Other entities represented in this entry:
HGNC Approved Gene Symbol: HP
Cytogenetic location: 16q22.2 Genomic coordinates (GRCh38): 16:72,054,505-72,061,055 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.2 | [Anhaptoglobinemia] | 614081 | 3 | |
| [Hypohaptoglobinemia] | 614081 | 3 |
Haptoglobin (HP), a plasma glycoprotein that binds free hemoglobin (see 141800), has a tetrameric structure of 2 alpha and 2 beta polypeptides that are covalently associated by disulfide bonds. In human populations, there are 3 common genetic haptoglobin types, Hp1 (140100.0001), Hp2 (140100.0002), and the heterozygous phenotype Hp2-1, reflecting inherited variations in the HP polypeptides (summary by Yang et al., 1983).
Two loci had been thought to be involved in haptoglobin synthesis, 1 for alpha chains and 1 for beta chains. The findings of Haugen et al. (1981) indicated that the alpha and beta chains are encoded by a single gene. They studied de novo biosynthesis of haptoglobin in a rabbit reticulocyte cell-free translation system using mRNA preparations from the livers of turpentine-treated rats. Analysis of the translation mixtures with antiserum specific for the alpha subunit, the beta subunit, or the native heterotetramer always resulted in recovery of a single protein with molecular mass about 38.0 kD, which on cyanogen bromide or trypsin digestion broke down into small peptic fragments that reacted specifically with either anti-alpha or anti-beta antibodies. The authors concluded that the primary translation product of haptoglobin mRNA is a single polypeptide that contains the elements of both the alpha and the beta subunits. Haptoglobin is synthesized as a single precursor protein that is proteolytically processed after translation to form the dissimilar alpha and beta subunits.
Black and Dixon (1968) reported the amino acid sequences of the alpha chains of haptoglobin. There are similarities between the primary structures of the alpha chain and of light chains of gamma globulins; there are also functional homologies since both form complexes with specific proteins. A common evolutionary origin was postulated. Amino acid sequence data were summarized by Dayhoff (1972).
According to amino acid sequence data, haptoglobin is homologous to serine proteases of the chymotrypsinogen family (Kurosky et al., 1980).
Yang et al. (1983) isolated recombinant plasmids containing cDNA coding for haptoglobin by screening an adult human liver library with a mixed oligonucleotide probe. A hitherto unknown arginine residue was deduced between the alpha and beta sequences, which was the probable site of the limited proteolysis that leads to the formation of the separate alpha and beta polypeptides of mature haptoglobin. Comparison of the haptoglobin alpha-beta junction region with the heavy-light-chain junction of tissue-type plasminogen activator strengthens the evolutionary homology of haptoglobin and serine proteases.
The alpha-2 chain is not found in any species but man. Black and Dixon (1968) suggested that alpha-2 chains give a selective advantage because their increased size reduces loss of the haptoglobin-hemoglobin complex by the kidney and at the same time hemoglobin binding is unimpaired and heme degradation enhanced.
Haptoglobin protects against the potentiation of bacterial growth by hemoglobin (Eaton et al., 1982); herein might lie a basis for polymorphism.
A major function of haptoglobin is to bind hemoglobin (Hb) to form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance of the Hp-Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163 (605545). Asleh et al. (2003) assessed the scavenging function of Hp using radiolabeled Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. They found that the rate of clearance of Hp1-1-Hb by CD163 was markedly greater than that of Hp2-2-Hb. Because diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb, Asleh et al. (2003) also assessed the antioxidant function of Hp with glycosylated and nonglycosylated Hb. They identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb, and proposed that the specific interaction between diabetes, cardiovascular disease, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb-Hp complexes from the subendothelial space before they can oxidatively modify low density lipoprotein to atherogenic oxidized low density lipoprotein.
Haptoglobin is an unusual secretory protein in that it is proteolytically processed in the endoplasmic reticulum and not in the Golgi. Wicher and Fries (2004) found that C1RL (608974) mediates this cleavage. Coexpression of the proform of HP (proHP) and C1RL in COS-1 cells resulted in the cleavage of proHP in the endoplasmic reticulum. C1RL showed specificity for proHP, in that it did not cleave the proform of complement C1s, a protein similar to HP, particularly around the cleavage site. Suppression of C1RL expression by RNA interference reduced the cleavage of proHP by up to 45%.
Robson et al. (1969) presented evidence that the alpha haptoglobin locus is on the long arm of chromosome 16. In a family with 46t(2G-;16G+) and one with 46t(1-;16+), haptoglobin type was linked with the translocation chromosome.
