LPA Gene, Ethnicity, and Cardiovascular Events

Abstract

Background The relationship of LPA single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular (MACE) events in different ethnic groups is not well known. Methods LPA SNPs, apolipoprotein(a) isoforms, Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 Black, 1030 White and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined. Results LPA SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in Whites (14.27%) and rs9457951 in Blacks (32.927%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (HR) (95% CI) for time to MACE of 2.35 (1.50-3.69), p<0.001) and 1.89 (1.26-2.84), p=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating specific ethnic groups, in Blacks Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform and inverse predictor, in Whites the size of the major apolipoprotein(a) isoform was an inverse predictor and in Hispanics OxPL-apoB was a predictor of time to MACE. Conclusion The prevalence and association of LPA SNPs with size of apolipoprotein(a) isoforms, Lp(a) and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in LPA genetic markers.

HEART UK consensus statement on Lipoprotein(a): A call to action

“…The apo(a)-size allele affects serum Lp(a) concentrations to different degrees in different populations, with one study reporting that the variation in KIV-2 repeat number accounted for 63.2% of the total variability in Lp(a) levels in Caucasians and just 38.6% in African Blacks [28]. In Caucasians, 80% of the population have a serum Lp (a) < 90 nmol/l (40 mg/dl) and the distribution is positively skewed [12], however, people of African descent have levels twice as high as Caucasians, Hispanics and certain Asian populations, whereas South Asians have intermediate levels [1,[29][30][31][32]. No sex-specific differences in distributions of Lp(a) levels have previously been noted [33].…”

“…Although Lipoprotein(a) (Lp(a)) is now established as a causal risk factor for cardiovascular disease (CVD) [1][2][3], there is little consensus between the different national guidelines on how to use this information on Lp(a) to more accurately estimate and modify cardiovascular risk [4,5]. For instance, the 2012 Australian Guideline does not mention Lp(a) [6].…”

Characterization of the I4399M variant of apolipoprotein(a): implications for altered prothrombotic properties of lipoprotein(a)

“…We found, however, that the I4399M substitution does not impact on apo(a) secretion. Interestingly, it has been reported that the rs3798220 SNP is associated with increased Lp(a) levels in Caucasians, but not in non-Caucasians [10,12], which also argues against a direct functional impact of the SNP on plasma Lp(a) concentrations. It cannot be excluded that the I4399M substitution affects other processes that impact on plasma Lp(a) levels, such as Lp(a) assembly or catabolism.…”

Relationship of Autoantibodies to MDA-LDL and ApoB-Immune Complexes to Sex, Ethnicity, Subclinical Atherosclerosis, and Cardiovascular Events

“…In turn, elevated Lp(a) and/or OxPL-apoB were independent predictors of MACE, even after adjusting for apo(a) isoforms and LPA snps with consistent results in the 3 ethnic groups. 44 …”