affective psychosis. We conclude that in persons with psychotic disorders, activation of mononuclear phagocyte system was mostly related to metabolic comorbidity and antipsychotic medication use, whereas T-cell activation had a more direct relationship with both psychotic disorders and depressive symptoms.

Follow‐ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: Levels and 6‐year changes in risk factors

Abstract.  Raiko JRH, Viikari JSA, Ilmanen A, Hutri‐Kähönen N, Taittonen L, Jokinen E, Pietikäinen M, Jula A, Loo B.‐M, Marniemi J, Lehtimäki T, Kähönen M, Rönnemaa T, Raitakari OT, Juonala M (University of Turku; University of Tampere and Tampere University Hospital, Tampere; University of Oulu, Oulu; Vaasa Central Hospital, Vaasa; University of Helsinki, Helsinki; and Center of Social and Health Services, Kuopio; Finland). Follow‐ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: Levels and 6‐year changes in risk factors. J Intern Med 2010; 267: 370–384.

Alcohol consumption is directly associated with carotid intima-media thickness in Finnish young adults: the Cardiovascular Risk in Young Finns Study.

OBJECTIVES There is substantial epidemiological data suggesting a J- or U-shaped association between alcohol consumption and coronary events. However, some studies in experimental animals suggest that alcohol may increase atherosclerosis. Therefore, our aim was to study whether alcohol consumption is associated with carotid intima-media thickness (IMT), marker of subclinical atherosclerosis, in young, healthy adults. METHODS Alcohol consumption, carotid IMT and conventional cardiovascular risk factors were investigated in 2074 subjects, aged 24-39 years. RESULTS In subjects consuming none, >0 to <2, 2 to <4 or >or=4 units of alcohol per day, the respective carotid IMT values were 0.57+/-0.004, 0.59+/-0.003, 0.59+/-0.006, and 0.60+/-0.012 mm (mean+/-S.E.M., P<0.0001 for increasing IMT trend across alcohol consumption categories). This direct association between alcohol consumption and IMT was independent of age, sex and several cardiovascular risk factors, e.g. blood pressure, LDL-cholesterol, HDL-cholesterol, BMI, smoking, CRP and insulin (P=0.008 in multivariable regression model). The frequencies of drinking wine or strong alcohol beverages (respective P-values 0.03 and 0.01 for increasing IMT trend across beverage consuming frequency) were directly correlated with carotid IMT in models adjusted for age, sex and risk factors. CONCLUSIONS We found a direct relationship between alcohol consumption and carotid IMT in young adults. This association was independent of cardiovascular risk factors suggesting that in young healthy adults alcohol consumption may have pro-atherogenic effects.

Conventional and Mendelian randomization analyses suggest no association between lipoprotein(a) and early atherosclerosis: the Young Finns Study

BACKGROUND Lipoprotein(a) [Lp(a)] is an established risk factor for coronary disease and stroke, but mechanisms underlying this association are unknown. We examined the association of Lp(a) with early atherosclerosis by using conventional epidemiologic analysis and a Mendelian randomization analysis. The latter utilized genetic variants that are associated with Lp(a) to estimate causal effect. METHODS A prospective population-based cohort study of 939 men and 1141 women was conducted. Lp(a) was measured repeatedly at mean ages 17 and 38 years. Measurements of carotid intima-media thickness (IMT) and brachial flow-mediated dilation (FMD) at mean ages 32 and 38 years were used to determine the level and 6-year progression of subclinical atherosclerosis. Lp(a)-related genetic variant, rs783147, was identified by a genome wide association analysis (P = 3.1 × 10⁻⁵⁸), and a genetic score was constructed based on 10 Lp(a)-related variants. Mendelian randomization test was performed using a two-stage instrumental variables analysis. RESULTS rs783147 and the genetic score were strong instruments for nonconfounded Lp(a) levels (F-statistics 269.6 and 446.0 in the first-stage instrumental variable analysis). However, Lp(a) levels were not associated with the levels of or change in IMT or FMD in any of the conventional and instrumental variables tests. The null finding was observed both with rs783147 and the genetic score as instruments and remained unchanged after adjustment for clinical characteristics, such as age, sex, HDL and LDL cholesterol, ApoB, systolic and diastolic blood pressure, diabetes and smoking. CONCLUSIONS Data from conventional and Mendelian randomization analyses provide no support for early atherogenic effects of increased Lp(a) levels.

Socioeconomic Status, Cardiovascular Risk Factors, and Subclinical Atherosclerosis in Young Adults: The Cardiovascular Risk in Young Finns Study

Objective—The goal of this study was to investigate the extent to which socioeconomic status (SES) in young adults is associated with cardiovascular risk factor levels and carotid intima-media thickness (IMT) and their changes over a 6-year follow-up period. Methods and Results—The study population included 1813 subjects participating in the 21- and 27-year follow-ups of the Cardiovascular Risk in Young Finns Study (baseline age 24–39 years in 2001). At baseline, SES (indexed with education) was inversely associated with body mass index (P=0.0002), waist circumference (P<0.0001), glucose (P=0.01), and insulin (P=0.0009) concentrations; inversely associated with alcohol consumption (P=0.02) and cigarette smoking (P<0.0001); and directly associated with high-density lipoprotein cholesterol levels (P=0.05) and physical activity (P=0.006). Higher SES was associated with a smaller 6-year increase in body mass index (P=0.001). Education level and IMT were not associated (P=0.58) at baseline, but an inverse association was observed at follow-up among men (P=0.004). This became nonsignificant after adjustment with conventional risk factors (P=0.11). In all subjects, higher education was associated with a smaller increase in IMT during the follow-up (P=0.002), and this association remained after adjustments for conventional risk factors (P=0.04). Conclusion— This study shows that high education in young adults is associated with favorable cardiovascular risk factor profile and 6-year change of risk factors. Most importantly, the progression of carotid atherosclerosis was slower among individuals with higher educational level.

