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Complexity of a complex trait locus: HP, HPR, haemoglobin and cholesterol.

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  • Additional Information
    • Source:
      Publisher: Elsevier/North-Holland Country of Publication: Netherlands NLM ID: 7706761 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0038 (Electronic) Linking ISSN: 03781119 NLM ISO Abbreviation: Gene Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam, Elsevier/North-Holland, 1976-
    • Subject Terms:
    • Abstract:
      HP and HPR are related and contiguous genes in strong linkage disequilibrium (LD), encoding haptoglobin and haptoglobin-related protein. These bind and chaperone free Hb for recycling, protecting against oxidation. A copy number variation (CNV) within HP (Hp1/Hp2) results in different possible haptoglobin complexes which have differing properties. HPR rs2000999 (G/A), identified in meta-GWAS, influences total cholesterol (TC) and LDL-cholesterol (LDL-C). We examined the relationship between HP CNV, HPR rs2000999, Hb, red cell count (RCC), LDL-C and TC in the British Women's Heart and Health Study (n=2779 for samples having CNV, rs2000999, and phenotypes). Analysing single markers by linear regression, rs2000999 was associated with LDL-C (β=0.040 mmol/L, p=0.023), TC (β=-0.040 mmol/L, p=0.019), Hb (β=-0.044 g/dL, p=0.028) and borderline with RCC (β=-0.032 × 10(12)/L, p=0.066). Analysis of CNV by linear regression revealed an association with Hb (Hp1 vs Hp2, β=0.057 g/dL, p=0.004), RCC (β=0.045 × 10(12)/L, p=0.014), and showed a trend with LDL-C and TC. There were 3 principal haplotypes (Hp1-G 36%; Hp2-G 45%; Hp2-A 18%). Haplotype comparisons showed that LDL-C and TC associations were from rs2000999; Hb and RCC associations derived largely from the CNV. Distinct genotype-phenotype effects are evident at the genetic epidemiological level once LD has been analysed, perhaps reflecting HP-HPR functional biology and evolutionary history. The derived Hp2 allele of the HP gene has apparently been subject to malaria-driven positive selection. Haptoglobin-related protein binds Hb and apolipoprotein-L, i.e. linking HPR to the cholesterol system; and the HPR/apo-L complex is specifically trypanolytic. Our analysis illustrates the complex interplay between functions and haplotypes of adjacent genes, environmental context and natural selection, and offers insights into potential use of haptoglobin or haptoglobin-related protein as therapeutic agents.
      (Copyright © 2012 Elsevier B.V. All rights reserved.)
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    • Grant Information:
      G0600705 United Kingdom Medical Research Council; PG/07/131/24254 United Kingdom British Heart Foundation
    • Accession Number:
      0 (Antigens, Neoplasm)
      0 (HPR protein, human)
      0 (Haptoglobins)
      0 (Hemoglobins)
      97C5T2UQ7J (Cholesterol)
    • Publication Date:
      Date Created: 20120322 Date Completed: 20120619 Latest Revision: 20211021
    • Publication Date:
      20211214
    • Accession Number:
      PMC3405512
    • Accession Number:
      10.1016/j.gene.2012.03.034
    • Accession Number:
      22433445