Haptoglobin (HP) and Haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis

Robert J. Hardwick,Jacqueline Milet,Edward J. Hollox,David Courtin,Anne Ménard,Manuela Sironi,Fengtang Yang,Beiyuan Fu,André Garcia,Claude Sese

doi:10.1007/s00439-013-1352-x

Abstract

Haptoglobin, coded by the HP gene, is a plasma protein that acts as a scavenger for free heme, and haptoglobin-related protein (coded by the HPR gene) forms part of the trypanolytic factor TLF-1, together with apolipoprotein L1 (ApoL1). We analyse the polymorphic small intragenic duplication of the HP gene, with alleles Hp1 and Hp2, in 52 populations, and find no evidence for natural selection either from extended haplotype analysis or from correlation with pathogen richness matrices. Using fiber-FISH, the paralog ratio test, and array-CGH data, we also confirm that the HPR gene is copy number variable, with duplication of the whole HPR gene at polymorphic frequencies in west and central Africa, up to an allele frequency of 15 %. The geographical distribution of the HPR duplication allele overlaps the region where the pathogen causing chronic human African trypanosomiasis, Trypanosoma brucei gambiense, is endemic. The HPR duplication has occurred on one SNP haplotype, but there is no strong evidence of extended homozygosity, a characteristic of recent natural selection. The HPR duplication shows a slight, non-significant undertransmission to human African trypanosomiasis-affected children of unaffected parents in the Democratic Republic of Congo. However, taken together with alleles of APOL1, there is an overall significant undertransmission of putative protective alleles to human African trypanosomiasis-affected children.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-013-1352-x) contains supplementary material, which is available to authorized users.

Highlights

Haptoglobin (Hp), encoded by the gene HP, is an abundant acute-phase glycoprotein in the plasma which binds free haemoglobin (Hb) that has been released by lysis of erythrocytes, often as a result of infection
Initial inspection of arrayCGH copy number calls for this region, generated by the Agilent copy number variations (CNVs) association chip, together with previous copy number calling on aCGH data, suggested that there were three genotype classes, with the two classes showing an increase in signal most likely reflecting heterozygous and homozygous duplications of the HPR gene (3 and 4 copies respectively) (Conrad et al 2009)
We found no evidence of higher HPR copy numbers beyond a simple duplication, so we consider that these high-copy number HPR chromosomes are very rare in the population

Summary

Introduction

Haptoglobin (Hp), encoded by the gene HP, is an abundant acute-phase glycoprotein in the plasma which binds free haemoglobin (Hb) that has been released by lysis of erythrocytes, often as a result of infection. The resulting haptoglobin-haemoglobin complex is cleared by binding to the macrophage scavenging receptor CD163, followed by endocytosis. This process prevents oxidative damage and disruption to nitrous oxide homeostasis caused by free heme molecules (Nielsen and Moestrup 2009). Because of its abundance in blood plasma, Hp was one of the first blood serum proteins to be analysed by native. A. Garcia IRD, UMR 216 Mere et enfant face aux infections tropicales, Universite Paris Descartes, Paris, France. A. Garcia Facultede Pharmacie, Universite Paris Descartes, Sorbonne Paris Cite, France

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