[Show abstract][Hide abstract] ABSTRACT: We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes.
PLoS ONE 06/2013; 8(6):e67406. DOI:10.1371/journal.pone.0067406 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To study whether high intestinal cholesterol absorption may represent a cardiovascular risk factor and link ABCG8 and ABO variants to cardiovascular disease (CVD). BACKGROUND: Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a two-fold increase in circulating plant sterol levels which equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. METHODS: The cholestanol to cholesterol ratio (CR) was used as an estimate of cholesterol absorption, as it is independent of plant sterols. Firstly, we investigated the associations of six single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC and YFS cohorts. Secondly, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. RESULTS: In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including six studies and 4,362 individuals, showed that CR was significantly increased in individuals with CVD. CONCLUSIONS: High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.
Journal of the American College of Cardiology 05/2013; 62(4). DOI:10.1016/j.jacc.2013.01.100 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association
International Journal of Epidemiology 10/2012; 41(5):1419-1433. DOI:10.1093/ije/dys086 · 9.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Liver transplantation (LT) predisposes to metabolic derangements and increases the risk for cardiovascular disease. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. We measured serum levels of noncholesterol sterols (surrogate markers of cholesterol synthesis and intestinal absorption) and fibroblast growth factor 21 (FGF21) in 49 patients (74% of survivors) at a median of 10 years posttransplant and in 93 controls matched for age and gender. Although serum cholesterol levels were similar in patients and controls, patients displayed increased whole-body synthesis and decreased intestinal absorption of cholesterol compared with controls (lathosterol to cholesterol ratio 129 ± 55 vs. 96 ± 41, respectively, p < 0.001; campesterol to cholesterol ratio 233 ± 91 vs. 316 ± 107, respectively; p < 0.001). Azathioprine (r =-0.383, p = 0.007) and low-dose methylpredisolone (r =-0.492, p < 0.001) were negatively associated with lathosterol/sitosterol ratio reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in patients than in controls (248 pg/mL vs. 77 pg/mL, p < 0.001). In healthy controls, FGF21 was associated with cholesterol metabolism, an association missing in LT recipients. Normal serum lipids are achievable in long-term survivors of pediatric LT, but changes in cholesterol metabolism and increased FGF21 levels may explicate later cardiovascular risk.
American Journal of Transplantation 06/2012; 12(10):2815-2824. DOI:10.1111/j.1600-6143.2012.04147.x · 5.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Physical activity has been associated with alterations in telomere length, a potential indicator of biological aging, but several inconsistencies exist. Our aim was to investigate the associations between physical activity in midlife and leukocyte telomere length (LTL) measured in old age in the Helsinki Businessmen Study, Finland. At entry, in 1974, 782 men (mean age 47) completed a questionnaire about their physical activity and this was collapsed into 3 categories: low (n=148), moderate (n=398) and high physical activity (n=236, 7 of whom had a competitive activity level). After 29-year follow-up in 2003, mean LTL and the proportion of short (<5kB) telomeres were measured from DNA samples of a random subcohort of survivors (n=204, mean age 76) using the Southern blot technique. Adjusted for age, body mass index (BMI), cholesterol and smoking in 1974, the moderate physical activity group had longer mean LTL (8.27kB, SE 0.05) than the low (8.10kB, SE 0.07), or high (8.10kB, SE 0.05) physical activity groups (P=0.03 between groups). Conversely, the proportion of short telomeres was lowest in the moderate physical activity group (11.35%, SE 0.25), and higher in the high (12.39%, SE 0.29), and the low physical activity (12.21%, SE 0.39) groups (P=0.02 between groups). We conclude that the results of this observational cohort study give support to the idea that both low and high physical activity is in the long-term associated with factors shortening LTL.
[Show abstract][Hide abstract] ABSTRACT: We prospectively evaluated incidence of prolonged (>28 days) parenteral nutrition (PN), associated complications, and significance of parenteral plant sterols (PS) in neonatal intestinal failure-associated liver disease (IFALD) compared with children.
We recruited 28 neonates (mean age 50 days, range 28-126) and 11 children (6.9 y, 2.1-16.6) in all of Finland. Patients underwent repeated measurements of serum cholesterol, noncholesterol sterols, including PS, cholestanol and cholesterol precursors, and liver biochemistry during and 1 month after discontinuation of PN. Healthy matched neonates (n=10) and children (n=22) served as controls.
