Jukka Kontto

Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts

Background More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

Coffee and Tea Consumption and Risk of Stroke Subtypes in Male Smokers

Background and Purpose— Coffee and tea consumption could potentially reduce the risk of stroke because these beverages have antioxidant properties, and coffee may improve insulin sensitivity. We examined the associations of coffee and tea consumption with risk of stroke subtypes. Methods— We used prospective data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a cohort study of 26 556 male Finnish smokers aged 50 to 69 years without a history of stroke at baseline. Coffee and tea consumption was assessed at baseline using a validated food-frequency questionnaire. During a mean follow-up of 13.6 years, from 1985 through December 2004, 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were ascertained from national registries. Results— After adjustment for age and cardiovascular risk factors, both consumption of coffee and tea was statistically significantly inversely associated with the risk of cerebral infarction but not intracerebral or subarachnoid hemorrhage. The multivariate relative risk of cerebral infarction for men in the highest category of coffee consumption (≥8 cups/d) was 0.77 (95% CI, 0.66 to 0.90; P for trend <0.001) compared with those in the lowest category (<2 cups/d). The corresponding relative risk comparing men in the highest category of tea consumption (≥2 cups/d) with those in the lowest category (nondrinkers) was 0.79 (95% CI, 0.68 to 0.92; P for trend=0.002). Conclusions— These results suggest that high consumption of coffee and tea may reduce the risk of cerebral infarction among men, independent of known cardiovascular risk factors.

Dairy Foods and Risk of Stroke

Background: Consumption of milk and other dairy foods has been associated with reduced risk of stroke, although not all studies have shown this consistently. Methods: We examined the association between dairy food intake and risk of stroke subtypes within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Between 1985 and 1988, 26,556 Finnish male smokers aged 50–69 years who had no history of stroke completed a food frequency questionnaire. We used Cox proportional hazards models to estimate relative risks (RRs) and 95% confidence intervals (CIs), adjusted for potential confounders. Results: During a mean follow-up of 13.6 years, 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were ascertained. We observed positive associations between whole milk intake and risk of intracerebral hemorrhage (RR = 1.41 for the highest vs. lowest quintile of intake; 95% CI = 1.02–1.96) and between yogurt intake and subarachnoid hemorrhage (RR = 1.83 for the highest vs. lowest quintile of intake; 95% CI = 1.20–2.80). Men in the highest quintile of cream intake had a moderate decreased risk of cerebral infarction (0.81; 0.72–0.92) and intracerebral hemorrhage (0.72; 0.52–1.00). There were no strong associations between intakes of total dairy, low-fat milk, sour milk, cheese, ice cream, or butter and risk of any stroke subtype. Conclusions: These findings suggest that intake of certain dairy foods may be associated with risk of stroke.

Dietary fiber and fiber-rich food intake in relation to risk of stroke in male smokers

Background/Objectives:There is convincing evidence that a high dietary fiber intake may lower the risk of coronary heart disease. However, the role of fiber in the prevention of stroke is unclear. We examined the associations of dietary fiber and fiber-rich food intake with risk of stroke within the Alpha-tocopherol, Beta-carotene Cancer Prevention Study.Subjects/Methods:Between 1985 and 1988, 26 556 Finnish male smokers aged 50–69 years, who had no history of stroke, completed a dietary questionnaire. During a mean follow-up of 13.6 years, 2702 cerebral infarctions, 383 intracerebral hemorrhages and 196 subarachnoid hemorrhages were ascertained.Results:After adjustment for cardiovascular risk factors and folate and magnesium intakes, there was no significant association between intake of total fiber, water-soluble fiber, water-insoluble fiber, or fiber derived from fruit or cereal sources and risk of any stroke subtype. Vegetable fiber intake, as well as the consumption of fruit, vegetables and cereals, was inversely associated with the risk of cerebral infarction; the multivariate relative risks for the highest quintile of intake as compared with the lowest were 0.86 (95% confidence interval (CI): 0.76–0.99) for vegetable fiber, 0.82 (95% CI: 0.73–0.93) for fruit, 0.75 (95% CI: 0.66–0.85) for vegetables and 0.87 (95% CI: 0.74–1.03) for cereals. Vegetable consumption was inversely associated with risk of subarachnoid hemorrhage (relative risk for highest versus lowest quintile: 0.62; 95% CI: 0.40–0.98), and cereal consumption was inversely associated with risk of intracerebral hemorrhage (relative risk: 0.64; 95% CI: 0.41–1.01).Conclusions:These findings suggest a beneficial effect of the consumption of fruits, vegetables and cereals on stroke risk.

High processed meat consumption is a risk factor of type 2 diabetes in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study.

Relatively small lifestyle modifications related to weight reduction, physical activity and diet have been shown to decrease the risk of type 2 diabetes. Connected with diet, low consumption of meat has been suggested as a protective factor of diabetes. The aim of the present study was to examine the association between the consumption of total meat or the specific types of meats and the risk of type 2 diabetes. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort included middle-aged male smokers. Up to 12 years of follow-up, 1098 incident cases of diabetes were diagnosed from 24 845 participants through the nationwide register. Food consumption was assessed by a validated FFQ. In the age- and intervention group-adjusted model, high total meat consumption was a risk factor of type 2 diabetes (relative risk (RR) 1.50, 95 % CI 1.23, 1.82, highest v. lowest quintile). The result was similar after adjustment for environmental factors and foods related to diabetes and meat consumption. The RR of type 2 diabetes was 1.37 for processed meat (95 % CI 1.11, 1.71) in the multivariate model. The results were explained more by intakes of Na than by intakes of SFA, protein, cholesterol, haeme Fe, Mg and nitrate, and were not modified by obesity. No association was found between red meat, poultry and the risk of type 2 diabetes. In conclusion, reduction of the consumption of processed meat may help prevent the global epidemic of type 2 diabetes. It seems like Na of processed meat may explain the association.

