Therese Karlsson

Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes.

BACKGROUNDnSeveral compounds in the choline oxidation pathway are associated with insulin resistance and prevalent diabetes; however, prospective data are scarce.We explored the relationships between systemic and urinary choline-related metabolites and incident type 2 diabetes in an observational prospective study among Norwegian patients.nnnMETHODSnWe explored risk associations by logistic regression among 3621 nondiabetic individuals with suspected stable angina pectoris, of whom 3242 provided urine samples. Reclassification of patients was investigated according to continuous net reclassification improvement (NRI >0).nnnRESULTSnAfter median (25th to 75th percentile) follow-up of 7.5 (6.4-8.7) years, 233 patients (6.4%) were registered with incident type 2 diabetes. In models adjusted for age, sex, and fasting status, plasma betaine was inversely related to new-onset disease [odds ratio (OR) per 1 SD, 0.72; 95% CI, 0.62-0.83; P < 0.00001], whereas positive associations were observed for urine betaine (1.25; 1.09-1.43; P = 0.001), dimethylglycine (1.22; 1.06-1.40; P = 0.007), and sarcosine (1.30; 1.13-1.49; P < 0.001). The associations were maintained in a multivariable model adjusting for body mass index, hemoglobin A1c, urine albumin-to-creatinine ratio, estimated glomerular filtration rate, C-reactive protein, HDL cholesterol, and medications. Plasma betaine and urine sarcosine, the indices most strongly related to incident type 2 diabetes, improved reclassification [NRI >0 (95% CI) 0.33 (0.19-0.47) and 0.16 (0.01-0.31), respectively] and showed good within-person reproducibility.nnnCONCLUSIONSnSystemic and urinary concentrations of several choline metabolites were associated with risk of incident type 2 diabetes, and relevant biomarkers may improve risk prediction.

Serum Acylcarnitines and Risk of Cardiovascular Death and Acute Myocardial Infarction in Patients With Stable Angina Pectoris

Background Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris. Methods and Results This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl‐, octanoyl‐, palmitoyl‐, propionyl‐, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios (HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow‐up, 10.0% of the patients died of cardiovascular disease and 12.8% suffered a fatal or nonfatal acute myocardial infarction. Higher levels of the even‐chained acetyl‐, octanoyl‐, and palmitoyl‐carnitines were significantly associated with elevated risk of cardiovascular death, also after multivariable adjustments (HR [95% CI]: 1.52 [1.12, 2.06]; P=0.007; 1.73 [1.23, 2.44]; P=0.002; and 1.61 [1.18, 2.21]; P=0.003, respectively), whereas their associations with acute myocardial infarction were less consistent. Conclusions Among patients with suspected stable angina pectoris, elevated serum even‐chained acylcarnitines were associated with increased risk of cardiovascular death and, to a lesser degree with acute myocardial infarction, independent of traditional risk factors. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354081.

Associations between intake of fish and n-3 long-chain polyunsaturated fatty acids and plasma metabolites related to the kynurenine pathway in patients with coronary artery disease

PurposeEnhanced tryptophan degradation via the kynurenine pathway has been related to several pathological conditions. However, little is known about the effect of diet on individual metabolites of this pathway. We investigated cross-sectional associations between reported intake of fish and omega-3 (n-3) long-chain PUFA (LC-PUFA) and plasma metabolites related to the kynurenine pathway.MethodsParticipants were 2324 individuals with coronary artery disease from the Western Norway B Vitamin Intervention Trial. Fish and n-3 LC-PUFA intakes were assessed using a food frequency questionnaire. Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid, neopterin, and kynurenine-to-tryptophan ratio (KTR) were analyzed. Associations were investigated using partial Spearman’s rank correlations and multiple linear regressions.ResultsMedian age at inclusion was 62xa0years (80xa0% males), and 84xa0% had stable angina pectoris. Intake of fatty fish and n-3 LC-PUFA was inversely associated with plasma 3-hydroxykynurenine. Consumption of total fish, lean fish, and n-3 LC-PUFA was inversely associated with plasma neopterin. Intake of total fish, fatty fish, and n-3 LC-PUFA was inversely associated with KTR. All these correlations were weak (ρ between −0.12 and −0.06, Pxa0<xa00.01). In 306 patients with diabetes, lean fish intake was positively associated with plasma 3-hydroxyanthranilic acid (ρxa0=xa00.22, Pxa0<xa00.001, P for interactionxa0=xa00.01), and total fish intake was inversely associated with KTR (ρxa0=xa0−0.17, Pxa0<xa00.01, P for interactionxa0=xa00.02).ConclusionFish intake was not an important determinant of individual metabolites in the kynurenine pathway. However, some correlations were stronger in patients with diabetes. The inverse associations of fish or n-3 LC-PUFA with neopterin and KTR may suggest a slightly lower IFN-γ-mediated immune activation with a higher intake.

