Abstract
Haptoglobin (Hp) is a major plasma acute-phase glycoprotein, which binds free haemoglobin to neutralize its toxicity. The HP gene exists as two copy number variants (CNV), Hp1 and HP2, which differ in two ways: serum Hp level and functional differences in Hp protein products. Both mechanisms may underlie the HP CNV's influence on susceptibility and/or outcome in several diseases. A single nucleotide polymorphism rs2000999 has also been associated with serum Hp level. In a meta-analysis of three studies from England, France and Japan, with a combined sample size of 1210 participants, we show that rs2000999's effect on circulating Hp level is independent from that of the HP CNV. The combined use of rs2000999 and the HP CNV can be an important genetic epidemiological tool to discriminate between the two potential mechanisms underlying differences between HP1 and HP2 alleles.
Highlights
Haptoglobin (Hp) is a major plasma acute-phase glycoprotein
Data from the two mixed gender British and Japanese cohorts and the female-only French cohort was used to assess the contribution of the two HP genetic polymorphisms to circulating Hp level
The analysis identified that the rs2000999 minor allele (A) was associated with a Hp change of −0.14 g/L, and the HP copy number variant (CNV) was associated with Hp level, Fig. 1
Summary
Haptoglobin (Hp) is a major plasma acute-phase glycoprotein. The main biological function of Hp is to bind free haemoglobin (Hb) to prevent the loss of iron and subsequent kidney damage following intravascular hemolysis [1]; it may have immunomodulatory properties [1]. The basic structure of Hp is of an alpha and beta chain that form a monomer; a disulphide bond between the alpha chains of two monomers leads to the formation of a dimer in the mature form of Hp. An intragenic duplication of exons 3 and 4 of the ancestral HP gene produced the HP2 allele, after which recurrent deletions produced the modern HP1 allele [2]. Individuals could be one of three genotypes: HP1–1, HP2–1 or HP2–2 [3]. This copy number variant (CNV) codes for an extra cysteine residue in the alpha chain that forms an additional disulphide bond; trimeric, tetrameric and higher order polymers are formed in individuals carrying the HP2 allele [3]
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