DNA polymorphisms in the controlling region of the human haptoglobin genes: a molecular explanation for the haptoglobin 2-1 modified phenotype.

A haptoglobin 2-1 modified (Hp2-1mod) phenotype results when the amount of Hp2 polypeptide synthesized in Hp2/Hp1 heterozygotes is less than that of Hp1 polypeptide.Cloned Hp2 DNA from an individual with the Hp2-1mod phenotype is here shown to have a C in place of the normal A at nucleotide position -61 in one of the interleukin-6 (IL-6) responsive elements of the haptoglobin promoter region.Direct sequencing of the haptoglobin promoter region, amplified by PCR, from DNA from unrelated American blacks showed a C at -61 in all of 10 individuals with the Hp2-1mod phenotype, in two of four with a "possible Hp2-1mod" phenotype, but in none of 15 with the Hp2-1 phenotype.Thus the -61C mutation in the Hp2-61C allele is strongly associated with the Hp2-1mod phenotype.Sequencing results also show that there are three other promoter sequences in the population studied;each can be associated with either Hp2 or Hp1.The variability seen in the Hp2-1mod phenotype, a variability which ranges from close to Hp2-1 to close to Hp1-1, can be explained, in part, by the existence of several Hp2 alleles differing in their promoters--and possibly, in part, by differences in the promoters of the accompanying Hp1 allele.A further part of the variability may be the consequence of differences in the way that the Hp2-61C and the Hp2 alleles respond to the IL-6-dependent factor during an acute-phase response.