Increased plasma trimethylamine-N-oxide is associated with incident atrial fibrillation

BACKGROUNDnPlasma trimethylamine-N-oxide (TMAO) is associated with cardiovascular disease; however specific relationships with cardiac arrhythmias are unknown. We evaluated the association between plasma TMAO and incident atrial fibrillation (AF).nnnMETHODSnRisk associations were explored among 3797 patients with suspected stable angina in the Western Norway Coronary Angiography Cohort (WECAC) and verified in 3143 elderly participants in the community-based Hordaland Health Study (HUSK). Information on endpoints was obtained from nationwide registries.nnnRESULTSnMedian follow-up was 7.3 and 10.8u202fyears in the WECAC and HUSK cohorts, respectively, and 412 (10.9%) and 484 (15.4%) subjects were registered with incident AF. The age and gender adjusted HRs were 1.16, 95% CI 1.05-1.28 and 1.10, 95% CI 1.004-1.19 per 1 SD increase in log-transformed plasma TMAO. Adjusting for hypertension, BMI, smoking, diabetes, or intake of total choline, a TMAO precursor, did not materially influence the risk associations. Among patients in WECAC, further extensive adjustment for other AF risk factors yielded similar results. Adding TMAO to traditional AF risk factors (age, gender, hypertension, BMI, smoking and diabetes) yielded a continuous net reclassification improvement of 0.108, 95% CI 0.015-0.202 and 0.139, 95% CI 0.042-0.235.nnnCONCLUSIONSnPlasma TMAO was associated with and improved reclassification of incident AF in two independent Norwegian cohorts with long-term follow-up. The relationship was independent of traditional AF risk factors, as well as of dietary choline intake. Our findings motivate further studies to explore endogenous metabolic factors influencing the relationship between TMAO and cardiovascular disease.

Total and lean fish intake is positively associated with bone mineral density in older women in the community-based Hordaland Health Study

PurposeFish is a source of various nutrients beneficial for bone health, but few studies have investigated the association between bone mineral density (BMD) and fish consumption. Thus, the aim was to investigate the relationship between total fish intake and BMD and between both lean and fatty fish intake and BMD.MethodThese cross-sectional analyses include 4656 participants in the Hordaland Health Study, a community-based study conducted in 1997–1999. The study includes two birth cohorts of men and women from Hordaland county (Norway) born in 1950–1951 and 1925–1927. BMD was measured by dual-energy X-ray absorptiometry and dietary intake was obtained from a semi-quantitative food-frequency questionnaire.ResultsThe average total fish intake was 33u2009±u200918xa0g/1000xa0kcal and was primarily lean fish. Older women had significantly lower BMD than older men and middle-aged men and women. In older women, total and lean fish intake (50xa0g/1000xa0kcal) was significantly and positively associated with BMD also after multivariate adjustments (β-coefficient 0.018, pu2009=u20090.017 and 0.026, pu2009=u20090.021).ConclusionA high intake of fish, in particular lean fish, was positively associated with BMD in older women. No association between intake of fatty fish and BMD was found in either of the age and sex groups.

Associations between fish intake and the metabolic syndrome and its components among middle-aged men and women: the Hordaland Health Study

ABSTRACT In epidemiologic studies, the relationship between fish consumption and the metabolic syndrome (MetS) have been inconclusive and sex differences reported. The aim was to investigate associations between fish intake and the MetS in a cross-sectional study of men and women. Fish intake, waist circumference, triglycerides (TG), HDL-C, glucose and blood pressure were assessed among 2874 men and women (46–49 y) in the Hordaland Health Study (1997–1999). Fatty fish intake was inversely associated with TG in men only; mean difference in TG between highest and lowest quartile of fatty fish intake was –0.33 mmol/L (95% CI: –0.51, –0.15). Lean fish intake was inversely associated with TG in women only; mean difference in TG between highest and lowest quartile of lean fish intake was –0.23 mmol/L (95% CI: –0.34, –0.11). Fatty fish intake was positively associated with serum HDL-C in both men and women. Total fish intake was inversely associated with MetS; adjusted OR 0.75 (95% CI 0.57, 0.97). Higher fish intake was associated with lower odds of having MetS possibly driven by associations of higher fish intake with lower TG and higher HDL-C. The findings of differential associations by sex needs to be confirmed and possible biologic mechanisms explored.

