Satu Männistö

Genome-wide association study of circulating vitamin D levels

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses’ Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10−5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

Thirty-five-year trends in cardiovascular risk factors in Finland

BACKGROUND In the late 1960s, coronary heart disease (CHD) mortality among Finnish men was the highest in the world. From 1972 to 2007, risk factor surveys have been carried out to monitor risk factor trends and assess their contribution to declining mortality in Finland. METHODS The first risk factor survey was carried out in the North Karelia and Kuopio provinces in 1972 as the basis for the evaluation of the North Karelia Project. Since then, up to five geographical areas have been included in the surveys. The target population has been persons aged 25-74 years, except in the first two surveys where the sample was drawn from a population aged 30-59 years. Risk factor contribution on mortality change was assessed by a logistic regression model. RESULTS A remarkable decline in serum cholesterol levels was observed between 1972 and 2007. Blood pressure declined among both men and women until 2002 but levelled off during the last 5 years. Prevalence of smoking decreased among men. Among women, smoking increased throughout the survey years until 2002 but did not increase between 2002 and 2007. Body mass index (BMI) has continuously increased among men. Among women, BMI decreased until 1982, but since then an increasing trend has been observed. Risk factor changes explained a 60% reduction in coronary mortality in middle-aged men while the observed reduction was 80%. CONCLUSIONS The 80% decline in coronary mortality in Finland mainly reflects a great reduction of the risk factor levels; these in turn have been associated with long-term comprehensive chronic disease prevention and health promotion interventions.

Emotional eating, depressive symptoms and self-reported food consumption. A population-based study.

We examined the associations of emotional eating and depressive symptoms with the consumption of sweet and non-sweet energy-dense foods and vegetables/fruit, also focusing on the possible interplay between emotional eating and depressive symptoms. The participants were 25-64-year-old Finnish men (n=1679) and women (n=2035) from the FINRISK 2007 Study (DILGOM substudy). The Three-Factor Eating Questionnaire-R18, Center for Epidemiological Studies Depression Scale, and a 132-item Food Frequency Questionnaire were used. Emotional eating and depressive symptoms correlated positively (r=0.31 among men and women), and both were related to a higher body mass. Emotional eating was related to a higher consumption of sweet foods in both genders and non-sweet foods in men independently of depressive symptoms and restrained eating. The positive associations of depressive symptoms with sweet foods became non-significant after adjustment for emotional eating, but this was not the case for non-sweet foods. Depressive symptoms, but not emotional eating, were related to a lower consumption of vegetables/fruit. These findings suggest that emotional eating and depressive symptoms both affect unhealthy food choices. Emotional eating could be one factor explaining the association between depressive symptoms and consumption of sweet foods, while other factors may be more important with respect to non-sweet foods and vegetables/fruit.

Dietary Carotenoids and Risk of Lung Cancer in a Pooled Analysis of Seven Cohort Studies

Intervention trials with supplemental β-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7–16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. β-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87–1.11; highest versus lowest quintile). The RRs for α-carotene, lutein/zeaxanthin, and lycopene were also close to unity. β-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67–0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in β-cryptoxanthin, such as citrus fruit, may modestly lower the risk.

Increasing prevalence of underreporting does not necessarily distort dietary surveys

Objectives: To study the magnitude of and trends in energy underreporting and to compare food consumption, nutrient intake and socioeconomic characteristics of underreporters to those of other Finnish adults. Design: Cardioavscular risk factor surveys in 1982 and 1992 using a 3 d food record. Underreporting was defined as energy intake lower than 1.27*BMR, since energy intake <1.27*BMR is improbable. Setting: Four areas in Finland, both rural and urban. Subjects: 1746 men and 1921 women, aged 25–64 y. Results: Proportion of underreporters has increased from 33% in 1982 to 46% in 1992 among women and from 27% in 1982 to 42% in 1992 among men. In a logistic regression model, BMI over 25 kg/m2, female gender, age over 45 y and high educational level predicted underreporting. Shares of energy intake from fat, carbhoydrates, protein and alcohol remained the same whether or not underreporters were excluded. However, underreporters consumed significantly higher proportion of vegetables, fish, meat, potatoes, fruit and berries and less fat than others. In the 1992 data the absolute intake of most micronutrients increased and micronutrient densities decreased when underreporters were excluded. Conclusions: The proportion of underreporters has grown from 1982 to 1992. Results expressed as a percentage of energy intake are not affected by the exclusion of underreporters. In contrast, micronutrient intakes, both absolute and energy density values, were distorted by underreporting. Underreporting should be taken into account in future studies. Sponsorship: National Public Health Institute.

