👤 Marianne Benn

Anti-obesity therapies co-targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor achieve greater weight loss compared with glucagon-like peptide-1 receptor agonists. However, the implications for cardiovascular risk reduction and the mechanisms involved remain unclear. This study aimed to (i) investigate whether genetically proxied body weight reduction via the GIP receptor pathway lowers cardiovascular disease risk and (ii) compare the effect to polygenic weight reduction, excluding GIP-related genes, to assess if the observed benefits are attributable to weight loss per se or involve additional GIP-related effects. Genetic scores were constructed using four variants in GIP-related genes associated with lower body mass index (BMI) and 31 variants linked to lower BMI in general. Observational and one-sample Mendelian randomization (MR) analyses were performed in 408 056 individuals from the UK Biobank and two-sample MR analyses using summary statistics from 419 821 individuals in FinnGen. In one-sample MR analyses, 1 kg/m² lower BMI via the GIP/GIPR score was associated with 29% lower risk of major adverse cardiovascular events (MACE) (P = .0002) and 43% lower risk of heart failure (P = 5 × 10⁻⁵). Corresponding lower risks with the polygenic BMI score were 3% (P = .002) and 13% (P < 1 × 10-300). Two-sample MR analyses showed similar results. Of the reduced risk via the GIP/GIPR score, BMI and glycated haemoglobin (HbA1c) mediated 13% and 22% of the lower risk of MACE and 16% and 17% of the lower risk of heart failure (all P ≤ 7 × 10-5). Genetic proxies for body weight reduction via GIP receptor targeting reduces the risk of MACE and heart failure, mediated partly through lower BMI and partly through lower HbA1c. Show less

Individuals with familial hypercholesterolemia (FH) are at high risk of premature cardiovascular disease. A healthy lifestyle and lipid-lowering medication are essential to reduce this risk. We examined if adherence to a heart healthy diet provides additional risk reduction independent of lipid-lowering medication. The Dutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH (n=559 individuals with probable or definite FH) in the Copenhagen General Population Study(n=106,899) and the Copenhagen City Heart Study(n=7,451). Individuals were categorised by their level of heart healthy dietary adherence to Danish dietary guidelines, corresponding to international guidelines. Concentrations of low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, triglycerides, and lipoprotein(a) (Lp(a)), and risk of ischaemic heart disease (IHD) were assessed by clinical FH category and level of dietary adherence. Women had a higher heart healthy dietary adherence compared to men. Mean concentrations of LDL cholesterol, apoB, non-HDL cholesterol, remnant cholesterol, and triglycerides increased stepwise by lower dietary adherence category, regardless of clinical FH category. Lp(a) concentration did not change by adherence to dietary guidelines. Results were similar in individuals taking lipid-lowering medication. Risk of ischemic heart disease (IHD) was lower in individuals with a higher dietary adherence (ranging from 8 to 57 % lower risk) compared to individuals with a very low dietary adherence regardless of clinical FH category. Adherence to a heart healthy diet is associated with lower concentrations of atherogenic lipids and lipoproteins, and lower risk of IHD in individuals with clinical FH, independent of treatment with lipid-lowering medication. Dietary adherence should be emphasised as an important tool in addition to treatment with lipid-lowering medication in individuals with FH. Show less

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. Show less