Macular Layer Thickness and Effect of BMI, Body Fat, and Traditional Cardiovascular Risk Factors: The Tromsø Study.

Purpose: The purpose of this study was to investigate associations between cardiovascular risk factors and the thickness of retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), and outer retina layers (ORL). Methods: In this population-based study, we included participants from the Tromsø Study: Tromsø6 (2007 to 2008) and Tromsø7 (2015 to 2016). Persons with diabetes and/or diagnosed glaucoma were excluded from this study. Retinal thickness was measured on optical coherence tomography (Cirrus HD-OCT) macula-scans, segmented on RNFL, GCIPL, and ORL and associations were analyzed cross-sectionally (N = 8288) and longitudinally (N = 2595). We used directed acyclic graphs (DAGs) for model selection, and linear regression to adjust for confounders and mediators in models assessing direct effects. Factors examined were age, sex, blood pressure, daily smoking, serum lipids, glycated hemoglobin, body mass index (BMI), total body fat percentage (BFP), and the adjustment variables refraction and height. Results: The explained variance of cardiovascular risk factors was highest in GCIPL (0.126). GCIPL had a strong negative association with age. Women had thicker GCIPL than men at higher age and thinner ORL at all ages (P < 0.001). Systolic blood pressure was negatively associated with RNFL/GCIPL (P = 0.001/0.004), with indication of a U-shaped relationship with GCIPL in women. The negative association with BMI was strongest in men, with significant effect for RNFL/GCIPL/ORL (P = 0.001/<0.001/0.019) and in women for GCIPL/ORL (P = 0.030/0.037). BFP was negatively associated with GCIPL (P = 0.01). Higher baseline BMI was associated with a reduction in GCIPL over 8 years (P = 0.03). Conclusions: Cardiovascular risk factors explained 12.6% of the variance in GCIPL, with weight and blood pressure the most important modifiable factors.

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium.

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Neuropsychological functions of verbal recall and psychomotor speed significantly affect pain tolerance.

BACKGROUND: Effects from cognitive performance on pain tolerance have been documented, however, sample sizes are small and confounders often overlooked. We aimed to establish that performance on neuropsychological tests was associated with pain tolerance, controlling for salient confounders. METHODS: This was a cross-sectional study nested within the Tromsø-6 survey. Neuropsychological test performance and the cold pressor test were investigated in 4,623 participants. Due to significant interaction with age, participants were divided into three age groups (<60, ≥60 to <70 and ≥70 years). Cox proportional hazard models assessed the relationship between neuropsychological tests and cold pressure pain tolerance, using hand-withdrawal as event. The fully adjusted models controlled for sex, education, BMI, smoking status, exercise, systolic blood pressure, sleep problems and mental distress. RESULTS: In the adjusted models, participants aged ≥70 years showed a decreased hazard of hand withdrawal of 18% (HR 0.82, 95% CI (0.73, 0.92) per standard deviation on immediate verbal recall, and a decreased hazard of 23% (HR 0.77, 95% CI (0.65, 0.08) per standard deviation on psychomotor speed. Participants aged ≥60 to <70 years had a significant decreased hazard of 11% (HR 0.89, 95% CI (0.80, 0.98) per standard deviation on immediate word recall. In participants aged <60 years, there was a decreased hazard of 14% (HR 0.86 95% CI: 0.76, 0.98), per standard deviation on psychomotor speed. CONCLUSION: Better performance on neuropsychological tests increased pain tolerance on the cold pressor test. These exposure effects were present in all age groups. SIGNIFICANCE: This paper describes substantial associations between cognitive functioning and cold pressor tolerance in 4,623 participants. Reduced psychomotor speed and poor verbal recall gave greater odds for hand-withdrawal on the cold pressor task. The associations were stronger in older participants, indicating an interaction with age.

Impact of Venous Thromboembolism on the Formation and Progression of Carotid Atherosclerosis: The Tromsø Study.

