Andries Smit

• Professor at University of Groningen

We aimed to assess the association of SAF with cardiovascular mortality in the general population and the possible association between SAF with other disease-specific mortality rates. We evaluated 77,143 participants without known diabetes or cardiovascular disease. The cause of death was ascertained by the municipality database. The associations b...

Objective To address the relationship between tissue accumulation of advanced glycation end-products, assessed by skin autofluorescence (SAF), and subclinical atherosclerosis quantified with coronary artery calcium score (CACS) in the general Dutch population. Methods A total of 3,839 participants of the LifeLines Cohort Study without diabetes or...

We aimed to assess the association of SAF with cardiovascular mortality in the general population and the possible association between SAF with other disease-specific mortality rates. We evaluated 77,143 participants without known diabetes or cardiovascular disease. The cause of death was ascertained by the municipality database. The associations b...

Aims: To define endotypes of carotid subclinical atherosclerosis. Methods and results: We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atheros...

Introduction Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RA...

Background: Smoking is associated with carotid intima-media thickness (C-IMT). However, knowledge about how genetics may influence this association is limited. We aimed to perform nonhypothesis driven gene-smoking interaction analyses to identify potential genetic variants, among those included in immune and metabolic platforms, that may modify th...

Raynaud’s Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for...

Background We investigated the causality of IL-8 on carotid intima-media thickness (c-IMT), a measure of sub-clinical atherosclerosis. Methods The IMPROVE is a multicenter European study (n = 3,711). The association of plasma IL-8 with c-IMT (mm) was estimated by quantile regression. Genotyping was performed using the Illumina CardioMetabo and Imm...

Increased skin autofluorescence (SAF) predicts the development of diabetes-related complications and cardiovascular disease. We assessed the performance of a simple model which includes SAF to identify individuals at high risk for undiagnosed and incident type 2 diabetes, in 58,377 participants in the Lifelines Cohort Study without known diabetes....

Objective : Follow-up of patients with treatment-resistant Raynaud's phenomenon (RP) one-year after single-port thoracoscopic sympathicotomy (SPTS). Methods : Eight patients (six males, two females, median age of 45 years) with treatment-resistant RP underwent left-sided SPTS at the third rib (R3), unilaterally. Questionnaires were taken, and numb...

Background We evaluated the performance of skin autofluorescence to select groups at risk for undiagnosed and incident DM2 in a simple and fast risk model. Methods We evaluated 58,377 participants without known diabetes of whom SAF measurements. Newly diagnosed diabetes was defined as fasting blood glucose ≥7.0 mmol/l and/or HbA1c ≥48 mmol/mol (≥6....

Increased skin autofluorescence (SAF) predicts the development of diabetes-related complications and cardiovascular disease. We assessed the performance of a simple model which includes SAF to identify individuals at high risk for undiagnosed and incident type 2 diabetes, in 58,377 participants in the Lifelines Cohort Study without known diabetes....

Background The association between elevated serum uric acid (SUA), cardiovascular disease (CVD) risk, and carotid atherosclerosis has long been explored, and contrasting results have been reported. Therefore, the role of SUA as an independent risk factor for vascular events (VEs) and carotid atherosclerosis deserves further attention. We investigat...

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 in...

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 w...

Background/AimThe association between alcohol consumption and subclinical atherosclerosis is still unclear. Using data from a European multicentre study, we assess subclinical atherosclerosis and its 30-month progression by carotid intima-media thickness (C-IMT) measurements, and correlate this information with self-reported data on alcohol consump...

Abstract Background Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may pred...

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For in...

Aims Non-invasively assessed skin autofluorescence (SAF) measures advanced glycation endproducts (AGEs) in the dermis. SAF correlates with dermal AGEs in Caucasians and Asians, but studies in dark-skinned subjects are lacking. In this pilot we aimed to assess whether SAF signal is representative of intrinsic fluorescence (IF) and AGE accumulation i...

Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (...

Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of low-density lipoprotein cholesterol plasma levels and circulating PCSK9, which differs between genders. PCSK9 represents a valid pharmacological target for preventing cardiovascular (CV) events. We aimed to investigate sex-related associations...

Understanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researcher. We expl...

Background: Advanced glycation end products (AGEs) are associated with aging, diabetes mellitus (DM), and other chronic diseases. Recently, the accumulation of AGEs can be evaluated by skin autofluorescence (SAF). However, the relationship between SAF levels and exercise capacity in patients with cardiovascular disease (CVD) remains unclear. This...

The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 an...

The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 an...

Objective: Our aim was to study whether recovery from a Raynaud’s attack and involvement of the thumb are differentiators for systemic sclerosis (SSc) in patients with Raynaud’s phenomenon (RP). Method: A stepwise cooling and recovery procedure was performed, provoking an RP attack, in patients with primary Raynaud’s phenomenon (PRP, n = 68) and SS...

Objective: To assess the minimally invasive single-port thoracoscopic sympathicotomy feasibility and efficacy in patients with treatment-resistant RP. Methods: Single-port thoracoscopic sympathicotomy was performed unilaterally on the left side in eight patients with RP (six males, two females, with a median age of 45.2 years). Five patients had...

Background: Hyperlipidemia is a major risk factor for cardiovascular disease and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective: We sought...

Background Systemic sclerosis (SSc) is a progressive fibro-inflammatory autoimmune disease of which the pathogenetic pathways are incompletely understood. Advanced glycation endproducts (AGEs) are oxidative stress derived compounds with potential proinflammatory effects. Their exact role in fibrosis remains unknown. The receptor for AGEs is RAGE, w...

Background Systemic sclerosis (SSc)-related vasculopathy is generally thought to occur on a microvascular level. However, some observations also suggest involvement of arterial vessels. Macrovascular involvement (e.g., aorta or upper extremity) can be non-invasively assessed by measuring pulse wave velocity (PWV). Although, several studies have ass...

Background Distinguishing primary Raynaud’s phenomenon (PRP) from Raynaud’s phenomenon secondary to systemic sclerosis (SSc) is crucial in the early detection of SSc. Recently we reported that patients with more severe vasculopathy suffer from a prolonged ischemia time during Raynaud’s attack. [1] additionally, it appears that the thumb is more fre...

Background In some patients, Raynaud’s Phenomenon (RP) symptoms prove resistant to conventional vasodilatory treatment. Thoracic sympathectomy is shown to be effective as treatment of RP, but is associated with surgical burden. During this procedure, the sympathetic nerve traversing to the upper extremity is dissected, subsequently leading to vasod...

CADM2 has been associated with a range of behavioural and metabolic traits, including physical activity, risk-taking, educational attainment, alcohol and cannabis use and obesity. Here, we set out to determine whether CADM2 contributes to mechanisms shared between mental and physical health disorders. We assessed genetic variants in the CADM2 locus...

Raynaud's phenomenon (RP) is often the first sign of systemic sclerosis (SSc). Molecular mechanisms involved are incompletely understood, but reactive oxygen, nitrogen, and sulfur species are thought to play an important role in the pathogenesis of SSc. Free thiol groups play a protective role against oxidative stress and may represent an attractiv...

Aims/hypothesis: Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4 year risk...

Data presented in this article are related to the research article entitled “A priori-defined Mediterranean-like dietary pattern predicts cardiovascular events better in north Europe than in Mediterranean countries” [Veglia et al., 2018]. Data contain information about the incidence of cardiovascular events in a high-risk European population (IMPRO...

Objective To assess the presence of a systemic sclerosis (SSc) pattern on nailfold capillary microscopy (NCM) in patients with Raynaud phenomenon (RP) and to explore its association with abnormal pulmonary function tests (PFT). Methods NCM patterns were assessed in 759 consecutive patients with RP. Patterns were classified as normal (n = 354), non...

