👤 Erika Levy

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. Show less

The tricho-rhino-phalangeal syndrome type II (TRPS II) is characterized by sparse scalp hair, a long nose with a bulbous tip, a long flat philtrum, cone-shaped epiphyses of the phalanges, retarded bone age in infancy and multiple cartilaginous exostoses. All patients have a hemizygous deletion on chromosome 8q23.3-24.11 which spans at least the 2.8 Mb-region from TRPS1 through EXT1. Only patients with deletions that extend beyond this interval tend to have mental retardation. Here we describe a 14.5-year-old girl with mental retardation and TRPS II. Her facial features are only mild, but she has the typical skeletal features including cone-shaped epiphyses at the phalanges, retarded bone age, multiple exostoses and short stature. She is the first patient with TRPS II and a molecularly proven mosaic interstitial deletion in 8q22.3-q24.13. The deletion is one of the largest ever found in TRPS II, and spans 19.79 Mb and 50 genes or loci including TRPS1 and EXT1. The degree of mosaicism is 7% in lymphocytes from peripheral blood and 97% in skin fibroblasts. Show less

Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown. We studied 1862 unrelated participants (52% women; age, 59+/-9 years) from the community-based Framingham Heart Study who had echocardiograms and provided DNA samples but did not have severe hypertension, aortic prosthesis, or significant aortic stenosis. Eight sarcomere protein genes, 3 storage cardiomyopathy-causing genes, and 27 mitochondrial genes were sequenced in unrelated individuals with increased LVWT (maximum LVWT >13 mm). Fifty eligible participants (9 women) had unexplained increased LVWT. We detected 8 mutations in 9 individuals (2 women); 7 mutations in 5 sarcomere protein genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL3), and 1 GLA mutation. In individuals with increased LVWT, participants with sarcomere protein and storage mutations were clinically indistinguishable from those without mutations. In a community-based cohort, about 3% of eligible participants had increased LVWT, of whom 18% had sarcomere protein or lipid storage gene mutations. Increased LVWT in the community is a very heterogeneous condition, which sometimes may arise from single-gene variants in one of a number of genes. Show less

The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRalpha induces a high energy expenditure in the presence of the coactivator PGC-1alpha. However, ERRalpha knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRalpha is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRalpha plays a function in dietary energy handling. Gene expression profiling in the intestine identified a subset of genes involved in oxidative phosphorylation that were down-regulated in the absence of ERRalpha. In support of the physiological role of ERRalpha in this pathway, isolated enterocytes from ERRalpha knockout mice display lower capacity for beta-oxidation. Microarray results also show altered expression of genes involved in dietary lipid digestion and absorption, such as pancreatic lipase-related protein 2 (PLRP2), fatty acid-binding protein 1 and 2 (L-FABP and I-FABP), and apolipoprotein A-IV (apoA-IV). In agreement, we found that ERRalpha-/- pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRalpha and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRalpha, in cooperation with PGC-1alpha, activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. Our results demonstrate that apoA-IV is a direct ERRalpha target gene and suggest a function for ERRalpha in intestinal fat transport, a crucial step in energy balance. Show less

Apolipoprotein (apo) A-IV, first identified 28 years ago as a plasma lipoprotein moiety, is now known to participate in the regulation of various metabolic pathways. It is synthesized primarily in the enterocytes of the small intestine during fat absorption. After entry into the bloodstream, the 46-kDa glycoprotein apo A-IV appears associated with chylomicrons, high-density lipoproteins, and in the lipoprotein-free fraction. It has a role in lipid absorption, transport and metabolism, and may act as a post-prandial satiety signal, an anti-oxidant and a major factor in the prevention of atherosclerosis. After summarizing and discussing these functions for reader's comprehension, the current review focuses on the regulation of apo A-IV by nutrients, biliary components, drugs, hormones and gastrointestinal peptides. The understanding of the involved mechanisms that underline apo A-IV regulation may in the long run allow us to switch on its gene, which may confer multiple beneficial effects, including the protection from atherosclerosis. Show less

It has been postulated that apolipoprotein (apo) A-IV plays various significant roles in lipid transport and lipoprotein metabolism. Although it is controlled by fat feeding, so far little else is known about its regulation by specific fatty acids. In this study, we focused on the modulation of apo A-IV mRNA levels, mass, and biogenesis by mono- and polyunsaturated fatty acids (FA) in the human intestinal Caco-2 cell line. In confluent cells incubated with 1 mM oleic (n-9), linoleic (n-6), alpha-linolenic (n-3), or docosahexaenoic (n-3) acids for a long-term period, both apo A-IV protein levels and de novo synthesis were increased. The induction resulted from the up-regulation of apo A-IV mRNA transcripts. In contrast, an inhibitory effect was evident with short-term incubation. FA chain length and degree of unsaturation had little effect altering apo A-IV transcript and biogenesis. These data offer evidence that isolated fatty acids regulate gene expression and the production of apo A-IV in the enterocyte. Show less