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

Philip A.I Guthrie,Santiago Rodriguez,Tom R Gaunt,Debbie A Lawlor,George Davey Smith,Ian N.M Day

doi:10.1016/j.gene.2012.03.034

Philip A.I Guthrie, Santiago Rodriguez + Show 4 more

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https://doi.org/10.1016/j.gene.2012.03.034

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Journal: Animal Gene	Publication Date: Mar 10, 2012
Citations: 18	License type: cc-by

Affiliation: University of Bristol

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=0.040mmol/L, p=0.023), TC (β=−0.040mmol/L, p=0.019), Hb (β=−0.044g/dL, p=0.028) and borderline with RCC (β=−0.032×1012/L, p=0.066). Analysis of CNV by linear regression revealed an association with Hb (Hp1 vs Hp2, β=0.057g/dL, p=0.004), RCC (β=0.045×1012/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.

Highlights

The haptoglobin gene exists in the human population in two forms: Hp1 and Hp2
Using haplotypes comprised of haptoglobin gene (HP) copy number variation (CNV) and haptoglobin-related protein gene (HPR) rs2000999, we performed association analyses of cholesterol- and haemogobinrelated phenotypes in a cohort of British women
We found evidence of association between HP CNV and Hb levels/red cell count (RCC), and between HPR rs2000999 and LDL-C/total cholesterol (TC)

Summary

Introduction

The haptoglobin gene exists in the human population in two forms: Hp1 and Hp2. Hp1 is the less frequent allele in Europeans. Exons 5 and 6 of Hp2 represent duplication of a 1.7 kb segment containing exons 3 and 4 of Hp1. The protein product of Hp1,1 is a dimer, whereas the products of Hp1,2 or Hp2,2 are multimers of respectively increasing complexity which have reduced availability to tissues. The haptoglobin/Hb complex is cleared from the bloodstream by circulating monocytes or in the liver by Kuppfer cells, and the heme iron is recycled; at sites of tissue damage, the complex is cleared by macrophages. The range of possible forms of haptoglobin, from dimer to large multimer depending on genotype, results in a gene product with a range of properties and potentially complex interactions.

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