Genetic variation in the apolipoprotein H (beta 2-glycoprotein I) gene affects plasma apolipoprotein H concentrations

Apolipoprotein H (apoH, protein; APOH, gene) is a single chain glycoprotein that exists in plasma both in a free form and in combination with lipoprot ein particles. ApoH has been implicated in several physiologic pathways, in cluding lipid metabolism, coagulation, and the production of antiphospholip id antibodies. The wide range of interindividual variation in plasma apoH l evels is thought to be under genetic control, but its molecular basis is un known. APOH displays a common structural polymorphism with the occurrence o f three common alleles (APOH*1, APOH*2, and APOH*3), the APOH*2 allele bein g the most frequent in all populations. The relationship between the APOH p olymorphism and plasma apoH levels is unknown. In this study, we have deter mined the impact of this APOH polymorphism on apoH levels in 455 normoglyce mic non-Hispanic Whites (220 men and 235 women) from the San Luis Valley, C olorado. Mean plasma apoH levels, determined by capture enzyme-linked immun osorbent assay, were 20.0 +/- 0.2 mg/dl (range: 3.4-31.2 mg/dl) with no sig nificant difference between men and women. In women, but not in men, age ha d a significant effect on plasma apoH levels explaining 3.4% of its phenoty pic variance. ApoH levels also correlated positively with cholesterol (P = 0.015), HDL-cholesterol (P = 0.044), and triglyceride (P = 0.037) in women, but not in men. An analysis of variance (ANOVA) of adjusted plasma apoH le vels showed significant association with the APOH polymorphism in both men and women (P < 0.0001), and the APOH polymorphism accounted for 11.4% and 1 3.6% of the variation in apoH levels in men and women, respectively. Compar ed with the APOH*1 and APOH*2 alleles, the APOH*3 allele was associated wit h significantly lower plasma apoH levels. At the molecular level, APOH*3 ca n be further subdivided into two distinct forms, called APOH*3(W) and APOH* 3(B). The APOH*3(W) form is more common in US Whites and is the result of a missense mutation at codon 316. An ANOVA for the codon 316 polymorphism re vealed that this polymorphism is a major determinant of plasma apoH variati on (P < 0.0001). This study indicates that common genetic variation in the APOH gene is a significant determinant of plasma apoH levels in non-Hispani cs Whites and should be useful in evaluating the role of the APOH genetic v ariation in various metabolic pathways in which apoH has been implicated.