Gerner-Smidt et al. (1978) found evidence in a family with a balanced translocation consistent with the view that the alpha-haptoglobin locus is in the proximity of band 16q22. Povey et al. (1980) presented new data suggesting that the male recombination fraction for 16qh (the paracentromeric heterochromatin heteromorphism) and alpha-Hp is about 0.2.
By in situ hybridization, Simmers et al. (1985, 1986) showed that the haptoglobin gene is distal to the fragile site that is precisely localized at the proximal end of band 16q22.1. The fragile site with which haptoglobin was found to be linked (Magenis et al., 1970) is referred to as fra(16)(q22) or FRA16B (136580).
Crystal Structure
Andersen et al. (2012) presented the crystal structure of the dimeric porcine haptoglobin-hemoglobin (see 141800) complex determined at 2.9-angstrom resolution. This structure revealed that haptoglobin molecules dimerize through an unexpected beta-strand swap between 2 complement control protein (CCP) domains, defining a new fusion CCP domain structure. The haptoglobin serine protease domain forms extensive interactions with both the alpha- and beta-subunits of hemoglobin, explaining the tight binding between haptoglobin and hemoglobin. The hemoglobin-interacting region in the alpha-beta dimer is highly overlapping with the interface between the 2 alpha-beta dimers that constitute the native hemoglobin tetramer. Several hemoglobin residues prone to oxidative modification after exposure to heme-induced reactive oxygen species are buried in the haptoglobin-hemoglobin interface, thus showing a direct protective role of haptoglobin. The haptoglobin loop previously shown to be essential for binding of haptoglobin-hemoglobin to the macrophage scavenger receptor CD163 (605545) protrudes from the surface of the distal end of the complex, adjacent to the associated hemoglobin alpha-subunit. Small-angle x-ray scattering measurements of human haptoglobin-hemoglobin bound to the ligand-binding fragment of CD163 confirmed receptor binding in this area, and showed that the rigid dimeric complex can bind 2 receptors.
See review of the evolution of the haptoglobin gene by Maeda and Smithies (1986).
In the chimpanzee, there are 3 genes in the haptoglobin family (haptoglobin, HP; haptoglobin-related, HPR; and haptoglobin-primate, HPP), whereas only 2 genes exist in humans (HP and HPR). The 2-gene cluster of the human was formed after the separation of the human and chimpanzee lineages by an unequal homologous crossover that deleted most of the third gene. The 3-gene haptoglobin cluster in chimpanzees shows evidence of many recombinations, insertions, and deletions during its evolution. In the rhesus monkey, Erickson and Maeda (1994) found 6 different haplotypes among 11 individuals from 2 rhesus monkey families. The 6 haplotypes included 2 types of haptoglobin gene clusters: one type with a single gene and the other with 2 genes. DNA sequence analysis indicated that the 1-gene and the 2-gene clusters were both formed by unequal homologous crossovers between 2 genes of an ancestral 3-gene cluster, near exon 5, the longest exon of the gene. This exon is also the location of a separate unequal homologous crossover that occurred in the human lineage to form the human 2-gene haptoglobin gene cluster from an ancestral 3-gene cluster. The occurrence of independent homologous unequal crossovers in rhesus monkey and human within the same region of DNA suggests that the evolutionary history of the haptoglobin gene cluster in primates is a consequence of frequent homologous pairings facilitated by the longest and most conserved exon of the gene. Exon 5 contains more than 700 nucleotides.
The haptoglobins, alpha-2-globulins whose name comes from their ability to bind protein, were found to be polymorphic when studied by starch gel electrophoresis by Smithies (1955). Several haptoglobin variants have been identified in addition to the main types (Hp1, 140100.0001; Hp2, 140100.0002), and evidence of genic evolution through duplication (by unequal crossingover) and subsequent independent mutation has been provided.
A haptoglobin 2-1 modified (Hp2-1mod) phenotype results when the amount of Hp2 polypeptide synthesized in Hp2 (140100.0002)/Hp1 heterozygotes is less than that of Hp1 polypeptide. Maeda (1991) showed that the Hp2 DNA from an individual with the modified phenotype had a C in place of the normal A at nucleotide position -61 in one of the interleukin-6 (IL6) responsive elements of the haptoglobin promoter region. Direct sequencing of the haptoglobin promoter region, amplified by PCR, in DNA from unrelated American blacks showed a C at -61 in all of 10 persons with the modified phenotype, in 2 of 4 with a possible modified phenotype, and in none of 15 with the standard Hp2-1 phenotype. The 2-1 modified phenotype was first described by Connell and Smithies (1959). Giblett (1959) found it to be relatively common in blacks but, as found by Harris et al. (1960), it occurs in other races. In the population studied, Maeda (1991) found 3 other promoter sequences. This may explain the variability of the modified phenotype. There may be variation in the response of Hp2 alleles to the IL6-dependent factor during an acute-phase response.
