👤 Andrej Teren

A low ankle-brachial Index (ABI) is an established condition for peripheral artery disease (PAD) and cardiovascular disease risk. The search for genetic determinants of the ankle-brachial index (ABI) is important to better understand molecular patho-cmechanisms of PAD and its commonalities with cardiovascular diseases (CVD), supporting development of new drug targets and tailored preventive or therapeutic measures. To search for genetic factors contributing to ankle-brachial index, we integrated genome-wide association meta-analysis and transcriptome-wide association meta-analysis (TWAMA) of two German cohorts, the population-based LIFE-Adult cohort and LIFE-Heart, a cohort of patients with suspected or confirmed coronary artery disease. Pathway analysis of identified genes was used to explore biological mechanisms potentially involved in ABI pathophysiology. Finally, we analysed co-associations of known CAD or carotid plaque associations with ABI to detect possible genetic commonalities. By our GWAS meta-analysis, we identified four new gene loci associated with ABI that are also linked with coronary artery diseases (CAD) (6q26: LPA and 11q14.1: DLG2) or cholesterol levels (12q21.31: TMTC2 and Xp21.1: DMD). Furthermore, we replicated a known ABI locus on cytoband 9p21.3 (CDKN2B) and four loci associated with PAD. In our TWAMA, we identified 145 blood transcripts associated with ABI at FDR 5% level. Gene set enrichment analysis of all TWAMA results revealed the inflammation-related pathways interferon gamma response, neutrophil degranulation, and interferon alpha response as the top three upregulated pathways in patients with lower ABI. Among overlapping genes between blood TWAMA and tissue-specific genetically regulated gene-expression association analysis, 24 genes showed consistent effect directions at nominal significance, with lower ABI-associated genes relating to stress response and vascular integrity, while higher ABI-associated genes linked to cellular homeostasis and metabolism. In our integrated genome- and transcriptome-wide meta-analysis, we identified novel and confirmed known candidate genes and pathways associated with ABI. Association signals partly overlap with those of other cardiovascular traits such as CAD and carotid plaque formation. The integration of gene-expression data, validated known and added new molecular insight how inflammatory signalling can contribute to atherosclerosis and vascular dysfunction. These findings pave the way for improved understanding of the molecular underpinnings of PAD and inform future strategies for targeted prevention and therapy. Show less

Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment. ApoA-I, apoA-II, apoA-IV, apoB-100, apoC-I, apoC-III, apoE, and apoJ were simultaneously quantified in 3 μL EDTA-plasma by LC-MS/MS in a case-control subgroup of the Leipziger LIFE-Heart Study (N = 911). Confounder analysis with demographic, clinical covariates and serum lipids, cardiac, inflammatory, and hepatic markers were performed. Apos were associated with CAD, CAP, and PAD in a multivariate regression model. Fasting and statin therapy showed strongest effects on apo concentrations. Inverse correlations of HDL-related apos A-I, A-II, A-IV, and C-I were observed for troponin T and interleukin 6. Concentrations of apos A-II, B-100, C-I, and E were decreased under statin therapy. After adjustment for influencing factors and related lipids, only apoB-100 (odds ratio per one SD [OR], 1.39; 95% confidence interval [CI], 1.05-1.84) was independently associated with CAD while apoA-IV (OR, 0.74; 95% CI 0.58-0.95) indicated PAD. ApoB-100 (OR, 1.55; 95% CI, 1.18-2.04), apoC-III (OR, 1.30; 95% CI, 1.06-1.58), and apoE (OR, 1.34; 95% CI, 1.13-1.58) were associated with CAP. Triglyceride rich lipoproteins (TRLs) associated apos A-IV, B-100, C-III, and E are independently associated with stable ASCVD, providing further evidence for a potential role of TRLs in atherogenesis. Show less

Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed. Our main objective was to identify genetic loci influencing steroid hormone levels. As a secondary aim, we searched for causal effects of steroid hormones on CAD. We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, dehydroepiandrosterone sulfate (DHEAS), estradiol, and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, maximum n = 7667), and progesterone, 17-hydroxyprogesterone, androstenedione, and aldosterone in LIFE-Heart only (maximum n = 2070). All genome-wide significant loci were tested for sex interactions. Furthermore, we tested whether previously reported CAD single-nucleotide polymorphisms were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian randomization (MR) approaches. We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEAS, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism, that is, CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, for example, to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone, and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits. Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sexual dimorphism in other complex diseases. Show less