Main results in the last 3 years
Atherosclerosis is a complex multifactorial condition involving multiple pathways influenced by both genetic and environmental factors. We investigated the role of inflammatory, oxidative stress, and hemostasis markers on cardiometabolic disorders. We found EN-RAGE as a novel inflammatory marker for pre-diabetes and for CHD [
82,
83], IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy [
83]. We identified novel epigenetic correlates of circulating TNF-α and linked these loci to CHD risk [
84]. We reported serum apoCIII levels, apoCIII-to-apoA1 ratio, visceral adiposity index, lipid accumulation product, the product of triacylglycerol and glucose to be associated with incident T2D, in particular in women [
85,
86]. Mendelian randomization (MR) did not support the causal role of serum gamma-glutamyl transferase, as a marker of oxidative stress, on T2D risk [
87]. ADAMTS13, a novel homeostatic factor, was an independent risk factor for incident T2D and CVD [
88‐
91]. Our MR study did not support a large causal effect of fibrinogen on CHD [
92].
Besides contribution to the global genetic discovery for CHD, HF, AF, and T2D [
93‐
95], we also showed the biological interactions between genetic variants driving differential methylation and gene expression for T2D and highlighted the role of differential methylation in the crosstalk between adaptive immune system and glucose homeostasis [
96]. We provided insights into potential biological mechanisms connecting tobacco smoking to excess risk of T2D and showed differential association of tobacco smoking with DNA methylation of the diabetes genes [
97]. Among diabetic individuals, we identified 26 blood metabolomic measures to be associated with insufficient glycemic control, the strongest association was with glutamine [
98]. Taking into account smoking behavior, multiple new loci for pulse pressure, mean arterial pressure, and blood pressure were identified, highlighting the importance of accounting for lifestyle factors and shared pathophysiology between cardiometabolic and addiction traits [
99,
100]. We, however, did not find evidence of genetic interactions with body mass index on AF risk [
101]. Despite similar lifetime risks of CVD at age 55 for men and women, men were more likely to develop CHD as a first event and women more likely to have stroke or HF [
102]. Moreover, atherosclerosis (i.e. CAC) was present in approximately one-third of women categorized as being at low CVD risk based on the recent American guidelines [
103]. CAC presence among low-risk women was associated with an increased risk of CVD [
103]. Only 9.3% of men and 10.4% of women in the Rotterdam Study reached optimal cardiovascular health which was associated with sex steroids and sex hormone-binding globulin (SHBG) levels [
104]. Total estradiol levels were also associated with presence of vulnerable carotid plaque and higher stroke risk in women [
105]. Low levels of SHBG and high levels of total estradiol were associated with increased risk of T2D in women and higher serum dehydroepiandrosterone levels were associated with lower risk of T2D in both women and men [
106,
107]. Among high-risk women with a history of polycystic ovary syndrome or premature ovarian insufficiency, we affirmed the potent impact of androgens on cardiometabolic features [
108‐
110].
Early onset of natural menopause was an independent marker for T2D in women [
111]. Women who experienced early menopause lived less long and spent fewer years without T2D than women who experienced normal or late menopause [
112]. Moreover, genetic variants associated with earlier age at menopause increased the risk of CVD in women [
113]. Furthermore, we showed that genetic variants associated with earlier age at natural menopause were associated with increased CVD risk in women, but not men, suggesting sex-specific genetic effects on CVD risk. Regarding the lifestyle factors, we further showed that smoking among women and metabolic factors (T2D and body mass index) among men had larger deleterious associations with longitudinal changes in left ventricular cardiac function [
114].
We found lower levels of healthy ageing score (HAS) and sharper age-related decline in HAS among women compared to men [
115]. Late first and last reproduction were associated with lower and a longer maternal lifespan, post-maternal fertile lifespan, and endogenous estrogen exposure were associated with higher all-cause mortality rates [
116].
At age 55 years, the remaining lifetime risks for CHD, stroke, HF, AF, and T2D were 27.2%, 22.8%, 14.9%, 24.8%, and 28.1% for men and 16.9%, 29.8%, 17.5%, 22.9%, and 30.1% for women respectively [
32,
102,
117,
118]. We further showed the implications of the major American and European guidelines at population level, quantifying the discrepant proportions of individuals eligible for statin treatment [
119]. Among a range of newer markers, CAC and NT-ProBNP provide the largest increment in CVD risk prediction accuracy above the traditional risk factors [
120]. We further examined the predictive ability of CAC versus age and showed CAC to be an alternative marker besides age to better discriminate between lower and higher CHD risk in older adults [
121]. We took part in devising the updated global World Health Organization (WHO) algorithms for CVD risk estimation [
122,
123]. To allow for routine use of risk charts in clinical practice, we showed that the non-laboratory-based models could predict CVD risk as accurately as the laboratory-based models [
124]. Incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improved risk predictions [
125]. However, employing the novel deep learning algorithms using repeated-measures data led to greater discriminative accuracy for identifying people at high CVD risk compared to Cox regression approaches [
126].
Although atherosclerosis is a systemic condition, we found persons with migraine, compared to those without, had less arterial calcification in the intracranial carotid artery, but not in other arterial beds [
127]. We also showed that the association of impaired kidney function and larger volumes of arterial calcification was partly explained by cardiovascular risk factors. Arterial calcification did not mediate the association between kidney function and CVD beyond cardiovascular risk factors [
128].
Higher cIMT, presence of carotid plaque, greater arterial stiffness, and larger volumes of epicardial fat were associated with higher AF incidence, indicating the role of atherosclerosis and arterial stiffness in AF pathogenesis [
129,
130]. Carotid atherosclerosis was also associated with poorer hearing in older adults, suggesting that CVD prevention may also be beneficial for hearing loss in older adults [
131]. Larger carotid artery diameter was also associated with risk of CVD, stroke, and mortality but not with CHD [
132]. Among high-risk individuals, we showed baseline cIMT, but not cIMT change over time, to be associated with future CVD [
133]. We further characterized vascular ageing by increasing arterial stiffness (PWV) and showed that participants with healthy vascular ageing were at the lowest end of the PWV distribution and had up to 14 years estimated younger biological (vascular) age than those with higher PWV values [
134].
Active, high-dosage statin use beneficially influenced the composition of carotid atherosclerosis and shifted the composition from vulnerable plaque with a lipid core to more stable calcified plaque [
135]. We showed both visual progression and regression of intra-plaque hemorrhage (IPH) volume during 17 months of follow-up [
136], suggesting IPH as a dynamic process with potential for growth or resolution over time. Moreover, antithrombotic treatment related to a higher frequency of IPH in carotid plaques [
137].
Our recent GWAs and colocalization analysis of cIMT and carotid plaque with vascular expression quantitative loci (cis-eQTLs) from relevant arterial wall and metabolic tissues implicated cIMT and carotid plaque loci in cardiovascular outcomes [
138]. Our exome-wide association meta-analysis demonstrated that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. We showed the first significant association for APOE ε2 with multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical CHD [
139].
We characterized serum metabolic signatures associated with atherosclerosis in the coronary and carotid arteries and subsequently their association with incident CVD. The metabolites associated with atherosclerosis were largely consistent between the coronary (CAC) and carotid (cIMT) beds and predominantly tagged pathways that overlap with known cardiovascular risk factors [
140]. However, we found differences in metabolic association patterns of intra- and extra-cranial carotid beds [
141].
For additional EJE references please see [
142‐
160].