Haptoglobin variants with change in electrophoretic mobility of the alpha polypeptide have been found (Giblett et al., 1966), whereas others, e.g., the 'Marburg' phenotypes, have been found to have alterations in the beta polypeptide chain (Cleve and Deicher, 1965). Javid (1967) described a genetic variant of the haptoglobin beta polypeptide chain and suggested that the locus be called Bp (for 'binding peptide,' since the beta chain binds hemoglobin), the longer-known locus for the alpha chain being called Hp. Cleve et al. (1969) concluded that haptoglobin Marburg is the result of a mutational event other than a single base substitution. Haptoglobin P is another beta variant.
Chapelle et al. (1982) found an association between Hp 2-2 and severity of myocardial infarction.
The human haptoglobin HP*2 allele contains a 1.7-kb intragenic duplication that arose after a unique nonhomologous recombination between the prototype HP*1 alleles. During a genetic screening of 13,000 children of survivors exposed to atomic-bomb radiation and 10,000 children of unexposed persons, Asakawa et al. (1999) identified 2 children suspected of carrying de novo mutations at the HP locus (1 in each group). DNA analysis of single-cell-derived colonies of Epstein-Barr virus-transformed B cells revealed that the 2 children were mosaics comprising HP*2/HP*2 and HP*2/HP*1 cells at a ratio of approximately 3 to 1. It was inferred that the latter cells were caused by reversion of 1 HP*2 allele to HP*1 through an intramolecular homologous recombination between the duplicated segments of the HP*2 allele that excised 1 of the segments. Because the mosaicism was substantial (approximately 25%), this recombination must have occurred in early embryogenesis. The frequency of finding these children and the extent of their mosaicism corresponded to an HP*2-to-HP*1 reversion rate of 8 x 10(-6) per cell during development. This led to the prediction that the HP*1 allele also will be represented, although usually at a very low frequency, in any HP2-2 person. Asakawa et al. (1999) tested this prediction by using PCR for a single individual and found the HP*1 allele at frequencies of 4 x 10(-6) and 3 x 10(-6) in somatic and sperm cells, respectively. The HP*1 allele was detected by PCR in all 4 other HP2-2 individuals, which supported the regular but rare occurrence somatically of homologous recombination within duplicated regions in humans, as well as previous observations in mouse and Drosophila.
Levy et al. (2002) determined the haptoglobin phenotype in 206 individuals with cardiovascular disease and 206 matched controls. In multivariate analyses controlling for conventional cardiovascular disease risk factors, Levy et al. (2002) found that for individuals with diabetes mellitus, the odds ratio of having cardiovascular disease was 5.0 times greater with the Hp2-2 phenotype than with the Hp1-1 phenotype (p = 0.002). An intermediate risk of cardiovascular disease was associated with the Hp2-1 phenotype, and there were no significant differences in risk by haptoglobin type for individuals without diabetes.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Hardwick et al. (2014) found no evidence for natural selection of HP variants Hp1 and Hp2 in 52 populations either from extended haplotype analysis or from correlation with pathogen richness matrices.
Anhaptoglobinemia and Hypohaptoglobinemia
In a Japanese individual with anhaptoglobinemia (also termed ahaptoglobinemia) (614081) found by ELISA analysis of 9,711 unrelated blood samples, Koda et al. (1998) identified a homozygous 28-kb deletion allele on chromosome 16q22 (140100.0003) extending from the promoter region of the HP gene to exon 5 of the haptoglobin-related gene (HPR; 140210), resulting in a null allele, HP0. Seven Japanese persons from 3 families with hypohaptoglobinemia (see 614081) carried the HP0 deletion allele in compound heterozygosity with 1 of the codominant HP polymorphisms. Six individuals with genotype HP2/HP0 had an extremely low level of haptoglobin compared to controls with the HP2/HP2 genotype, whereas 1 individual with the HP1/HP0 genotype had a serum level that was approximately half the level of controls with the HP1/HP1 genotype. This demonstrated a gene-dosage effect.
Teye et al. (2003) found that 17 (13.8%) of 123 Ghanaian individuals with undetectable malaria infection had decreased serum haptoglobin as assessed by double immunodiffusion followed by Western blotting. Nine (7.3%) were ahaptoglobinemic and 8 (6.5%) were hypohaptoglobinemic. There was a strong association between a -61A-C polymorphism in the HP gene (140100.0004) and ahaptoglobinemia (p = 0.0125).
Teye et al. (2004) identified a heterozygous mutation in the HP gene (I247T; 140100.0005) in a Ghanaian individual who was ahaptoglobinemic as assessed by several assays. The I247T mutation caused reduced expression of the HP protein when transfected into COS-7 cells. This individual was also homozygous for the hypomorphic -61A-C allele (140100.0004).
