Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans

Abstract

Background: The extent which universally common or population-specific alleles can explain betweenpopulation variations in phenotypes is unknown. The heritable coronary heart disease risk factor lipoprotein(a) (Lp(a)) level provides a useful case study of between-population variation, as the aetiology of twofold higher Lp(a) levels in African populations compared with non-African populations is unknown. Objective: To evaluate the association between LPA sequence variations and Lp(a) in European Americans and African Americans and to determine the extent to which LPA sequence variations can account for between-population variations in Lp(a). Methods: Serum Lp(a) and isoform measurements were examined in 534 European Americans and 249 African Americans from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. In addition, 12 LPA variants were genotyped, including 8 previously reported LPA variants with a frequency of .2% in European Americans or African Americans, and four new variants. Results: Isoform-adjusted Lp(a) level was 2.23-fold higher among African Americans. Three singlenucleotide polymorphisms (SNPs) were independently associated with Lp(a) level (p,0.02 in both populations). The Lp(a)-increasing SNP (G-21A, which increases promoter activity) was more common in African Americans, whereas the Lp(a)-lowering SNPs (T3888P and G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European Americans, but all had a frequency of ,20% in one or both populations. Together, they reduced the isoform-adjusted African American Lp(a) increase from 2.23 to 1.37-fold(a 60% reduction) and the between-population Lp(a) variance from 5.5% to 0.5%. Conclusions: Multiple low-prevalence alleles in LPA can account for the large between-population difference in serum Lp(a) levels between European Americans and African Americans.

Structure, function, and genetics of lipoprotein (a)

“…In this review, we concentrate on variants for which a causal mechanism has either been described or appears plausible, and those which have been described extensively in significantly increased Lp(a) levels. Residing in KIV-8, rs41272110 (p.Thr1399Pro; or Thr3888Pro) has been found to be associated with lower than expected Lp(a) levels in Europeans by several studies (178,190), though with an inconsistent result to the study by Ogorelkova et al (179). All these results were reported for Lp(a) levels corrected for KIV-2 CNV size.…”

“…In contrast, no such association was found in Europeans, which might be explained by LD with long KIV-2/low Lp(a) alleles, thus masking any possible effect (189). For rs1800769, higher Lp(a) levels in vivo (156,178,183,190) and a higher transcriptional activity in vitro (183) have been reported for the variant allele. In African Americans, this promoter variant was strongly associated with intermediate KIV-2 CNV sizes, while for European Americans it was more frequent on longer alleles, but in both populations an increase of CNV-size-adjusted Lp(a) levels was observed for the variant allele, which consequently could explain, in part, the higher Lp(a) concentrations observed in Africans (178).…”

Lipoprotein (a): impact by ethnicity and environmental and medical conditions

“…Over time, sev eral genetic variants at the LPA locus have been identified predicting Lp(a) levels and explaining some of the vari ability in Lp(a) concentrations, again with a variable im pact across populations. Notably, three SNPs contribute to the AfricanAmerican/Caucasian difference in Lp(a) concentration (26). Two SNPs (T3888P and G+1/inKIV8A), both suppressing Lp(a) assembly, were more common in Caucasians, whereas the third SNP (G21A), increasing apo(a) promoter activity, was more common in African Americans.…”

ApoE genotype affects allele-specific apo[a] levels for large apo[a] sizes in African Americans: the Harlem-Basset Study

“…As African Americans have higher lipoprotein [a] (15,18,19). Furthermore, as described above, we and others have identified several genetic variations that affect allele-specific apo[a] levels (8,16,17,20). Genetic variability of apolipoprotein E (apoE) is a major determinant of plasma lipoprotein levels (21), and furthermore, apoE genotype frequencies differ between African Americans and Caucasians (22,23).…”