Venous thromboembolism (VTE) is associated with increased risk of arterial cardiovascular diseases (CVD), and development of atherosclerosis secondary to VTE may be an intermediate between VTE and CVD. Therefore, we aimed to investigate whether incident VTE was associated with subsequent carotid atherosclerosis formation and progression in a population-based observational study. Subjects attending two or more ultrasound examinations of the right carotid artery, with measurement of total plaque area (TPA), in the Tromsø Study in 1994-1995, 2001-2002, and/or 2007-2008 were eligible. We identified 150 subjects diagnosed with first-lifetime VTE between the initial and follow-up visit, and randomly selected 600 age- and sex-matched subjects without VTE between the visits. Subjects with VTE and carotid plaque(s) at the first visit had 4.1 mm 2 (ß: 4.13, 95% CI: -1.72 to 9.98) larger change in TPA between the first and second visit compared with subjects without VTE after adjustment for change in high-sensitivity C-reactive protein (hs-CRP) and traditional atherosclerotic risk factors. The association remained after restricting the analyses to VTE events diagnosed in the first half of the time interval between the carotid ultrasounds (ß: 4.02, 95% CI: -3.66 to 11.70), supporting that the change in TPA occurred subsequent to the VTE. No association was found between VTE and novel carotid plaque formation. In conclusion, we found a possible association between VTE and atherosclerosis progression in those with already established carotid plaques, but not between VTE and novel plaque formation. The association between VTE and carotid plaque progression was not mediated by low-grade inflammation assessed by hs-CRP.

Correction: Genetic Variations in the Vitamin D Receptor Predict Type 2 Diabetes and Myocardial Infarction in a Community-Based Population: The Tromsø Study.

[This corrects the article DOI: 10.1371/journal.pone.0145359.].

Temporal Trends in Incidence and Case Fatality of Intracerebral Hemorrhage: The Tromsø Study 1995-2012.

BACKGROUND: The aim of this study was to explore temporal trends in incidence and case fatality rates of intracerebral hemorrhage (ICH) over the last two decades in a Norwegian municipality. METHODS: Incident cases of primary ICH were registered in the period from 1995 through 2012 in 32,530 participants of the longitudinal population-based Tromsø Study. Poisson regression models were used to obtain incidence rates over time in age- and sex-adjusted and age- and sex-specific models. Case fatality rates were calculated and age- and sex-adjusted trends over time were estimated using logistic regression. RESULTS: A total of 226 ICHs were registered. The age- and sex-adjusted incidence rate [95% confidence interval (CI)] in the overall population was 0.42 (0.37-0.48) per 1,000 person-years. Age-adjusted incidence rates were 0.53 (0.43-0.62) in men and 0.33 (0.26-0.39) in women. In individuals aged <75 years, the age- and sex-adjusted incidence rate was 0.27 (0.22-0.32) and in individuals aged ≥75 years, it was 2.42 (1.95-2.89) per 1,000 person-years. There was no significant change in incidence rates over time. The incidence rate ratio (95% CI) in the overall population was 0.73 (0.47-1.12) in 2012 compared with 1995. The overall 30-day case fatality (95% CI) was 23.9% (18.3-29.5) and did not change substantially over time [odds ratio in 2012 vs. 1995 = 0.83 (95% CI 0.27-2.52)]. CONCLUSION: No significant changes in incidence and case fatality rates of ICH were observed during the last two decades.

Genetic Variations in the Vitamin D Receptor Predict Type 2 Diabetes and Myocardial Infarction in a Community-Based Population: The Tromsø Study.

BACKGROUND: Though the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population. METHODS AND FINDINGS: Measurements and DNA were obtained from the participants in the Tromsø Study in 1994-1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05-1.49) for T2D and 1.14 (1.02-1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints. CONCLUSIONS: The VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed.

Vitamin D and cognitive function: The Tromsø Study.