Kwon et al. (2019) found that Hp-deficient mice had reduced bone volume and increased number of osteoclasts compared with wildtype. In vitro studies showed that Hp inhibited osteoclastogenesis by reducing Fos (164810) protein levels at the early phase of osteoclast differentiation. Hp suppressed Fos by upregulating Ifn-beta (IFNB1; 147640) via a Tlr4 (603030)-dependent mechanism.
From study of cases of ring chromosome 13 and their families, Bloom et al. (1967) concluded that the haptoglobin alpha locus was located near one or the other end of chromosome 13. This later proved to be incorrect.
Castiglione et al. (1985) found no evidence of linkage between HP and APRT within 12 map units, despite the fact that both loci had previously been mapped within band 16q22. The apparent inconsistency was explained by the finding of Fratini et al. (1986) that APRT is located at 16q24 and that the gene order is cen--FRA16B--HP--FRA16D--APRT--qter.
The fast and slow forms of alpha-1, so-called from their electrophoretic mobilities, differ in the amino acid at position 54, lysine (F) or glutamic acid (S) (Black and Dixon, 1968).
Yang et al. (1983) stated that the lys-to-glu change occurs at codon 53.
Maeda (1991) stated that the HP1F and HP1S polypeptides differ by 2 amino acids at positions 52 and 53: aspartic acid and lysine in HB1F and asparagine and glutamic acid in HP1S.
The alpha-2 chain originated through a chromosomal aberration (unequal crossingover) in a person who was heterozygous alpha-1F/alpha-1S. The alpha-2 chain is nearly twice as long as the alpha-1 chain and consists of portions of alpha-1F and alpha-1S (Black and Dixon, 1968). The HP*2 allele has an internal duplication of 1.7 kb that includes 2 of the alpha-chain exons. The HP2-alpha polypeptide consists of 142 amino acids, while the HP1-alpha polypeptide has 83 amino acids (Maeda, 1991). Marles et al. (1993) showed that homologous crossingover between HP*2 and either an HP*1F or HP*1S allele in HP*2/HP*1 heterozygotes can change the usual type of HP*2 to 3 other forms: HP*2SS, HP*2FF, or HP*2SF. Marles et al. (1993) described a nuclear family in which the uncommon genotype HP*2SS in one parent caused initial confusion in assigning genotypes to the rest of the nuclear family.
In a Japanese person with anhaptoglobinemia (614081), Koda et al. (1998) found homozygosity for deletion of a segment of chromosome 16 extending from at least the promoter region of HP to HPR-alpha but not to HPR-beta. In addition, they found 7 persons with hypohaptoglobinemia (see 614081) in 3 families, and the genotype of 6 of the 7 individuals was found to be HP2/HP-del. The HP2/HP-del individuals with hypohaptoglobinemia had an extremely low level of haptoglobin, compared with the level obtained in 52 healthy volunteers with phenotype HP2, whereas the serum haptoglobin level of an individual with HP1/HP-del was 0.50 mg/ml, which was approximately half the level of haptoglobin in control sera from the HP1 phenotype, showing a gene-dosage effect. By DNA sequencing of all exons, the other allele (HP2) of individuals with HP2/HP-del was found to have no mutations. Hypohaptoglobinemia and anhaptoglobinemia have no clear pathologic consequences.
Anhaptoglobinemia due to homozygous deletion of a segment measuring approximately 28 kb on chromosome 16 and extending from the promoter region of the HP gene to exon 5 of the haptoglobin-related gene (HPR; 140210) had been found in Japan, Korea, and China but not elsewhere. In these countries, anhaptoglobinemia has important clinical consequences; it is responsible for anaphylactic reactions in blood transfusions (Koda et al., 2000; Morishita et al., 2000). Teye et al. (2003) found that the so-called Hp0 anhaptoglobinemia phenotype in Ghana (West Africa) (see 140100.0004) has a different genetic basis than that seen in Asia.
In Ghana, West Africa, Teye et al. (2003) found that a -61A-C base substitution in the promoter region of the HP gene was associated with anhaptoglobinemia (614081) and was strongly associated with the HP*2 allele (140100.0002). This base substitution was found to decrease transcriptional activity significantly.
In a Ghanaian patient with anhaptoglobinemia (614081) previously found to be homozygous for a -61A-C transversion in the promoter region of the HP gene (140100.0004) (Teye et al., 2003), Teye et al. (2004) identified a heterozygous 6802T-C transition in exon 7, resulting in an ile247-to-thr (I247T) mutation. The I247T mutation caused reduced expression of the HP protein when transfected into COS-7 cells, compared with the wildtype.