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight n...

Background The Mediterranean Diet (MD) is a model of healthy eating contributing to a favorable health status, but its clinical usefulness is still debated. The aim of this study was to relate the adherence to MD with the incidence of cardio/cerebro-vascular events (VEs) in north and south European participants of the IMPROVE study. Methods IMPROV...

Background: Although the exact etiology of systemic sclerosis (SSc) remains unknown, a current hypothesis is that reactive species (including reactive oxygen species (ROS), reactive nitrogen species (RNS and reactive sulfur species (RSS)) play an important role in the pathogenesis. In addition, the chemical interactions between these molecules, als...

Background Microvascular disease, characterised by rarefaction of capillaries, is the hallmark of systemic sclerosis. Remarkably, obliteration of the ulnar and radial artery is regularly observed, implicating involvement of the larger forearm arteries. Pulse wave velocity (PWV) is a widely accepted non-invasive measure for arterial stiffness and ma...

Background Although the exact etiology of systemic sclerosis (SSc) remains unknown, a current hypothesis is that reactive species (including reactive oxygen species (ROS), reactive nitrogen species (RNS and reactive sulfur species (RSS)) play an important role in the pathogenesis. In addition, the chemical interactions between these molecules, also...

Background Despite the extensive research on this subject, the exact pathogenesis of RP still remains incompletely understood. The current view on this rather complex phenomena is that the imbalance between vasoconstriction and vasodilatation is purely functional and that structural vascular changes do not occur in PRP patients Although RP is a fre...

Background Raynaud’s phenomenon of the hands is a great burden in daily life and reduces quality of live in patients with or without an underlying connective tissue disease. Although vasodilatory treatment may be effective in some patients, complaints may be resistant to treatment, for which additional treatment options are very limited. In earlier...

Background and aims: Non-LDL dyslipidemia (NLD) confers cardiovascular risk, and prevalence rates appear to be high in elderly populations. Small cohorts have identified several lifestyle, anthropometric, and medical factors associated with NLD. We aimed to assess sex- and age-specific prevalence of NLD in a contemporary population cohort (n = 167...

Background Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as Advanced Glycation End-products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The...

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Non-targeted metabolomics analysis was performed b...

Background and aims: We aimed to examine the association between socioeconomic status (SES) and subclinical atherosclerosis, as assessed by carotid intima-media-thickness (C-IMT) and to investigate whether the effect of social inequality on C-IMT is mediated by cardiovascular (CV) risk factors and whether it is dissimilar in men and women, and in...

Aim: The aim of the present study was to investigate whether skin autofluorescence would improve the Finnish Diabetes Risk Score (FINDRISC) in detecting undiagnosed diabetes in a large population-based cohort. Methods: Included were participants from the Dutch LifeLines Cohort Study. Skin autofluorescence was assessed in an unselected subset of...

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear...

Background: Ischemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-...

Objective Advanced glycation end products (AGEs) are implicated in the pathogenesis of cardiovascular disease. Accumulation of AGEs is driven by oxidative or glycemic stress and can be assessed by skin autofluorescence (SAF). SAF is increased in patients with peripheral artery disease (PAD) and independently associated with mortality and major adve...

Background Nailfold capillary microscopy (NCM) has been shown to be associated with disease severity and internal organ involvement in non-consecutive systemic sclerosis (SSc) cohorts. NCM may help in early recognition of connective tissue disease (CTD) but it is unclear to which extent NCM abnormalities occur in several CTD and whether these are a...

Background Underweight patients develop Raynaud's phenomenon (RP) more frequently. [1] In a small study, skin temperature and perfusion in RP patients was positively associated with body mass index (BMI). [2] In clinical practice, we frequently observe an abnormal nailfold capillary microscopy (NCM) in underweight subjects with presumably primary R...