Childhood 25-OH Vitamin D Levels and Carotid Intima-Media Thickness in Adulthood: The Cardiovascular Risk in Young Finns Study

CONTEXT Low vitamin D levels in adulthood have been associated with cardiovascular disease. OBJECTIVE To investigate if low vitamin D levels in childhood are related with increased carotid artery intima-media thickness (IMT) in adulthood. DESIGN, SETTING, AND PARTICIPANTS The analyses included 2148 subjects from the Cardiovascular Risk in Young Finns Study, aged 3-18 years at baseline (in 1980). Subjects were re-examined at age 30-45 years (in 2007). Childhood levels of 25-hydroxy-vitamin D were measured from stored serum in 2010. MAIN OUTCOME MEASURE The carotid artery IMT from 2007 was used. RESULTS When adjusted for age, sex, and childhood risk factors, continuous data of childhood 25-OH vitamin was inversely associated with adulthood carotid IMT levels among females (β ± SE -0.006 ± 0.003, P = 0.03), but not among males (0.001 ± 0.004, P = 0.88). Children with 25-OH vitamin D levels in the lowest quartile (<40 nmol/L) had significantly increased odds of having high-risk IMT (highest decile of common carotid or carotid bulb IMT or carotid plaque) as adults, in analyses adjusted for age, sex and either childhood risk factors (odds ratio 1.70 [95 % CI 1.15-2.31], P = 0.0007) or adult risk factors, including adult vitamin D levels (odds ratio 1.80 [1.30-2.48], P = 0.0004). In sex-specific analyses, these associations were significant both in females and males (P always <0.05). In sensitivity analyses, those with childhood vitamin D levels in the lowest quintile (<37 nmol/L), gave similar results to those using a quartile cut-point. CONCLUSIONS Low 25-OH vitamin D levels in childhood were associated with increased carotid IMT in adulthood.

Blood microRNA profile associates with the levels of serum lipids and metabolites associated with glucose metabolism and insulin resistance and pinpoints pathways underlying metabolic syndrome The cardiovascular risk in Young Finns Study

Since metabolic syndrome (MetS) is a collection of cardiovascular risk factors involving multiple signaling systems, we related the metabolic abnormalities associated with MetS with circulating microRNA profiles to pinpoint the affected signaling pathways. The blood microRNA profile, genome wide gene expression and serum NMR metabolomics were analyzed from 71 participants of the Young Finns Study. We found nine microRNAs that associated significantly with metabolites connected to MetS. MicroRNA-144-5p concentration correlated with glucose levels, hsa-1207-5p with glycosylated hemoglobin and hsa-miR-484 with metabolites related to insulin resistance. Hsa-miR-625-3p correlated with cholesterol levels, hsa-miR-1237-3p and hsa-miR-331-3p expression with certain fatty acids levels and hsa-miR-129-1-3p, -129-2-3p, and -1288-3p with glycerol levels. The down-regulated targets of miR-1207-5p and -129-2-3p were enriched in PI3K and MAPK pathways and 8 out of the 12 enriched pathways were down-regulated in individuals with MetS. In conclusion microRNAs associated with several aspects of MetS, possibly regulating glucose and lipid metabolism.

Cardiovascular risk factors in 2011 and secular trends since 2007: The Cardiovascular Risk in Young Finns Study

Aims: Cardiovascular risk factor levels in 2011 and 4-year changes between 2007 and 2011 were examined using data collected in follow-ups of the Cardiovascular Risk in Young Finns Study. Methods: The study population comprised 2063 Finnish adults aged 34–49 years (45% male). Lipid and blood pressure levels, glucose and anthropometry were measured and life style risk factors examined with questionnaires. Results: Mean total cholesterol level in 2011 was 5.19 mmol/l, low density lipoprotein (LDL)-cholesterol 3.27 mmol/l, high density lipoprotein (HDL)-cholesterol 1.33 mmol/l, and triglycerides 1.34 mmol/l. Using American Diabetes Association criteria, Type 2 diabetes (T2D) was observed in 4.1% and prediabetes (fasting glucose 5.6–6.9 mmol/l or glycated hemoglobin 5.7–6.4%) diagnosed for 33.8% of the participants. Significant changes (P < 0.05) between 2007 and 2011 included an increase in waist circumference (3.3%) in women. In both sexes, systolic (−3.0% in women, −4.0% in men) and diastolic (−3.0% in women, −3.3% in men) blood pressure and triglycerides (−3.4% in women, −6.5% in men) decreased during follow-up. Conclusions: Previously observed favorable trends in LDL-cholesterol levels have leveled off among a sample of young and middle-aged adults in Finland. Triglyceride and blood pressure levels have decreased. Over one-third of the study population had prediabetes and may be at increased risk for T2D.