Andersen, C. B. F., Torvund-Jensen, M., Nielsen, M. J., de Oliveira, C. L. P., Hersleth, H.-P., Andersen, N. H., Pedersen, J. S., Andersen, G. R., Moestrup, S. K. Structure of the haptoglobin-haemoglobin complex. Nature 489: 456-459, 2012. [PubMed: 22922649] [Full Text: https://doi.org/10.1038/nature11369]
Asakawa, J., Kodaira, M., Nakamura, N., Satoh, C., Fujita, M. Chimerism in humans after intragenic recombination at the haptoglobin locus during early embryogenesis. Proc. Nat. Acad. Sci. 96: 10314-10319, 1999. [PubMed: 10468605] [Full Text: https://doi.org/10.1073/pnas.96.18.10314]
Asleh, R., Marsh, S., Shilkrut, M., Binah, O., Guetta, J., Lejbkowicz, F., Enav, B., Shehadeh, N., Kanter, Y., Lache, O., Cohen, O., Levy, N. S., Levy, A. P. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res. 92: 1193-1200, 2003. [PubMed: 12750308] [Full Text: https://doi.org/10.1161/01.RES.0000076889.23082.F1]
Bensi, G., Raugei, G., Klefenz, H., Cortese, R. Structure and expression of the human haptoglobin locus. EMBO J. 4: 119-126, 1985. [PubMed: 4018023] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb02325.x]
Bias, W. B., Migeon, B. R. Haptoglobin: a locus on the D(1) chromosome? Am. J. Hum. Genet. 19: 393-398, 1967. [PubMed: 6026932]
Black, J. A., Dixon, G. H. Amino-acid sequence of alpha chains of human haptoglobins. Nature 218: 736-741, 1968. [PubMed: 4172407] [Full Text: https://doi.org/10.1038/218736a0]
Bloom, G. E., Gerald, P. S., Reisman, L. E. Ring D chromosome: a second case associated with anomalous haptoglobin inheritance. Science 156: 1746-1748, 1967. [PubMed: 5611035] [Full Text: https://doi.org/10.1126/science.156.3783.1746]
Castiglione, C. M., Kidd, J. R., Tischfield, J. A., Stambrook, P. J., Murphy, P. D., Sparkes, R. A., Kidd, K. K. Polymorphism and linkage of APRT. (Abstract) Cytogenet. Cell Genet. 40: 601 only, 1985.
Chapelle, J.-P., Albert, A., Smeets, J.-P., Heusghem, C., Kulbertus, H. E. Effect of the haptoglobin phenotype on the size of a myocardial infarct. New Eng. J. Med. 307: 457-463, 1982. [PubMed: 7099207] [Full Text: https://doi.org/10.1056/NEJM198208193070801]
Chow, V., Murray, R. K., Dixon, J. D., Kurosky, A. Biosynthesis of rabbit haptoglobin: chemical evidence for a single chain precursor. FEBS Lett. 153: 275-279, 1983. [PubMed: 6413248] [Full Text: https://doi.org/10.1016/0014-5793(83)80623-1]
Cleve, H., Bowman, B. H., Gordon, S. Biochemical characterization of the beta-chain variant haptoglobin Marburg. Humangenetik 7: 337-343, 1969. [PubMed: 5365574] [Full Text: https://doi.org/10.1007/BF00283555]
Cleve, H., Deicher, H. Haptoglobin 'Marburg': Untersuchungen ueber eine seltene erbliche Haptoglobin-variante mit zwei verschiedenen Phaenotypen inerhalb einer Familie. Humangenetik 1: 537-550, 1965. [PubMed: 5868430] [Full Text: https://doi.org/10.1007/BF00338342]
Connell, G. E., Smithies, O. Human haptoglobins: estimation and purification. Biochem. J. 72: 115-121, 1959. [PubMed: 13651145] [Full Text: https://doi.org/10.1042/bj0720115]
Cook, P. J. L., Gray, J. E., Brack, R. A., Robson, E. B., Howlett, R. M. Data on haptoglobin and the D group chromosomes. Ann. Hum. Genet. 33: 125-138, 1969. [PubMed: 5383979] [Full Text: https://doi.org/10.1111/j.1469-1809.1969.tb01639.x]
Dayhoff, M. O. Miscellaneous proteins. Atlas of Protein Sequence and Structure. Vol. 5 Washington: National Biomedical Research Foundation (pub.) 1972. Pp. D309, and D314-D315.