IFALD occurred more frequently among neonates (63%) than children (27%; P<0.05). Ratios of serum PS, including stigmasterol, sitosterol, avenasterol, and campesterol, and total PS were increased among neonates compared with healthy controls and children on PN by 2- to 22- and 2- to 5-fold (P<0.005), respectively. Neonates with IFALD had significantly higher ratios of serum PS and cholestanol compared with neonates without IFALD (P<0.05). Total duration of PN associated with serum cholestanol, stigmasterol, avenasterol, alanine aminotransferase, and aspartate aminotransferase (r=0.472-0.636, P<0.05). Cholestanol and individual serum PS, excluding campesterol, reflected direct bilirubin (r=0.529-0.688, P<0.05). IFALD persisted after discontinuation of PN in 25% of neonates with 4.2- and 2.2-times higher ratios of serum stigmasterol and cholestanol compared with neonates without IFALD (P<0.05).
Frequent occurrence of IFALD among neonates on PN displays an association to duration of PN and markedly increased serum PS, especially stigmasterol, in comparison to healthy neonates and children on PN. Striking accumulation of parenteral PS may contribute to IFALD among neonates.
Journal of pediatric gastroenterology and nutrition 12/2011; 54(6):803-11. DOI:10.1097/MPG.0b013e3182474118 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore the association of frailty according to questionnaire data (modified Fried criteria) with important endpoints in older men.
Prospective cohort study (the Helsinki Businessmen Study) in Finland.
In 1974, clinically healthy men (born 1919-1934, n=1815) of similar socioeconomic status were identified. After a 26-year follow-up in 2000 (mean age 73 years), disease prevalence, mobility-disability, and frailty status (80.9% of survivors, n=1125) were appraised using a postal questionnaire including RAND-36. Four criteria were used for definition: 1) >5% weight loss from midlife, or body mass index (BMI) <21 kg/m2; 2) reported physical inactivity; 3) low vitality (RAND-36); 4) physical weakness (RAND-36). Responders with 3-4, 1-2, and zero criteria were classified as frail (n=108), prefrail (n=567), and nonfrail (n=450), respectively. Eight-year mortality was assessed from registers, and in 2007, survivors were re-assessed with questionnaires.
Nonfrail as referent and adjusted for age, BMI and smoking, both prefrail (HR 2.26; 95% CI, 1.57-3.26), and frail status (4.09; 95% CI, 2.60-6.44) were significant predictors of mortality. Nonfrailty predicted better survival independently of the frailty components, diseases, and disability, and also predicted faster walking speed and less disability 7 years later.
Frailty, and also prefrailty, as defined using questionnaire data (RAND-36) independently predicted important endpoints in older men.
The Journal of Nutrition Health and Aging 11/2011; 15(9):783-7. DOI:10.1007/s12603-011-0131-4 · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic inhibition of cholesterol absorption with large doses of plant stanol esters (staest) alters profoundly cholesterol metabolism, but it is unknown how an acute inhibition with a large staest dose alters the postprandial serum and lipoprotein cholesterol precursor, plant sterol, and sitostanol contents.
Hypercholesterolemic subjects, randomly and double-blind divided into control (n = 18) and intervention groups (n = 20), consumed experimental diet without and with staest (plant stanols 8.8 g/day) for 10 weeks. Next morning after a fasting blood sample (0 h), the subjects had a breakfast without or with staest (4.5 g of plant stanols). Blood sampling was repeated 4 h later. Lipoproteins were separated with ultracentrifugation, and sterols were measured with gas-liquid chromatography.
In 0-h chylomicrons and VLDL, plant sterols were lower in staest than in controls. Postprandially, cholestenol (cholesterol synthesis marker) was reduced in chylomicrons in staest compared with controls (-0.13 ± 0.04 μg/dL vs. 0.01 ± 0.08 μg/dL, P < 0.05). Staest decreased postprandially avenasterol in chylomicrons (P < 0.05 from 0 h). Sitostanol was high at 0 h by chronic staest in serum and VLDL but not in chylomicrons. Postprandial sitostanol was increased by staest in VLDL only.
Chronic cholesterol absorption inhibition with large amount of plant stanol esters decreases plant sterols in triglyceride-rich lipoproteins. Acute plant stanol ester consumption increases sitostanol content in triglyceride-rich lipoproteins but suggests to decrease the risk of plant sterol and plant stanol accumulation into vascular wall by chylomicrons.
European Journal of Nutrition 09/2011; 51(5):615-22. DOI:10.1007/s00394-011-0249-5 · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study the whole-body cholesterol metabolism in man, cholesterol synthesis and absorption need to be measured. Because of the complicated methods of the measurements, new approaches were developed including the analysis of serum non-cholesterol sterols. In current lipidologic papers and even in intervention studies, serum non-cholesterol sterols are frequently used as surrogate markers of cholesterol metabolism without any validation to the absolute metabolic variables. The present review compares serum non-cholesterol sterols with absolute measurements of cholesterol synthesis and absorption in published papers to find out whether the serum markers are valid indicators of cholesterol metabolism in various conditions.
During statin treatment, during interventions of dietary fat, and in type 2 diabetes the relative and absolute variables of cholesterol synthesis and absorption were frequently but not constantly correlated with each other. In some occasions, especially in subjects with apolipoprotein E3/4 and E4/4 phenotypes, the relative metabolic markers were even more sensitive than the absolute ones to reflect changes in cholesterol metabolism during dietary interventions. Even in general population at very high absorption the homeostasis of cholesterol metabolism is disturbed damaging the validity of the serum markers.
It is worth using several instead of only one precursor and absorption sterol marker for making conclusions of altered synthesis or absorption of cholesterol, and even then the presence of at least some absolute measurement is valuable. During consumption of plant sterol-enriched diets and in situations of interfered cholesterol homeostasis the relative markers do not adequately reflect cholesterol metabolism. Accordingly, the validity of the relative markers of cholesterol metabolism should not be considered as self-evident.
[Show abstract][Hide abstract] ABSTRACT: The effect of cholesterol level on the health of older people is a matter of debate, probably because of the bidirectional association. We investigated this paradox in a long-term study. The baseline assessments of the Helsinki Businessmen Study (a cohort of mainly business executives, born 1919 to 1934) included the total cholesterol value and other cardiovascular risk factors from 1964 to 1973. These men were followed up for ≤46 years (through January 2010). During the follow-up period, the cholesterol value was assessed by self-report in 2000 (n = 1,292). Mortality was ascertained from the national registers, symptoms, and health-related quality of life with RAND-36 from questionnaires in 2000. A total of 3,277 healthy men without chronic diseases at baseline were included in the analyses. The median total cholesterol concentration at baseline was 6.5 mmol/L (251 mg/dl) (interquartile range 5.8 to 7.3 mmol/L, 224 to 282 mg/dl) and, in 2000, was 5.2 mmol/L (201 mg/dl) (interquartile range 4.6 to 5.9 mmol/L, 178 to 228 mg/dl). During the follow-up period, 1,773 men (54%) died. A strong and graded relation was found between the cholesterol level and total mortality, with the men with a cholesterol level ≤4 mmol/L (154 mg/dl) having the lowest mortality. In all, the men with the lowest cholesterol gained the most life years. However, no association was found with the cholesterol level in 2000 (when 16% were using statins) and subsequent mortality. The lowest (≤4 mmol/L) cholesterol value in midlife also predicted a higher score in the physical functioning scale of RAND-36 in old age. In conclusion, a low total cholesterol value in midlife predicts both better survival and better physical functioning in old age.
The American journal of cardiology 06/2011; 108(5):677-81. DOI:10.1016/j.amjcard.2011.04.016 · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leukocyte telomere length has been taken as a measure of biological age but several inconsistencies exist.
We investigated associations between leukocyte telomere length in old age, midlife risk factors, and mortality. The Helsinki Businessmen Study (a cohort of mainly business executives, born 1919-1934) had baseline assessments of cardiovascular risk factors including body mass index between 1964 and 1973 at a mean age of 40. Leukocyte telomere length and proportion of short telomeres were measured from DNA samples collected in 2002-2003 (n = 622, mean age 78 years). Body mass index and smoking in old age were assessed from questionnaires. Total mortality was verified from registers through January 2010. Main outcome measures were relationships between telomeres, body mass index, smoking, and mortality.
Leukocyte telomere length and notably proportion of short telomeres (<5kb) in old age were significantly (p =. 008 after full adjustments) and in a graded manner associated with midlife overweight and smoking. The associations were independent of age and cardiovascular risk factors including postload glucose. Associations with body mass index and smoking were nonsignificant in old age, and telomere length did not predict 7-year total mortality.