BACKGROUND AND PURPOSE: There are indications that vitamin D may be important for more than skeletal health, including cognitive function. METHODS: The study was performed in Tromsø, Northern Norway (The Tromsø Study). In a cross-sectional study serum 25-hydroxyvitamin D (25(OH)D) was measured and cognitive function (word recall, digit-symbol coding, finger tapping, Mini Mental State Examination) tested in 4624 subjects; in a prospective study serum 25(OH)D was measured in samples from 1994 and compared to cognitive function tested in 3436 subjects in 2001 and 2044 subjects in 2007; and in a Mendelian randomization study single nucleotide polymorphisms (SNPs) related to vitamin D were evaluated versus cognitive function in 5980 subjects. RESULTS: In the cross-sectional study all tests were positively associated with serum 25(OH)D levels with ~5% better performance in subjects in the highest versus lowest serum 25(OH)D quartile. This relation was only seen in subjects older than 65 years. After full adjustment for season, age, gender, body mass index, blood pressure, physical activity and education, the relation was only significant for finger tapping. In the prospective study, serum 25(OH)D from 1994 similarly predicted cognitive function 7-13 years later. In the Mendelian randomization study, only one SNP in the VDR gene (Apal, rs7975232) was significantly associated with cognition (word recall and digit-symbol coding). CONCLUSIONS: There is an association between serum 25(OH)D and cognition, but randomized controlled trials are needed to establish causality.

Clinically significant novel biomarkers for prediction of first ever myocardial infarction: the Tromsø Study.

BACKGROUND: Identification of individuals with high risk for first-ever myocardial infarction (MI) can be improved. The objectives of the study were to survey multiple protein biomarkers for association with the 10-year risk of incident MI and identify a clinically significant risk model that adds information to current common risk models. METHODS AND RESULTS: We used an immunoassay platform that uses a sensitive, sample-efficient molecular counting technology to measure 51 proteins in samples from the fourth survey (1994) in the Tromsø Study, a longitudinal study of men and women in Tromsø, Norway. A case control design was used with 419 first-ever MI cases (169 females/250 males) and 398 controls (244 females/154 males). Of the proteins measured, 17 were predictors of MI when considered individually after adjustment for traditional risk factors either in men, women, or both. The 6 biomarkers adjusted for traditional risk factors that were selected in a multivariable model (odds ratios [OR] per standard deviation) using a stepwise procedure were apolipoprotein B/apolipoprotein A1 ratio (1.40), kallikrein (0.73), lipoprotein a (1.29), matrix metalloproteinase 9 (1.30), the interaction term IP-10/CXCL10×women (0.69), and the interaction term thrombospondin 4×men (1.38). The composite risk of these biomarkers added significantly to the traditional risk factor model with a net reclassification improvement of 14% (P=0.0002), whereas the receiver operating characteristic area increased from 0.757 to 0.791, P=0.0004. CONCLUSIONS: Novel protein biomarker models improve identification of 10-year MI risk above and beyond traditional risk factors with 14% better allocation to either high or low risk group.

Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States.

OBJECTIVE: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. DESIGN: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. SETTING: General population. PARTICIPANTS: 26,018 men and women aged 50-79 years. MAIN OUTCOME MEASURES: All-cause, cardiovascular, and cancer mortality. RESULTS: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. CONCLUSIONS: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.

The phosphodiesterase 8B gene rs4704397 is associated with thyroid function, risk of myocardial infarction, and body height: the Tromsø study.

OBJECTIVE: High serum thyrotropin (TSH) levels predict cardiovascular disease (CVD). Recently several single nucleotide polymorphisms (SNPs) associated with TSH levels have been identified, one of them being the rs4704397 SNP in the phosphodiesterase 8B (PDE8B) gene. If the relation between thyroid function and CVD is causal, one could also expect rs4704397 genotypes to predict CVD and possibly health in general. METHODS: DNA was prepared and genotyping performed for rs4704397 in subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer, or death, as well as a randomly selected control group. Similarly, genotyping was performed in subjects who had participated in clinical trials where serum TSH, free T4 (fT4), and free T3 (fT3) were measured. RESULTS: From the Tromsø Study, 8938 subjects without thyroid disease or thyroid medication were successfully genotyped for rs4704397. Among these, 2098 were registered with MI, 1025 with T2DM, 2748 with cancer, and 3592 had died. The minor homozygote genotype (A:A) had a median serum TSH level that was 0.29 mIU/L higher than in the major homozygote genotype (G:G). The A:A genotype had a significantly increased risk of MI as compared to the G:G genotype (1.14 [1.00-1.29], hazard ratio [confidence interval], Cox regression with adjustment for age, sex, and body mass index). No significant associations were seen with the other endpoints or CVD risk factors. Furthermore, subjects with the G:G genotype were significantly taller than subjects with the A:A genotype (mean difference 1.5 cm). In 584 subjects with serum TSH, fT4, and fT3 measurements, the subjects with the A:A genotype had significantly higher serum TSH and nonsignificantly lower serum fT3 (mean difference 0.15 pmol/L) levels than subjects with the G:G genotype. CONCLUSION: rs4704397 is associated with thyroid function, risk of MI, and body height. However, confirmation in other cohorts is needed before firm conclusions can be drawn.

Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromsø Study.

OBJECTIVE: Low serum 25(OH)D levels are associated with cardiovascular risk factors, and also predict future myocardial infarction (MI), type 2 diabetes (T2DM), cancer and all-cause mortality. Recently several single nucleotide polymorphisms (SNPs) associated with serum 25-hydroxyvitamin D (25(OH)D) level have been identified. If these relations are causal one would expect a similar association between these SNPs and health. METHODS: DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints MI, T2DM, cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2007-2010. Genotyping was performed for 17 SNPs related to the serum 25(OH)D level. RESULTS: A total of 9528 subjects were selected for genetic analyses which were successfully performed for at least one SNP in 9471 subjects. Among these, 2025 were registered with MI, 1092 with T2DM, 2924 with cancer and 3828 had died. The mean differences in serum 25(OH)D levels between SNP genotypes with the lowest and highest serum 25(OH)D levels varied from 0.1 to 7.8 nmol/L. A genotype score based on weighted risk alleles regarding low serum 25(OH)D levels was established. There was no consistent association between the genotype score or individuals SNPs and MI, T2DM, cancer, mortality or risk factors for disease. However, for rs6013897 genotypes (located at the 24-hydroxylase gene (CYP24A1)) there was a significant association with breast cancer (P<0.05). CONCLUSION: Our results do not support nor exclude a causal relationship between serum 25(OH)D levels and MI, T2DM, cancer or mortality, and our observation on breast cancer needs confirmation. Further genetic studies are warranted, particularly in populations with vitamin D deficiency. TRIAL REGISTRATION: ClinicalTrials.gov NCT01395303.

The ApoC-I content of VLDL particles is associated with plaque size in persons with carotid atherosclerosis.

Previous studies have shown that postprandial triglyceride-rich lipoproteins (TRLs) are enriched with apolipoprotein-C-I (apoC-I) in healthy individuals with increased intima-media thickness and in patients with coronary artery disease. The purpose of the present study was to determine apoC-I in TRL in persons with carotid atherosclerosis and its relation to plaque area. A population-based case (n = 42)-control (n = 39) study was conducted in persons with carotid atherosclerosis, assessed by B-mode ultrasound, and healthy controls. VLDL (Sf 20-400) was isolated in the fasting state and 4 h after ingestion of a standard fat meal. In the fasting state, persons with carotid atherosclerosis had increased number of apoC-I per VLDL-particle compared to persons without carotid atherosclerosis (8.6 +/- 5.4 vs. 6.3 +/- 4.2, P = 0.018). Total plaque area increased linearly (P = 0.017) across tertiles of apoC-I per VLDL-particle. In the postprandial state, a similar increase in the number of apoC-I per VLDL-particle occurred in both cases and controls (P < 0.001), but no significant difference was observed between groups. The number of apoC-I per VLDL-particle in the fasting state was accompanied by delayed clearance of TRL in the postprandial state, and associated with cholesterol enrichment of the VLDL-particles. Our findings support the concept that the number of apoC-I per VLDL-particle may be of importance for initiation and progression of atherosclerosis.

Delayed metabolism of postprandial triglyceride-rich lipoproteins in subjects with echolucent carotid plaques.