Eaton, J. W., Brandt, P., Mahoney, J. R., Lee, J. T., Jr. Haptoglobin: a natural bacteriostat. Science 215: 691-693, 1982. [PubMed: 7036344] [Full Text: https://doi.org/10.1126/science.7036344]
Erickson, L. M., Maeda, N. Parallel evolutionary events in the haptoglobin gene clusters of rhesus monkey and human. Genomics 22: 579-589, 1994. [PubMed: 8001969] [Full Text: https://doi.org/10.1006/geno.1994.1431]
Ferguson-Smith, M. A., Aitken, D. A. Heterozygosity at the alpha-haptoglobin locus associated with a deletion, 16q22-16qter. (Abstract) Cytogenet. Cell Genet. 22: 513 only, 1978.
Fratini, A., Simmers, R. N., Callen, D. F., Hyland, V. J., Tischfield, J. A., Stambrook, P. J., Sutherland, G. R. A new location for the human adenine phosphoribosyltransferase gene (APRT) distal to the haptoglobin (HP) and fra(16)(q23) (FRA16D) loci. Cytogenet. Cell Genet. 43: 10-13, 1986. [PubMed: 3780312] [Full Text: https://doi.org/10.1159/000132291]
Gerald, P. S., Warner, S., Singer, J. D., Corcoran, P. A., Umansky, I. A ring D chromosome and anomalous inheritance of haptoglobin type. J. Pediat. 70: 172-179, 1967. [PubMed: 6018104] [Full Text: https://doi.org/10.1016/s0022-3476(67)80411-6]
Gerner-Smidt, P., Friedrich, U., Petersen, G. B., Tischfield, J. A. A balanced translocation t(11;16) (q13;p11), a cytogenetic study and an attempt at gene localization. Hum. Genet. 42: 61-66, 1978. [PubMed: 649170] [Full Text: https://doi.org/10.1007/BF00291626]
Giblett, E. R., Uchida, I. A., Brooks, L. E. Two rare haptoglobin phenotypes, 1-B and 2-B, containing a previously undescribed alpha polypeptide chain. Am. J. Hum. Genet. 18: 448-453, 1966. [PubMed: 5927287]
Giblett, E. R. Haptoglobin types in American Negroes. Nature 183: 192-193, 1959. [PubMed: 13622742] [Full Text: https://doi.org/10.1038/183192a0]
Giblett, E. R. Variant haptoglobin phenotypes. Cold Spring Harbor Symp. Quant. Biol. 29: 321-326, 1964. [PubMed: 14278478] [Full Text: https://doi.org/10.1101/sqb.1964.029.01.034]
Hardwick, R. J., Menard, A., Sironi, M., Milet, J., Garcia, A., Sese, C., Yang, F., Fu, B., Courtin, D., Hollox, E. J. Haptoglobin (HP) and haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis. Hum. Genet. 133: 69-83, 2014. [PubMed: 24005574] [Full Text: https://doi.org/10.1007/s00439-013-1352-x]
Harris, H., Lawler, S. D., Robson, E. B., Smithies, O. The occurrence of two unusual serum protein phenotypes in a single pedigree. Ann. Hum. Genet. 24: 63-69, 1960. [PubMed: 14399953] [Full Text: https://doi.org/10.1111/j.1469-1809.1959.tb01715.x]
Haugen, T. H., Hanley, J. M., Heath, E. C. Haptoglobin: a novel mode of biosynthesis of a liver secretory glycoprotein. J. Biol. Chem. 256: 1055-1057, 1981. [PubMed: 7451486]
Javid, J., Yingling, W. Immunogenetics of human haptoglobins. I. The antigenic structure of normal Hp phenotypes. J. Clin. Invest. 47: 2290-2296, 1968. [PubMed: 5676524] [Full Text: https://doi.org/10.1172/JCI105914]
Javid, J. Haptoglobin 2-1 Bellevue, a haptoglobin beta-chain mutant. Proc. Nat. Acad. Sci. 57: 920-924, 1967. [PubMed: 4291922] [Full Text: https://doi.org/10.1073/pnas.57.4.920]
Kirk, R. L. The haptoglobin groups in man. In: Monographs in Human Genetics. Vol. 4. Basel and New York: S. Karger (pub.) 1968.