Metabonomic, transcriptomic, and genomic variation of a population cohort

Comprehensive characterization of human tissues promises novel insights into the biological architecture of human diseases and traits. We assessed metabonomic, transcriptomic, and genomic variation for a large population‐based cohort from the capital region of Finland. Network analyses identified a set of highly correlated genes, the lipid–leukocyte (LL) module, as having a prominent role in over 80 serum metabolites (of 134 measures quantified), including lipoprotein subclasses, lipids, and amino acids. Concurrent association with immune response markers suggested the LL module as a possible link between inflammation, metabolism, and adiposity. Further, genomic variation was used to generate a directed network and infer LL modules largely reactive nature to metabolites. Finally, gene co‐expression in circulating leukocytes was shown to be dependent on serum metabolite concentrations, providing evidence for the hypothesis that the coherence of molecular networks themselves is conditional on environmental factors. These findings show the importance and opportunity of systematic molecular investigation of human population samples. To facilitate and encourage this investigation, the metabonomic, transcriptomic, and genomic data used in this study have been made available as a resource for the research community.

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

A scavenger that protects the heart Coronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Zanoni et al. found that some people with exceptionally high levels of HDL-C carry a rare sequence variant in the gene encoding the major HDL-C receptor, scavenger receptor BI. This variant destroys the receptors ability to take up HDL-C. Interestingly, people with this variant have a higher risk of heart disease despite having high levels of HDL-C. Science, this issue p. 1166 A human genetics study sheds light on how HDL (good) cholesterol protects against cardiovascular disease. Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits

Background— Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in 4 Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and nuclear magnetic resonance-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis, and built a genetic risk score for MetS. Methods and Results— A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all 4 study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 was associated with various very low density lipoprotein, triglyceride, and high-density lipoprotein metabolites (P=0.024–1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these were associated with lipid phenotypes, and none with 2 or more uncorrelated MetS components. A genetic risk score, calculated as the number of risk alleles in loci associated with individual MetS traits, was strongly associated with MetS status. Conclusions— Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits, such as hypertension and glucose intolerance.

Reproducibility and validity of a food frequency questionnaire in a case-control study on breast cancer

A 110-item food frequency questionnaire was tested among 152 community controls of the Kuopio Breast Cancer Study. They completed the questionnaire twice and kept two 7-day diet records at 3-month intervals. The intraclass correlations for nutrients varied from 0.49 (thiamine with supplements) to 0.81 (lactose), and for foods from 0.52 (poultry) to 0.84 (alcoholic drinks). The Pearson correlations between the first food frequency questionnaire and the 14-day diet records, after adjustment for energy, varied for nutrients from 0.18 (thiamine without supplements) to 0.80 (alcohol), and for foods from 0.30 (inner organs) to 0.90 (coffee). Comparison of quintile classification between the two methods is reasonably accurate when observed restrictions concerning some nutrients and foods are taken into account. A low association (r = 0.12) was observed between toenail selenium and dietary selenium intake, indicating the difficulty of estimating selenium intake in the Finnish diet.

A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk

Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow‐up. Study‐specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21–22.9 kg/m2, pancreatic cancer risk was 47% higher (95%CI:23–75%) among obese (BMI ≥ 30 kg/m2) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09–1.56 comparing BMI ≥ 25 kg/m2 to a BMI between 21 and 22.9 kg/m2). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m2) and not obese at baseline (BMI < 30 kg/m2), pancreatic cancer risk was 54% higher (95%CI = 24–93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI ≥ 10 kg/m2 between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03–1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.