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

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.