Lipoprotein(a) is associated with a larger systemic burden of arterial calcification

AIMS: Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for cardiovascular disease. However, population-based evidence on the link between Lp(a) and subclinical arteriosclerosis is lacking. We assessed associations of Lp(a) concentrations with arteriosclerosis in multiple arteries. METHODS AND RESULTS: From the population-based Rotterdam study, 2354 participants (mean age: 69.5 years, 52.3% women) underwent non-contrast computed tomography to assess arterial calcification as a hallmark of arteriosclerosis. We quantified the volume of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC), and intracranial carotid artery calcification (ICAC). All participants underwent blood sampling, from which plasma Lp(a) concentrations were derived. The association of plasma Lp(a) levels was assessed with calcification volumes and with severe calcification (upper quartile of calcification volume) using sex-stratified multivariable linear and logistic regression models. Higher Lp(a) levels were associated with larger ln-transformed volumes of CAC [fully adjusted beta 95% confidence interval (CI) per 1 standard deviation (SD) in women: 0.09, 95% CI 0.04-0.14, men: 0.09, 95% CI 0.03-0.14], AAC (women: 0.06, 95% CI 0.01-0.11, men: 0.09, 95% CI 0.03-0.14), ECAC (women: 0.07, 95% CI 0.02-0.13, men: 0.08, 95% CI 0.03-0.14), and ICAC (women: 0.09, 95% CI 0.03-0.14, men: 0.05, 95% CI -0.02 to 0.11]. In the highest Lp(a) percentile, severe ICAC was most prevalent in women [fully adjusted odds ratio (OR) 2.41, 95% CI 1.25-4.63] and severe AAC in men (fully adjusted OR 3.29, 95% CI 1.67-6.49). CONCLUSION: Higher Lp(a) was consistently associated with a larger calcification burden in all major arteries. The findings of this study indicate that Lp(a) is a systemic risk factor for arteriosclerosis and thus potentially an effective target for treatment. Lp(a)-reducing therapies may reduce the burden from arteriosclerotic events throughout the arterial system. TRANSLATIONAL PERSPECTIVE: In 2354 participants from the Rotterdam study, we assessed the link between Lp(a) concentrations and arterial calcifications, as proxy for arteriosclerosis, in major arteries. We found that higher Lp(a) levels were consistently associated with larger volumes of calcification in the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The findings of our study indicate that Lp(a) is a systemic risk factor for arteriosclerosis, suggesting that the systemic burden of arteriosclerosis throughout the arterial system could be reduced by targeting Lp(a).</p

The effects of APOE4 and familial Alzheimer's disease mutations on free fatty acid profiles in mouse brain are age- and sex-dependent

APOE4 encoding apolipoprotein (Apo)E4 is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is key in intercellular lipid trafficking. Fatty acids are essential for brain integrity and cognitive performance and are implicated in neurodegeneration. We determined the sex- and age-dependent effect of AD and APOE4 on brain free fatty acid (FFA) profiles. FFA profiles were determined by LC–MS/MS in hippocampus, cortex, and cerebellum of female and male, young (≤3 months) and older (&gt;5 months), transgenic APOE3 and APOE4 mice with and without five familial AD (FAD) mutations (16 groups; n = 7–10 each). In the different brain regions, females had higher levels than males of either saturated or polyunsaturated FFAs or both. In the hippocampus of young males, but not of older males, APOE4 and FAD each induced 1.3-fold higher levels of almost all FFAs. In young and older females, FAD and to a less extent APOE4-induced shifts among saturated, monounsaturated, and polyunsaturated FFAs without affecting total FFA levels. In cortex and cerebellum, APOE4 and FAD had only minor effects on individual FFAs. The effects of APOE4 and FAD on FFA levels and FFA profiles in the three brain regions were strongly dependent of sex and age, particularly in the hippocampus. Here, most FFAs that are affected by FAD are similarly affected by APOE4. Since APOE4 and FAD affected hippocampal FFA profiles already at young age, these APOE4-induced alterations may modulate the pathogenesis of AD. (Figure presented.)</p

Eating Fish and Risk of Type 2 Diabetes: A population-based, prospective follow-up study