Koda, Y., Soejima, M., Yoshioka, N., Kimura, H. The haptoglobin-gene deletion responsible for anhaptoglobinemia. Am. J. Hum. Genet. 62: 245-252, 1998. [PubMed: 9463309] [Full Text: https://doi.org/10.1086/301701]
Koda, Y., Watanabe, Y., Soejima, M., Shimada, E., Nishimura, M., Morishita, K., Moriya, S., Mitsunaga, S., Tadokoro, K., Kimura, H. Simple PCR detection of haptoglobin gene deletion in anhaptoglobinemic patients with antihaptoglobin antibody that causes anaphylactic transfusion reactions. Blood 95: 1138-1143, 2000. [PubMed: 10666182]
Kurosky, A., Barnett, D. R., Lee, T.-H., Touchstone, B., Hay, R. E., Arnott, M. S., Bowman, B. H., Fitch, W. M. Covalent structure of human haptoglobin: a serine protease homology. Proc. Nat. Acad. Sci. 77: 3388-3392, 1980. [PubMed: 6997877] [Full Text: https://doi.org/10.1073/pnas.77.6.3388]
Kwon, J.-O., Jin, W. J., Kim, B., Ha, H., Kim, H.-H., Lee, Z. H. Haptoglobin acts as a TLR4 ligand to suppress osteoclastogenesis via the TLR4-IFN-beta axis. J. Immun. 202: 3359-3369, 2019. [PubMed: 31076532] [Full Text: https://doi.org/10.4049/jimmunol.1800661]
Lefranc, G., Lefranc, M.-P., Seger, J., Salier, J.-P., Chakhachiro, L., Loiselet, J. Sex limited ahaptoglobinaemia. Hum. Genet. 58: 294-297, 1981. [PubMed: 7327550] [Full Text: https://doi.org/10.1007/BF00294926]
Levy, A. P., Hochberg, I., Jablonski, K., Resnick, H. E., Lee, E. T., Best, L., Howard, B. V. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the strong heart study. J. Am. Coll. Cardiol. 40: 1984-1990, 2002. [PubMed: 12475459] [Full Text: https://doi.org/10.1016/s0735-1097(02)02534-2]
Lush, I. E. The Biochemical Genetics of Vertebrates Except Man. Philadelphia: W. B. Saunders (pub.) 1966.
Maeda, N., Smithies, O. The evolution of multigene families: human haptoglobin genes. Annu. Rev. Genet. 20: 81-108, 1986. [PubMed: 2880559] [Full Text: https://doi.org/10.1146/annurev.ge.20.120186.000501]
Maeda, N., Yang, F., Barnett, D. R., Bowman, B. H., Smithies, O. Duplication within the haptoglobin Hp-2 gene. Nature 309: 131-135, 1984. [PubMed: 6325933] [Full Text: https://doi.org/10.1038/309131a0]
Maeda, N. DNA polymorphisms in the controlling region of the human haptoglobin genes: a molecular explanation for the haptoglobin 2-1 modified phenotype. Am. J. Hum. Genet. 49: 158-166, 1991. [PubMed: 2063867]
Magenis, R. E., Hecht, F., Lovrien, E. W. Heritable fragile site on chromosome 16: probable localization of haptoglobin locus in man. Science 170: 85-87, 1970. [PubMed: 5452897] [Full Text: https://doi.org/10.1126/science.170.3953.85]
Marles, S. L., McAlpine, P. J., Zelinski, T., Phillips, S., Maeda, N., Greenberg, C. R. Identification of an uncommon haptoglobin type using DNA and protein analysis. Hum. Genet. 92: 364-366, 1993. [PubMed: 8225317] [Full Text: https://doi.org/10.1007/BF01247336]
McGill, J. R., Yang, F., Baldwin, W. D., Brune, J. L., Barnett, D. R., Bowman, B. H., Moore, C. M. Localization of the haptoglobin alpha and beta genes (HPA and HPB) to human chromosome 16q22 by in situ hybridization. Cytogenet. Cell Genet. 38: 155-157, 1984. [PubMed: 6547898] [Full Text: https://doi.org/10.1159/000132050]
Morishita, K., Shimada, E., Watanabe, Y., Kimura, H. Anaphylactic transfusion reactions associated with anti-haptoglobin in a patient with ahaptoglobinemia. (Letter) Transfusion 40: 120-121, 2000. [PubMed: 10644822] [Full Text: https://doi.org/10.1046/j.1537-2995.2000.40010120.x]
Mulley, J. C., Hyland, V. J., Fratini, A., Bates, L. J., Gedeon, A. K., Sutherland, G. R. A linkage group with FRA16B (the fragile site at 16q22.2). Hum. Genet. 82: 131-133, 1989. [PubMed: 2722188] [Full Text: https://doi.org/10.1007/BF00284044]
Oliviero, S., DeMarchi, M., Bensi, G., Raugei, G., Carbonara, A. O. A new restriction fragment length polymorphism in the haptoglobin gene region. Hum. Genet. 70: 66-70, 1985. [PubMed: 2987106] [Full Text: https://doi.org/10.1007/BF00389461]
Oliviero, S., DeMarchi, M., Carbonara, A. O., Bernini, L. F., Bensi, G., Raugei, G. Molecular evidence of triplication in the haptoglobin Johnson variant gene. Hum. Genet. 71: 49-52, 1985. [PubMed: 2993157] [Full Text: https://doi.org/10.1007/BF00295668]
Povey, S., Jeremiah, S. J., Barker, R. F., Hopkinson, D. A., Robson, E. B., Cook, P. J. L., Solomon, E., Bobrow, M., Marritt, B., Buckton, K. E. Assignment of the human locus determining phosphoglycolate phosphatase (PGP) to chromosome 16. Ann. Hum. Genet. 43: 241-248, 1980. [PubMed: 6244770] [Full Text: https://doi.org/10.1111/j.1469-1809.1980.tb01557.x]
Robson, E. B., Polani, P. E., Dart, S. J., Jacobs, P. A., Renwick, J. H. Probable assignment of the alpha locus of haptoglobin to chromosome 16 in man. Nature 223: 1163-1165, 1969. [PubMed: 5810694] [Full Text: https://doi.org/10.1038/2231163a0]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Simmers, R. N., Stupans, I., Sutherland, G. R. The haptoglobin gene is distal to the fragile site at 16q22. (Abstract) Cytogenet. Cell Genet. 40: 745 only, 1985.
