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Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans
  1. J-P Chretien1,
  2. J Coresh1,
  3. Y Berthier-Schaad1,
  4. W H L Kao1,
  5. N E Fink1,
  6. M J Klag1,
  7. S M Marcovina2,
  8. F Giaculli2,
  9. M W Smith3
  1. 1Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
  2. 2Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, Washington, USA
  3. 3Laboratory of Genomic Diversity and Basic Research Program, Science Applications International Corp-Frederick, National Cancer Institute at Frederick, Frederick, Maryland, USA
  1. Correspondence to:
 J Coresh
 Johns Hopkins University, 2024 E Monument St, Suite 2-600, Baltimore, MD 21205, USA; coresh{at}jhu.edu

Abstract

Background: The extent which universally common or population-specific alleles can explain between-population 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 single-nucleotide 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.

  • apo(a), apolipoprotein(a)
  • Lp(a), lipoprotein(a)
  • SNP, single nucleotide polymorphism
  • CHOICE, Choices for Healthy Outcomes in Caring for End-Stage Renal Disease
  • ESRD, end-stage renal disease

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Footnotes

  • Published Online First 13 July 2006

  • This study was supported by grants R01-HS-08365 (AHRQ), R01-HL-62985 (NHLBI) and R01-DK-07024 (NIDDK), K24-DK-02856 (NIDDK; Klag), 01-40197N (AHA Established Investigator—JC), K01-DK067207 (NIDDK; WHLK), National Center for Research Resources (NIH) GCRC grant M01-RR00052. This study was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organisations imply endorsement by the US government.

  • Competing interests: None declared.

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