Genetic determinants of circulating haptoglobin concentration

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. • Haptoglobin (Hp) is a major plasma protein, with multiple biological functions. • HP1 and HP2 alleles differ in two ways: Hp expression level and biological function. • The single nucleotide polymorphism rs2000999 is related to Hp expression level. • In a sample size of 1210, we show that rs2000999 and HP allele status have independent effects on serum Hp level. • The use of rs2000999 can inform about the mechanism of differences between HP1 and HP2 alleles.