Screening for naturally occurring apolipoprotein A-I variants: apo A-I(?K107) is associated with low HDL-cholesterol levels in men but not in women

Abstract

Isoelectric focussing (IEF) in carrier ampholyte-generated pH gradients and hybrid isoelectric focussing (HIEF) in immobilized pH gradients under nondenaturing conditions were used in parallel to screen 5,500 plasma samples for naturally occurring variants of apolipoprotein A-I (apo A-I). The following defects were identified in four unrelated subjects heterozygous for apo A-I variants: apo A-I(delta K107)(2 x), apo A-I(K107M)(1 x), and apo A-I(E41R)(1 x). The later variant is a novel finding. Family studies did not reveal any association of apo A-I(K107M) and apo A-I(E41R) with dyslipidemia, but identified several heterozygotes for apo A-I(delta K107) who had low levels of high density lipoprotein (HDL)-cholesterol. Therefore, and since the apo A-I(delta K107) is the most frequent apo A-I variant in Germany (1: 5,000) we evaluated our data and that reported from 11 families with 32 heterozygous carriers and 30 unaffected controls. This analysis revealed that apo A-I(delta K107) is associated with lower HDL-cholesterol (-30%) and higher triglycerides (+48%) in men but not in women as compared with unaffected family members as well as with controls from the Prospective Cardiovascular Münster (PROCAM) study. Moreover, 11 of 15 male apo A-I(delta K107) heterozygotes but only 2 of 17 female apo A-I(delta K107) heterozygotes had HDL-cholesterol levels below the 20th percentile of sex-matched controls from the PROCAM study. We conclude that heterozygosity for apo A-I(delta K107) decreases HDL-cholesterol and increases triglycerides in men but not in women.

A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease

“…Similar reductions have been described for other apoA-I mutations (23,24) although some reports describe HDL-C reductions up to 80% of normal (24). Finally, we noted no effects on TG levels, which is in contrast with a study that revealed higher TG levels in men suffering from an other apoA-I (delta K107) defect (25). ApoA-I (L178P): cardiovascular disease.…”

Binding of human apoA-I[K107del] variant to TG-rich particles: implications for mechanisms underlying hypertriglyceridemia

“…The apoA-I[K107del] variant is found in Caucasian and Asian populations and is the most frequent apoA-I variant in the population of Germany (1:5,000) ( 13,19 ). It is associated with HTG, hypoalphacholesterolemia, and amyloidosis ( 12,13,19,20 ).…”

“…It is associated with HTG, hypoalphacholesterolemia, and amyloidosis ( 12,13,19,20 ). Several groups have investigated the properties of the apoA-I[K107del] in order to clarify the molecular mechanisms underlying the development of the hypoalphacholesterolemia in carriers of this variant.…”

“…Human K107del and apoA-I Nashua mutations are associated with HTG that is combined with low plasma HDL cholesterol ( 13,14 ). The engineered apoA-I variants that induce HTG in mice also lead to low plasma levels of HDL cholesterol and apoA-I ( 9-11 ).…”

A Thyroid Hormone Binding Motif Is Evolutionarily Conserved in Apolipoproteins

“…4 for the two apolipoproteins having the highest number of naturally occurring mutations reported thus far (30)(31)(32)(33)(34)(35)(36), it is then evident that such mutations do spare the "Y, L/I/V/M, X, X, V/L/I" motif and immediately adjacent residues, but not other functional domains. I therefore conclude that evolution dictated that preservation of the chemical integrity of the core (ie, the 5-residue motif) of the thyroid hormone binding domain is much more important than preservation of other binding sites or (sub-)domains, to such a point that its alteration could be lethal.…”