Objective: To investigate the relation between total fish, type of fish (lean and fatty), and EPA&DHA intake and risk of type 2 diabetes in a population-based cohort. Research design and methods: The analysis included 4,472 Dutch participants aged =55 years without diabetes at baseline. Dietary intake was assessed with a semi-quantitative food frequency questionnaire. Hazard ratios (RR) with 95% confidence intervals (95% CI) were used to examine risk associations adjusted for age, sex, lifestyle, and nutritional factors. Results: After 15 years of follow-up, 463 participants developed type 2 diabetes. Median fish intake, mainly lean fish (81% ), was 10 g/d. Total fish intake was associated positively with risk of type 2 diabetes; the RR was 1.32 (95% CI 1.02, 1.70) in the highest total fish group (=28 g/d) compared with non-fish eaters (p for trend= 0.04). Correspondingly, lean fish intake tended to be associated positively with type 2 diabetes (RR highest group (=23 g/d): 1.30 (95% CI 1.01, 1.68), p for trend= 0.06), but fatty fish was not. No association was observed between EPA&DHA intake and type 2 diabetes (RR highest group (=149.4 mg/d): 1.22 (95% CI 0.97, 1.53)). When additionally adjusted for intake of selenium, cholesterol, and vitamin D this RR decreased to 1.05 (95% CI 0.80, 1.38) (p for trend= 0.77). Conclusion: The findings do not support a beneficial effect of total fish, type of fish, or EPA&DHA intake on the risk of type 2 diabetes. Alternatively, other dietary components, like selenium, and unmeasured contaminants present in fish might explain our result

Breakfast partly restores the anti-inflammatory function of high-density lipoproteins from patients with type 2 diabetes mellitus

BACKGROUND AND AIMS: High-density lipoproteins (HDL) of patients with type 2 diabetes mellitus (T2DM) have impaired anti-inflammatory activities. The anti-inflammatory activity of HDL has been determined ex vivo after isolation by different methods from blood mostly obtained after overnight fasting. We first determined the effect of the HDL isolation method, and subsequently the effect of food intake on the anti-inflammatory function of HDL from T2DM patients. METHODS: Blood was collected from healthy controls and T2DM patients after an overnight fast, and from T2DM patients 3 h after breakfast (n = 17 each). HDL was isolated by a two-step density gradient ultracentrifugation in iodixanol (HDL(DGUC2)), by sequential salt density flotation (HDL(SEQ)) or by PEG precipitation (HDL(PEG)). The anti-inflammatory function of HDL was determined by the reduction of the TNFα-induced expression of VCAM-1 in human coronary artery endothelial cells (HCAEC) and retinal endothelial cells (REC). RESULTS: HDL isolated by the three different methods from healthy controls inhibited TNFα-induced VCAM-1 expression in HCAEC. With apoA-I at 0.7 μM, HDL(DGUC2) and HDL(SEQ) were similarly effective (16% versus 14% reduction; n = 3; p > 0.05) but less effective than HDL(PEG) (28%, p < 0.05). Since ultracentrifugation removes most of the unbound plasma proteins, we used HDL(DGUC2) for further experiments. With apoA-I at 3.2 μM, HDL from fasting healthy controls and T2DM patients reduced TNFα-induced VCAM-1 expression in HCAEC by 58 ± 13% and 51 ± 20%, respectively (p = 0.35), and in REC by 42 ± 13% and 25 ± 18%, respectively (p < 0.05). Compared to preprandial HDL, postprandial HDL from T2DM patients reduced VCAM-1 expression by 56 ± 16% (paired test: p < 0.001) in HCAEC and by 34 ± 13% (paired test: p < 0.05) in REC. CONCLUSIONS: The ex vivo anti-inflammatory activity of HDL is affected by the HDL isolation method. Two-step ultracentrifugation in an iodixanol gradient is a suitable method for HDL isolation when testing HDL anti-inflammatory function. The anti-inflammatory activity of HDL from overnight fasted T2DM patients is significantly impaired in REC but not in HCAEC. The anti-inflammatory function of HDL is partly restored by food intake

Predicting Type 2 Diabetes Based on Polymorphisms From Genome-Wide Association Studies : A Population-Based Study

OBJECTIVE—Prediction of type 2 diabetes based on genetic testing might improve identification of high-risk subjects. Genome-wide association (GWA) studies identified multiple new genetic variants that associate with type 2 diabetes. The predictive value of genetic testing for prediction of type 2 diabetes in the general population is unclear

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Background So far, more than 170 loci have been associated with circulating lipid levels through genomewide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ~60 000 individuals in the discovery stage and ~90 000 samples in the replication stage. Results Our study resu

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexit

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe