| 1. |
- de las Fuentes, Lisa, et al.
(author)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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In: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Journal article (peer-reviewed)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 3. |
- Coggi, D, et al.
(author)
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Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis-The IMPROVE Study
- 2021
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In: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:7
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Journal article (peer-reviewed)abstract
- (1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: the IMPROVE study enrolled 3703 European subjects (54–79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: in the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all p < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) (p = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) (p < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both p < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: in subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries.
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| 4. |
- Colombo, GI, et al.
(author)
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The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study
- 2021
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In: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:3
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Journal article (peer-reviewed)abstract
- The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMTmax; cIMTmean–max of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMTmax and cIMTmean–max, but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMTmax or cIMTmean–max were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMTmax and cIMTmean–max when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMTmax and cIMTmean–max, respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMTmax. rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMTmax. In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMTmax. This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.
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| 5. |
- Laguzzi, F, et al.
(author)
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Intake of food rich in saturated fat in relation to subclinical atherosclerosis and potential modulating effects from single genetic variants
- 2021
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 7866-
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Journal article (peer-reviewed)abstract
- The relationship between intake of saturated fats and subclinical atherosclerosis, as well as the possible influence of genetic variants, is poorly understood and investigated. We aimed to investigate this relationship, with a hypothesis that it would be positive, and to explore whether genetics may modulate it, using data from a European cohort including 3,407 participants aged 54–79 at high risk of cardiovascular disease. Subclinical atherosclerosis was assessed by carotid intima-media thickness (C-IMT), measured at baseline and after 30 months. Logistic regression (OR; 95% CI) was employed to assess the association between high intake of food rich in saturated fat (vs. low) and: (1) the mean and the maximum values of C-IMT in the whole carotid artery (C-IMTmean, C-IMTmax), in the bifurcation (Bif-), the common (CC-) and internal (ICA-) carotid arteries at baseline (binary, cut-point ≥ 75th), and (2) C-IMT progression (binary, cut-point > zero). For the genetic-diet interaction analyses, we considered 100,350 genetic variants. We defined interaction as departure from additivity of effects. After age- and sex-adjustment, high intake of saturated fat was associated with increased C-IMTmean (OR:1.27;1.06–1.47), CC-IMTmean (OR:1.22;1.04–1.44) and ICA-IMTmean (OR:1.26;1.07–1.48). However, in multivariate analysis results were no longer significant. No clear associations were observed between high intake of saturated fat and risk of atherosclerotic progression. There was no evidence of interactions between high intake of saturated fat and any of the genetic variants considered, after multiple testing corrections. High intake of saturated fats was not independently associated with subclinical atherosclerosis. Moreover, we did not identify any significant genetic-dietary fat interactions in relation to risk of subclinical atherosclerosis.
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| 6. |
- Ding, MZ, et al.
(author)
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The association of apolipoproteins with later-life all-cause and cardiovascular mortality: a population-based study stratified by age
- 2021
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 24440-
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Journal article (peer-reviewed)abstract
- Midlife lipid levels are important predictors of cardiovascular diseases, yet their association with mortality in older adults is less clear. We aimed to (1) identify lipid profiles based on cholesterol, triglycerides, and apolipoproteins using cluster analysis, and (2) investigate how lipid profiles and lipid levels at different ages are associated with later-life all-cause and cardiovascular mortality. We used data from 98,270 individuals in the Swedish AMORIS cohort who had blood measurements between 1985–1996 and were followed until 2012. Over the follow-up (mean 18.0 years), 30,730 (31.3%) individuals died. Three lipid profiles were identified. Compared with reference profile, a high lipid profile (low ApoA-I and high total cholesterol (TC), triglycerides, ApoB, and ApoB/ApoA-I ratio) at ages 39–59 or 60–79 was associated with higher all-cause mortality. A high lipid profile at ≥ 80 years, however, did not confer higher mortality. For the specific markers, high TC (≥ 7.25 mmol/L) was associated with higher all-cause mortality in ages 39–59 but lower mortality in ages 60–79 and ≥ 80. Low ApoA-I (< 1.28 g/L) and high ApoB/ApoA-I ratio (≥ 1.18), on the other hand, were associated with higher cardiovascular mortality regardless of age at lipid measurement, highlighting their potential relevance for survival in both young and older individuals.
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| 8. |
- Klaric, Lucija, et al.
(author)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Other publication (other academic/artistic)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 9. |
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| 10. |
- Miri, Y, et al.
(author)
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Interleukin 6 trans-signalling and the risk of future cardiovascular events in men and women
- 2021
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In: Open heart. - : BMJ. - 2053-3624. ; 8:2
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Journal article (peer-reviewed)abstract
- Pro-inflammatory interleukin 6 (IL6) trans-signalling is associated with increased risk of cardiovascular events (CVEs). Whether this association exists for both sexes is, however, uncertain. Hence, we analysed the risk of CVE associated with IL6 trans-signalling in men and women and investigated if potential interaction between IL6 trans-signalling and sex affects the risk.MethodsIn a prospective cohort of 60-year-old men and women without cardiovascular disease (men=2039, women=2193), subjects were followed for 20 years. To assess the IL6 trans-signalling activity, the proportion between the active binary and inactive ternary IL6 complexes, the binary/ternary ratio (B/T ratio), was estimated. CVE (myocardial infarction, angina pectoris and ischaemic stroke, n=629) risk was analysed with Cox regression, presented as HRs with 95% CIs. B/T ratio was dichotomised, with levels >median representing IL6 trans-signalling. Interaction was analysed on the additive scale and expressed as the synergy index (S). Analyses were adjusted for cardiovascular risk factors.ResultsB/T ratio >median was associated with increased CVE risk in men (HR 1.63; 95% CI 1.32 to 2.01), but not in women (HR 1.21; 95% CI 0.93 to 1.57). There was a significant synergistic interaction (S=1.98; 95% CI 1.15 to 3.42) between the B/T ratio and male sex, the combination increasing the risk by 88%.ConclusionsOur results suggest differential susceptibility to inflammation mediated by IL6 trans-signalling and subsequent CVE in men and women. The B/T ratio could be considered as a novel biomarker for cardiovascular risk in men, but not in women.
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