Effects of α-tocopherol and β-carotene supplementation on cancer incidence and mortality: 18-year postintervention follow-up of the Alpha-tocopherol, Beta-carotene Cancer Prevention Study.

In the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50–69 years, daily α‐tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β‐carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α‐tocopherol and β‐carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post‐trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β‐carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89–1.05) among α‐tocopherol recipients compared with nonrecipients with the preventive effect of α‐tocopherol continuing ∼8 years postintervention. Body mass index significantly modified the effect of α‐tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88–1.14) in normal‐weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post‐trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α‐tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β‐carotene recipients compared with nonrecipients. α‐Tocopherol decreased post‐trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β‐carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α‐tocopherol and β‐carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate‐dose α‐tocopherol on prostate cancer continued several years post‐trial and resulted in lower prostate cancer mortality.

High processed meat consumption is a risk factor of type 2 diabetes in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study

Relatively small lifestyle modifications related to weight reduction, physical activity and diet have been shown to decrease the risk of type 2 diabetes. Connected with diet, low consumption of meat has been suggested as a protective factor of diabetes. The aim of the present study was to examine the association between the consumption of total meat or the specific types of meats and the risk of type 2 diabetes. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort included middle-aged male smokers. Up to 12 years of follow-up, 1098 incident cases of diabetes were diagnosed from 24 845 participants through the nationwide register. Food consumption was assessed by a validated FFQ. In the age- and intervention group-adjusted model, high total meat consumption was a risk factor of type 2 diabetes (relative risk (RR) 1.50, 95 % CI 1.23, 1.82, highest v. lowest quintile). The result was similar after adjustment for environmental factors and foods related to diabetes and meat consumption. The RR of type 2 diabetes was 1.37 for processed meat (95 % CI 1.11, 1.71) in the multivariate model. The results were explained more by intakes of Na than by intakes of SFA, protein, cholesterol, haeme Fe, Mg and nitrate, and were not modified by obesity. No association was found between red meat, poultry and the risk of type 2 diabetes. In conclusion, reduction of the consumption of processed meat may help prevent the global epidemic of type 2 diabetes. It seems like Na of processed meat may explain the association.

Effects of alpha-tocopherol and beta-carotene supplementation on cancer incidence and mortality: 18-Year postintervention follow-up of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

In the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50–69 years, daily α‐tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β‐carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α‐tocopherol and β‐carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post‐trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β‐carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89–1.05) among α‐tocopherol recipients compared with nonrecipients with the preventive effect of α‐tocopherol continuing ∼8 years postintervention. Body mass index significantly modified the effect of α‐tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88–1.14) in normal‐weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post‐trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α‐tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β‐carotene recipients compared with nonrecipients. α‐Tocopherol decreased post‐trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β‐carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α‐tocopherol and β‐carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate‐dose α‐tocopherol on prostate cancer continued several years post‐trial and resulted in lower prostate cancer mortality.

Effect of alpha-tocopherol and beta-carotene supplementation on macrovascular complications and total mortality from diabetes: results of the ATBC Study

Abstract Aim. To determine whether alpha-tocopherol or beta-carotene supplementation affects diabetic macrovascular complications and total mortality. Methods. This study was carried out as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a double-blind, randomized trial with a 2×2 factorial design. A total of 29,133 middle-aged male smokers received either vitamin E 50 mg/day or beta-carotene 20 mg/day, or both, or placebo for a median of 6.1 years. At base-line, 1700 men had type 2 diabetes. Of these men, 662 were diagnosed with first-ever macrovascular complication, and 1142 died during the 19-year follow-up. Results. Neither supplementation affected the risk of macrovascular complication or total mortality during the intervention period. For the alpha-tocopherol-supplemented versus no alpha-tocopherol-supplemented, and beta-carotene-supplemented versus no beta-carotene-supplemented we found relative risk (RR) 0.84 (95% confidence interval (CI) 0.65–1.10) and RR 1.15 (95% CI 0.89–1.50) for macrovascular complication, respectively, and RR 1.00 (95% CI 0.80–1.25) and RR 1.06 (95% CI 0.85–1.33) for total mortality, respectively. No essential changes were found in these effects when the follow-up was extended up to 19 years. Conclusion. Alpha-tocopherol or beta-carotene supplementation has no protective effect on macrovascular outcomes or total mortality of diabetic male smokers.

Folate, Vitamin B6, Vitamin B12, and Methionine Intakes and Risk of Stroke Subtypes in Male Smokers

The associations of dietary folate, vitamin B(6), vitamin B(12), and methionine intakes with risk of stroke subtypes were examined among 26,556 male Finnish smokers, aged 50-69 years, enrolled in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Dietary intake was assessed at baseline by using a validated food frequency questionnaire. During a mean follow-up of 13.6 years, from 1985 through 2004, 2,702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were identified from national registers. In analyses adjusting for age and cardiovascular risk factors, a high folate intake was associated with a statistically significant lower risk of cerebral infarction but not intracerebral or subarachnoid hemorrhages. The multivariate relative risk of cerebral infarction was 0.80 (95% confidence interval: 0.70, 0.91; p(trend) = 0.001) for men in the highest versus lowest quintile of folate intake. Vitamin B(6), vitamin B(12), and methionine intakes were not significantly associated with any subtype of stroke. These findings in men suggest that a high dietary folate intake may reduce the risk of cerebral infarction.