Background Oxidative stress plays a role in systemic sclerosis (SSc), but the molecular mechanisms involved are incompletely understood. During an attack of Raynaud's phenomenon (RP) a period of ischemia (I), followed by reperfusion (R) occurs frequently, associated with the severity of vasculopathy. [1] Only in secondary RP digital ulcers develop....

Background and aims: Carotid plaque size and the mean common carotid intima-media thickness measured in plaque-free areas (PF CC-IMTmean) have been identified as predictors of vascular events (VEs), but their complementarity in risk prediction and stratification is still unresolved. The aim of this study was to evaluate the independence of carotid...

Arterial wall remodeling is a central multifactorial process in the development and progression of cardiovascular diseases. We employed an approach aimed at observing genetic variants associated with the progression of carotid intima-media thickness (cIMT) in order to identify novel pathways effecting vessel remodeling. This was achieved by conduct...

Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins ar...

Overview of standard curves for all proteins measured with the olink-platform. (XLSX)

Membership of the IMPROVE study group. (DOCX)

Overview of all associations between plasma protein and SNPs significant at genome-wide level. Trait–the plasma protein target; Dist (kb)–if cis, the distance between SNP and protein encoding gene; Likely mediator gene–the most likely cis-mediator gene. In cis-cases protein-encoding gene, but in trans-cased based the analyses presented in Table 2;...

Potential pleiotropy between genome-wide significant SNPs and measured trait proteins. This figure shows all lead SNPs that have at least 2 associations with distinct proteins at P<0.05 / (83* 79) = 7.7e-6. This cutoff reflects a conservative approach to the multiple testing burden for all identified lead SNPs (79) with all tested protein traits (8...

LocusZoom plots of eQTL and pQTL effects, for each locus with significant cis-eQTL association according to Table 2. (PDF)

Pleiotropy of reported trait protein SNPs with findings from previously published GWAS studies. Publically available studies were investigated and associations were reported for proxy SNPs with r2 LD above 0.6 and association P-value stronger than 5e-8. Other trait–the trait investigated in the published GWAS; Other SNP–the index SNP in the publish...

Overview of all 92 measured proteins, with quality control parameters, descriptive statistics and heritability estimates. All descriptive statistics are reported on the log10-transformed data that was used for analysis; #samples below LOD–the number of samples below limit of detection; CV%—coefficient of variation; Included–final choice on inclusio...

Introduction Diabetes mellitus is a well-defined risk factor for peripheral artery disease (PAD), but protects against the development and growth of abdominal aortic aneurysm (AAA). Diabetes mellitus is associated with arterial stiffening and peripheral arterial media sclerosis. Advanced glycation end-products (AGEs) are increased in diabetes melli...

Purpose Advanced glycation endproducts (AGEs) and their precursors α-dicarbonyls are implicated in the progression of diabetic retinopathy. The purpose of this study was to assess AGEs and α-dicarbonyls in the vitreous of patients with type 2 diabetes mellitus (T2DM) with early stages or absence of diabetic retinopathy. Methods We examined vitreou...

Aims: To evaluate the effects of the DPP-4 inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in early type 2 diabetes subjects. Materials and methods: A total of 45 type 2 diabetes subjects (median age 63 (IQR: 54-66) years, 61% male, mean hemoglobinA1c (HbA1c ) 6.3 ±...

Purpose: Advanced glycation endproducts (AGEs) have been suggested to play a role in retinal redetachment by promoting proliferative vitreoretinopathy (PVR). The purpose of this study was to investigate whether AGEs, in combination with other clinical characteristics, were able to identify patients at high risk for redetachment after vitrectomy fo...

Patients with peripheral artery disease (PAD) suffer from widespread atherosclerosis. Partly due to the growing awareness of cardiovascular disease, the incidence of PAD has increased considerably during the past decade. It is anticipated that algorithms to identify high risk patients for cardiovascular events require being updated, making use of n...