Genetic variation in the apolipoprotein H (β2-glycoprotein I) gene affects plasma apolipoprotein H concentrations

Abstract

Apolipoprotein H (apoH, protein; APOH, gene) is a single chain glycoprotein that exists in plasma both in a free form and in combination with lipoprotein particles. ApoH has been implicated in several physiologic pathways, including lipid metabolism, coagulation, and the production of antiphospholipid antibodies. The wide range of interindividual variation in plasma apoH levels is thought to be under genetic control, but its molecular basis is unknown. APOH displays a common structural polymorphism with the occurrence of three common alleles (APOH*1, APOH*2, and APOH*3), the APOH*2 allele being the most frequent in all populations. The relationship between the APOH polymorphism and plasma apoH levels is unknown. In this study, we have determined the impact of this APOH polymorphism on apoH levels in 455 normoglycemic non-Hispanic Whites (220 men and 235 women) from the San Luis Valley, Colorado. Mean plasma apoH levels, determined by capture enzyme-linked immunosorbent assay, were 20.0 +/- 0.2 mg/dl (range: 3.4-31.2 mg/dl) with no significant difference between men and women. In women, but not in men, age had a significant effect on plasma apoH levels explaining 3.4% of its phenotypic 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 levels showed significant association with the APOH polymorphism in both men and women (P < 0.0001), and the APOH polymorphism accounted for 11.4% and 13.6% of the variation in apoH levels in men and women, respectively. Compared with the APOH*1 and APOH*2 alleles, the APOH*3 allele was associated with significantly lower plasma apoH levels. At the molecular level, APOH*3 can be further subdivided into two distinct forms, called APOH*3W and APOH*3B. The APOH*3W 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 revealed that this polymorphism is a major determinant of plasma apoH variation (P < 0.0001). This study indicates that common genetic variation in the APOH gene is a significant determinant of plasma apoH levels in non-Hispanics Whites and should be useful in evaluating the role of the APOH genetic variation in various metabolic pathways in which apoH has been implicated.

Comprehensive evaluation of apolipoprotein H gene (APOH) variation identifies novel associations with measures of lipid metabolism in GENOA

“…1B; Table 3). Previous studies have found associations of Cys306Gly and Trp316Ser with plasma apoH levels (25,26). Because the strongest associations were found for SNP 14917 (Cys306Gly), we investigated the effects of this APOH variant on DCT measures in MAs.…”

Genetic determinants of plasma β2-glycoprotein I levels: a genome-wide association study in extended pedigrees from Spain

“…Moreover, the two SNPs from the CEP112 genomic region lie very close to APOH , which also appeared among the suggestive hits with intergenic polymorphism rs10048158 (at ~ 11 kbp upstream of APOH ). Subsequent LD analysis with data from the CEU population showed that the minor allele of rs10048158 is preferentially associated with the minor alleles of rs1801692 and rs1801690 ( D ′ = 1), the two missense mutations that have been reported to influence plasma β 2 ‐GPI levels . This observation suggests that rs10048158 actually represents the same association signal as rs1801692 and rs1801690 previously did.…”

ApoD mediates binding of HDL to LDL and to growing T24 carcinoma

“…We used a dualspecific ELISA in which antibodies to apoD bound intact apoB-containing lipoproteins equally efficient as antibodies specific for apoB. This property was unique for apoD and was not seen with other exchangeable apolipoproteins such apoE, apoH and apoJ, all of which are present in HDL and LDL/VLDL lipoprotein particles [32,33,34]. Adding detergent inhibited the apoD-mediated binding of apoB, demonstrating that changes in the LDL structure affect the formation of the complex.…”