Subjects with echolucent carotid plaques have an increased risk of ischemic cerebrovascular events independent of degree of stenosis. Low plasma lipoprotein lipase (LPL) activity promotes a proatherogenic lipid profile, and delayed chylomicron clearance is a risk factor for atherosclerosis. This study was conducted to determine plasma LPL activity and postprandial metabolism of triglycerides in relation to carotid plaque morphology. Plaque echogenicity was assessed by B-mode ultrasound and analysis of the grey scale median (GSM). Echolucent plaques were defined as GSM < or = 63 (the median) and echogenic plaques as GSM > 63, and 57 subjects with carotid plaques and 38 subjects without carotid plaques were recruited. Blood samples were collected before and at 2-h interval for 8 h after a standard high fat meal. LPL activity and mass was determined before and after heparin administration. Postheparin LPL activity was decreased in subjects with echolucent plaques compared to subjects with echogenic plaques (P = 0.06) and to controls (P = 0.04). Plaque echogenicity increased linearly with increasing levels of postheparin LPL activity (P = 0.02) and mass (P = 0.03). Subjects with echolucent plaques had delayed postprandial clearance of chylomicron triglycerides compared to controls (P = 0.04). Low postheparin LPL activity due to attenuated mobilization of LPL from capillary endothelium may play an important role in the formation of echolucent plaques by modulation of postprandial lipids and subsequent fat accumulation in the arterial wall.

Increased thrombin generation in persons with echogenic carotid plaques.

Echolucent carotid plaques are associated with higher risk for future ischemic cerebrovascular events (CVE) than echogenic plaques independent of the degree of stenosis. Elevated markers of thrombin generation are associated with atherosclerotic plaques and are increased in the acute and chronic phases of CVE. The present study was conducted to investigate the influence of plaque morphology on thrombin generation in persons with carotid stenosis. One hundred twenty-eight persons with carotid stenosis (>or=35% lumen diameter reduction) and 136 matched controls without stenosis were recruited from the health survey of the Tromsø Study. Blood samples were collected and plaque morphology determined by ultrasonography. Thrombin generation was assessed by thrombin-antithrombin complexes (TAT) and by prothrombin fragment 1+2 (F1+2). Persons with echogenic plaques (n = 63) had significantly higher levels of TAT (5.24 microg/l, 4.33-6.14) (mean, 95%CI) than persons with echolucent plaques (n = 65) (3.44 microg/l, 2.91-3.96, p < 0.001) and controls (n = 136) (3.33 microg/l, 3.06-3.60, p < 0.001). They also had significantly higher levels of F1+2 (2.14 nM, 1.83-2.45) than persons with echolucent plaques (1.54 nM, 1.38-1.71, p < 0.001) and controls (1.49 nM, 1.40-1.58, p < 0.001). TAT and F1+2 increased linearly with plaque echogenicity (p = 0.002 and p = 0.001, respectively) independent of the degree of stenosis. Increased thrombin generation was associated with a significant increase in plasma factor V levels among persons with echogenic plaques compared to echolucent plaques (p = 0.049) and controls (p = 0.025). The present findings indicate that increasing plaque echogenicity, rather than plaque echolucency and the degree of stenosis, is associated with thrombin generation in persons with carotid stenosis.

[Risk factors for cerebral stroke]. / Risikofaktorer for hjerneslag.

BACKGROUND: Stroke is a heterogenic group of disorders. Cerebral infarction is the largest group (80-85%) and is followed by primary intracerebral hemorrhage and subarachnoid hemorrhage. This article gives a review of risk factors for cerebral stroke, with an emphasis on cerebral infarction. MATERIAL AND METHODS: The article is based on literature identified through Medline, with emphasis on prospective, population-based studies. RESULTS AND INTERPRETATION: Genetic studies of the Icelandic population have shown associations between single genes and common types of stroke, but it remains to be seen whether the results can be replicated in other populations. High blood pressure and cigarette smoking are the most important modifiable risk factors for stroke. Serum cholesterol is positively associated with cerebral infarction, but not with intracerebral hemorrhage. Diabetes, atrial fibrillation and carotid stenosis are important predictors of cerebral infarcts, especially in the elderly. Cohort studies and randomized trials have shown that hormone replacement therapy in women increases the risk of stroke, while modern oral contraceptives do not represent a risk factor for stroke in young women. There is a clear social gradient in stroke occurrence, with a higher incidence in lower social classes.