We conclude that smoking and overweight in midlife, irrespective of glucose, cholesterol and blood pressure, are related to shorter leukocyte telomeres in old men. Telomere length in old age did not predict total mortality possibly due to competing causes.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2011; 66(7):815-20. DOI:10.1093/gerona/glr064 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND. Low serum total cholesterol is frequently associated with worse survival in older people, but mechanisms of this association are poorly understood. AIMS. Characteristics of cholesterol metabolism were related to survival in a random 75 + population sample. METHODS. Serum cholesterol and lathosterol, and sitosterol were measured in random persons (n = 623) of birth cohorts (1904, 1909, and 1914) in 1990, and all persons were followed for 17 years. RESULTS. Total cholesterol declined in old age, and low cholesterol was associated with poor health and multi-morbidity. Cholesterol below 5.0 mmol/L was associated with accelerated all-cause mortality (age- and gender-adjusted hazard ratio (HR) 1.54; 95% CI 1.21-1.97; P < 0.001) and vascular mortality (HR 2.13 (1.42-3.07); P < 0.001). Lathosterol (indicating cholesterol synthesis) and sitosterol (indicating cholesterol absorption) also decreased with deteriorating health. Low lathosterol, sitosterol, and cholesterol predicted mortality additively and independently of each other. When all three sterols were high (> median) or low, the age- and gender-adjusted survival was 9.9 and 5.6 years (P < 0.001). CONCLUSION. Lower synthesis and absorption of cholesterol, and low serum cholesterol level are associated with deteriorating health and indicate impaired survival in old age.
Annals of Medicine 06/2011; 43(4):292-301. DOI:10.3109/07853890.2010.546363 · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Plant sterols (PS) in parenteral nutrition (PN) may contribute to intestinal failure-associated liver disease. We investigated interrelations between serum PS, liver function and histology, cholesterol metabolism, and characteristics of PN.
Eleven patients with intestinal failure (mean age 6.3 years) receiving long-term PN were studied prospectively (mean 254 days) and underwent repeated measurements of serum lipids, noncholesterol sterols, including PS, and liver enzymes. PS contents of PN were analyzed. Liver biopsy was obtained in 8 patients. Twenty healthy children (mean age 5.7 years) served as controls.
Median percentage of parenteral energy of total daily energy (PN%) was 48%, including 0.9 g · kg(-1) · day(-1) of lipids. Respective amounts of PN sitosterol, campesterol, avenasterol, and stigmasterol were 683, 71, 57, and 45 μg · kg(-1) · day(-1). Median serum concentrations of sitosterol (48 vs 7.5 μmol/L, P < 0.001), avenasterol (2.9 vs 1.9, P < 0.01), stigmasterol (1.9 vs 1.2, P < 0.005), but not that of campesterol (9.8 vs 12, P = 0.22), were increased among patients in relation to controls, and correlated with PN% (r = 0.81-0.88, P < 0.005), but not with PN fat. Serum cholesterol precursors were higher in patients than in controls. Serum liver enzymes remained close to normal range. Glutamyl transferase correlated with serum PS (r = 0.61-0.62, P < 0.05). Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55-0.60, P = 0.16-0.12).
Serum PS moderately increase during olive oil-based PN, and correlate positively with PN% and glutamyl transferase. Despite well-preserved liver function, histology often revealed significant liver damage.
Journal of pediatric gastroenterology and nutrition 04/2011; 53(4):440-6. DOI:10.1097/MPG.0b013e3182212130 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of plant stanol esters (STAEST) on serum cholesterol and lipoprotein lipid concentrations and serum non-cholesterol sterols in patients with type 1 diabetes who were on statin treatment.
In a randomized, double-blind, parallel study the intervention group (n=12) consumed vegetable oil-based spread enriched with STAEST (3.0 g/d of plant stanols), and the control group (n=12) consumed the same spread containing no added plant stanols for 4 weeks.
Serum total, LDL and non-HDL cholesterol concentrations were decreased by 9.6, 16.4 and 15.3% compared with the baseline concentrations in the STAEST group (P<0.05 for all). The respective reductions were 7.8, 14.8 and 12.2% compared with the controls (P<0.05 for all). No effects on HDL cholesterol or serum triglyceride concentrations were found. The STAEST consumption significantly decreased serum plant sterol concentrations and the ratios to cholesterol by 30-32 and 25-27% (P<0.05 for all) compared with the baseline levels, respectively. Cholesterol synthesis markers were not increased in the STAEST group, but serum lathosterol to campesterol ratio was significantly increased by 57% compared with the baseline levels indicating increased cholesterol synthesis at least to some extent in compensation for decreased cholesterol absorption. However, cholesterol homeostasis, intact at baseline and in the control group also during the intervention was lost in the STAEST group.
STAEST significantly decreased serum total, LDL and non-HDL cholesterol concentrations and thus offers an additional benefit to cholesterol lowering in patients with type 1 diabetes who are on statin treatment.