Simmers, R. N., Stupans, I., Sutherland, G. R. Localization of the human haptoglobin genes distal to the fragile site at 16q22 using in situ hybridization. Cytogenet. Cell Genet. 41: 38-41, 1986. [PubMed: 3455911] [Full Text: https://doi.org/10.1159/000132193]
Smithies, O., Connell, G. E., Dixon, G. H. Chromosomal rearrangements and the evolution of haptoglobin genes. Nature 196: 232-236, 1962. [PubMed: 13989613] [Full Text: https://doi.org/10.1038/196232a0]
Smithies, O., Connell, G. E., Dixon, G. H. Inheritance of haptoglobin subtypes. Am. J. Hum. Genet. 14: 14-21, 1962. [PubMed: 13914473]
Smithies, O., Walker, N. F. Genetic control of some serum proteins in normal humans. Nature 176: 1265-1266, 1955. [PubMed: 13321879] [Full Text: https://doi.org/10.1038/1761265a0]
Smithies, O. Zone electrophoresis in starch gels: group variations in the serum proteins of normal human adults. Biochem. J. 61: 629-641, 1955. [PubMed: 13276348] [Full Text: https://doi.org/10.1042/bj0610629]
Smithies, O. An improved procedure for starch-gel electrophoresis: further variations in the serum proteins of normal individuals. Biochem. J. 71: 585-587, 1959. [PubMed: 13638269] [Full Text: https://doi.org/10.1042/bj0710585]
Sutton, H. E. The haptoglobins. Prog. Med. Genet. 7: 163-216, 1970. [PubMed: 4911918]
Teye, K., Quaye, I. K. E., Koda, Y., Soejima, M., Pang, H., Tsuneoka, M., Amoah, A. G. B., Adjei, A., Kimura, H. A novel I247T missense mutation in the haptoglobin 2 beta-chain decreases the expression of the protein and is associated with ahaptoglobinemia. Hum. Genet. 114: 499-502, 2004. [PubMed: 14999562] [Full Text: https://doi.org/10.1007/s00439-004-1098-6]
Teye, K., Quaye, I. K. E., Koda, Y., Soejima, M., Tsuneoka, M., Pang, H., Ekem, I., Amoah, A. G. B., Adjei, A., Kimura, H. A-61C and C-101G Hp gene promoter polymorphisms are, respectively, associated with ahaptoglobinaemia and hypohaptoglobinaemia in Ghana. Clin. Genet. 64: 439-443, 2003. [PubMed: 14616769] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00149.x]
van der Straten, A., Herzog, A., Cabezon, T., Bollen, A. Characterization of human haptoglobin cDNAs coding for alpha(2FS)beta and alpha(1S)beta variants. FEBS Lett. 168: 103-107, 1984. [PubMed: 6546723] [Full Text: https://doi.org/10.1016/0014-5793(84)80215-x]
Weerts, G., Nix, W., Deicher, H. Isolierung und naehere Charakterisierung eines neuen Haptoglobins: HP-Marburg. Blut 12: 65-77, 1965. [PubMed: 4955080] [Full Text: https://doi.org/10.1007/BF01631544]
Wicher, K., Fries, E. Prohaptoglobin is proteolytically cleaved in the endoplasmic reticulum by the complement C1r-like protein. Proc. Nat. Acad. Sci. 101: 14390-14395, 2004. [PubMed: 15385675] [Full Text: https://doi.org/10.1073/pnas.0405692101]
Yang, F., Brune, J. L., Baldwin, W. D., Barnett, D. R., Bowman, B. H. Identification and characterization of human haptoglobin cDNA. Proc. Nat. Acad. Sci. 80: 5875-5879, 1983. [PubMed: 6310599] [Full Text: https://doi.org/10.1073/pnas.80.19.5875]