👤 Janne Pott

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

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player of lipid metabolism with higher plasma levels in women throughout their life. Statin treatment affects PCSK9 levels also showing evidence of sex-differential effects. It remains unclear whether these differences can be explained by genetics. We performed genome-wide association meta-analyses (GWAS) of PCSK9 levels stratified for sex and statin treatment in six independent studies of Europeans (8936 women/11,080 men respectively 14,825 statin-free/5191 statin-treated individuals). Loci associated in one of the strata were tested for statin- and sex-interactions considering all independent signals per locus. Independent variants at the PCSK9 gene locus were then used in a stratified Mendelian Randomization analysis (cis-MR) of PCSK9 effects on low-density lipoprotein cholesterol (LDL-C) levels to detect differences of causal effects between the subgroups. We identified 11 loci associated with PCSK9 in at least one stratified subgroup (p < 1.0 × 10 We performed the first double-stratified GWAS of PCSK9 levels and identified multiple biologically plausible loci with genetic interaction effects. Our results indicate that the observed sexual dimorphism of PCSK9 and its statin-related interactions have a genetic basis. Significant differences in the causal relationship between PCSK9 and LDL-C suggest sex-specific dosages of PCSK9 inhibitors. Show less

To help differentiate CLN3 (Batten) disease, a devastating childhood metabolic disorder, from the similarly presenting early-onset Stargardt disease (STGD1). Early clinical identification of children with CLN3 disease is essential for adequate referral, counselling and rehabilitation. Medical chart review of 38 children who were referred to a specialized ophthalmological centre because of rapid vision loss. The patients were subsequently diagnosed with either CLN3 disease (18 patients) or early-onset STGD1 (20 patients). Both children who were later diagnosed with CLN3 disease, as children who were later diagnosed with early-onset STGD1, initially presented with visual acuity (VA) loss due to macular dystrophy at 5-10 years of age. VA in CLN3 disease decreased significantly faster than in STGD1 (p = 0.01). Colour vision was often already severely affected in CLN3 disease while unaffected or only mildly affected in STGD1. Optic disc pallor on fundoscopy and an abnormal nerve fibre layer on optical coherence tomography were common in CLN3 disease compared to generally unaffected in STGD1. In CLN3 disease, dark-adapted (DA) full-field electroretinogram (ERG) responses were either absent or electronegative. In early-onset STGD1, DA ERG responses were generally unaffected. None of the STGD1 patients had an electronegative ERG. Already upon presentation at the ophthalmologist, the retina in CLN3 disease is more extensively and more severely affected compared to the retina in early-onset STGD1. This results in more rapid VA loss, severe colour vision abnormalities and abnormal DA ERG responses as the main differentiating early clinical features of CLN3 disease. 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