Limited Benefit of Fish Consumption on Risk of Hip Fracture among Men in the Community-Based Hordaland Health Study

Hip fractures have a high prevalence worldwide. Few studies have investigated whether fish consumption is associated with risk of hip fractures. The objective of the present study was to investigate the effect of fish intake on the subsequent risk of a hip fracture because of the low number of studies on this topic. A community-based prospective cohort study of 2865 men and women from Hordaland county in Norway, born between 1925–1927 and enrolled in the study in 1997–1999. Information on hip fracture cases was extracted from hospital records until 31 December 2009. Baseline information on the intake of fish was obtained from a semi-quantitative food frequency questionnaire. Cox proportional hazard regression models with death as a competing risk were used to evaluate the association of fish intake with risk of hip fracture. During a mean (SD) follow-up time of 9.6 (2.7) years, 226 hip fractures (72 in men, 154 in women) were observed. The mean (SD) fish intake was 48 (25) g/1000 kcal. The association between fish intake and risk of hip fracture was not linear and displayed a threshold, with low intake of fish being associated with an increased risk of hip fracture in men (HR (Hazard Ratio) = 1.84, 95% CI 1.10, 3.08). In this community-based prospective study of men and women, a low intake of fish was associated with the risk of a hip fracture in men.

Adherence to the Healthy Nordic Food Index and the incidence of acute myocardial infarction and mortality among patients with stable angina pectoris

BACKGROUNDnThe Healthy Nordic Food Index (HNFI) has been associated with beneficial effects on markers of cardiovascular disease (CVD). Whether such effects are present among patients with established coronary heart disease is unknown. In the present study, we investigated the association between adherence to the HNFI and the risk of acute myocardial infarction (AMI) (fatal or nonfatal) and death among patients with stable angina pectoris.nnnMETHODSnIn the Western Norway B-vitamin Intervention Trial, participants completed a 169-item semi-quantitative food frequency questionnaire. The HNFI was calculated from six food groups (fish, cabbage, apples/pears, root vegetables, whole grain bread and oatmeal), scoring 0-6. Three adherence groups were defined: 0-1 points (low), 2-3 points (medium) or 4-6 points (high). Cox regression analyses investigated associations between adherence to the HNFI and outcomes.nnnRESULTSnAmong 2019 men (79.7%) and women with mean age of 61.7xa0years, 307 patients experienced an AMI event during a median (25th and 75th percentiles) follow-up of 7.5 (6.3 and 8.7) years. Median follow-up for total mortality was 10.5 (9.3 and 11.7) years; 171 patients died from CVD and 380 from any cause. No association between HNFI and the risk of AMI was detected. However, the HNFI was associated with a reduced risk of all-cause death, both by linear estimates [hazard ratio (95% confidence intervalxa0=xa00.91 (0.84-0.98)] and by comparison of the highest with the lowest adherence group [hazard ratio (95% confidence intervalxa0=xa00.70 (0.52-0.95)].nnnCONCLUSIONSnThe results of the present study suggest that a Healthy Nordic diet may reduce mortality in patients with established CVD.

Dietary Choline Intake Is Directly Associated with Bone Mineral Density in the Hordaland Health Study

Background: Choline is an important nutrient either obtained from a variety of foods or synthesized endogenously, and it is the precursor of betaine. We previously reported positive associations between plasma free choline and bone mineral density (BMD). Animal studies suggest an impact of dietary choline on bone metabolism, but the role of dietary intake of choline and betaine for human bone health is unknown.Objectives: The main aims were to examine the associations of dietary choline, choline species, and betaine with BMD and to study the relations between dietary and plasma free choline and betaine.Methods: Study subjects were participants in the Hordaland Health Study, including 2649 women and 1983 men (aged 46-49 or 71-74 y). BMD was measured by dual-energy X-ray absorptiometry, and dietary intake was obtained by using a validated 169-item food-frequency questionnaire. Risk associations were assessed by logistic regression and correlations by ρ (Spearmans bivariate rank order correlation).Results: Subjects in the lowest compared with the highest tertile of dietary total choline, free choline, glycerophosphocholine, phosphocholine, phosphatidylcholine, and sphingomyelin had a higher risk of low-femoral neck BMD, defined as the lowest BMD quintile. Particularly strong associations were found among middle-aged men for intake of free choline (OR: 1.83; 95% CI: 1.24, 2.69; P = 0.002) and glycerophosphocholine (OR: 2.13; 95% CI: 1.43, 3.16; P < 0.001) and among elderly women for total choline (OR: 1.96; 95% CI: 1.33, 2.88; P = 0.001) and phosphatidylcholine (OR: 1.94; 95% CI: 1.33, 2.84: P = 0.001) intake. No significant associations were observed between dietary betaine and BMD. Dietary total choline, free choline, glycerophosphocholine, phosphatidylcholine, and sphingomyelin correlated weakly with plasma free choline (ρ: 0.07, 0.05, 0.07, 0.07, and 0.05, respectively; P < 0.01). Dietary betaine correlated with plasma betaine (ρ: 0.23; P < 0.001).Conclusion: Dietary choline was positively associated with BMD in middle-aged and elderly participants.