YPERTRIGLYCERIDEMIA IS A heterogeneous disorder with an unclear association with atherosclerosis. [1][2][3][4] Patients with high triglyceride levels of more than 25 mmol/L (Ͼ2212.4 mg/dL) and the familial chylomicronemia syndrome rarely develop atherosclerosis, 4 perhaps because their plasma lipoprotein particles are too large to enter into the arterial intima. 5,6 However, patients with moderate hypertriglyceridemia and conditions like familial hypertriglyceridemia, familial combined hyperlipidemia, the metabolic syndrome, and remnant hyperlipidemia often develop premature atherosclerosis. [1][2][3][4] With moderate hypertriglyceridemia, chylomicron remnants and very low-density lipoprotein remnants are present in plasma. These smaller triglyceride-rich lipoproteins penetrate the arterial intima 7 and appear to be preferentially trapped within the arterial wall. 8,9 Triglycerides are routinely measured in the fasting state excluding remnant lipoproteins; however, except for the first hours in the early morning, most individuals are in the nonfasting state most of the time. Atherosclerosis may be a postprandial phenomenon in which remnant lipoproteins play a dominant role. [10][11][12] If this is true, increased levels of nonfasting triglycerides, reflecting increased levels of rem-nant lipoproteins, may predict risk of myocardial infarction (MI), ischemic heart disease (IHD), and death.See also pp 309 and 336.

A nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of triglyceride-rich lipoprotein particles causes ischemic heart disease. However, because pleiotropic effects of the genetic variants studied cannot be totally excluded, these findings need to be confirmed using additional genetic variants and/or randomized intervention trials.

Summary Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate to large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.