What are the three types of haptoglobin?

November 29, 2025 •

3 min read

Haptoglobin (Hp) is an abundant plasma protein that binds to free hemoglobin released from red blood cells. In humans, there are three main types of haptoglobin, known as phenotypes Hp 1-1, Hp 2-1, and Hp 2-2, which result from a genetic polymorphism in the HP gene.

Quick Summary

The three major haptoglobin types, Hp 1-1, Hp 2-1, and Hp 2-2, differ structurally due to genetic variation in the alpha chain, impacting their function and association with various diseases. These phenotypes affect the protein's hemoglobin-binding capacity and antioxidant activity.

Key Points

Three Main Types: The three primary human haptoglobin phenotypes are Hp 1-1, Hp 2-1, and Hp 2-2, determined by genetic variation.
Structural Differences: These types have distinct structures, with Hp 1-1 being a small dimer, Hp 2-1 an intermediate linear polymer, and Hp 2-2 a large, complex cyclic polymer.
Functional Variation: Their ability to bind and neutralize free hemoglobin and provide antioxidant protection varies significantly, with Hp 1-1 being the most efficient and Hp 2-2 the least.
Associated Disease Risks: Hp polymorphism is linked to different risks for diseases, especially cardiovascular complications in diabetics, where the Hp 2-2 phenotype confers higher risk.
Clinical Significance: Knowing an individual's haptoglobin phenotype has prognostic value for disease risk and can inform clinical management, especially concerning oxidative stress and inflammation.
Genetic Origins: The Hp2 allele, which creates the larger polymeric proteins, arose from a gene duplication event unique to humans.

Haptoglobin (Hp) is a crucial serum glycoprotein that manages free hemoglobin following red blood cell destruction. It acts as an antioxidant, preventing iron loss by binding free hemoglobin to form a complex cleared by the liver. Differences among haptoglobin types stem from genetic variations in the HP gene's alpha chain, influencing structure and efficiency. The beta-chain is consistent, but alpha-chain polymorphism creates distinct structural and functional variations among the three types.

Haptoglobin Type 1-1 (Hp 1-1)

Individuals with two copies of the HP1 allele produce the Hp 1-1 phenotype. This type is a small dimer of two alpha-1 and two beta chains. The alpha-1 chain is shorter and forms this unique tetramer.

Highest Efficiency: Hp 1-1 effectively binds free hemoglobin and provides strong antioxidant protection.
Higher Serum Levels: This phenotype typically results in higher haptoglobin plasma concentrations.
Protection: Hp 1-1's superior function offers greater protection against oxidative stress and may lower the risk of certain diseases, including diabetic vascular complications.

Haptoglobin Type 2-2 (Hp 2-2)

Individuals with two copies of the HP2 allele, resulting from a gene duplication, have the Hp 2-2 phenotype. The alpha-2 chain is longer with cysteines facilitating multimerization, creating a large, heterogeneous, cyclic polymeric molecule.

Lower Efficiency: The large structure of Hp 2-2 is less efficient at binding and clearing free hemoglobin than Hp 1-1.
Reduced Antioxidant Capacity: Lower antioxidant capacity in Hp 2-2 can increase oxidative stress and inflammation, especially with elevated hemoglobin.
Associated Disease Risks: Hp 2-2 is linked to a higher risk of cardiovascular complications, particularly in diabetics.

Haptoglobin Type 2-1 (Hp 2-1)

The Hp 2-1 phenotype is heterozygous, with one HP1 and one HP2 allele. It combines properties of the other types, forming intermediate-sized multimeric linear polymers.

Intermediate Functionality: Hp 2-1's effectiveness is between Hp 1-1 and Hp 2-2, with moderate antioxidant and hemoglobin-binding efficiency.
Variable Health Outcomes: Individuals with Hp 2-1 may have intermediate risk for associated conditions, with outcomes influenced by other factors.

A Comparative Look at Haptoglobin Types


Feature	Haptoglobin 1-1 (Hp 1-1)	Haptoglobin 2-1 (Hp 2-1)	Haptoglobin 2-2 (Hp 2-2)
Genetic Make-up	Homozygous for HP1 allele.	Heterozygous (HP1 and HP2 alleles).	Homozygous for HP2 allele.
Alpha-Chain	Two alpha-1 chains.	Mixed alpha-1 and alpha-2 chains.	Two alpha-2 chains.
Structure	Homogeneous dimer; single, fast-migrating band on electrophoresis.	Heterogeneous linear polymers of various sizes.	Heterogeneous cyclic polymers; slow-migrating bands.
Molecular Size	Smallest (approx. 86 kDa).	Intermediate and variable (86–300 kDa).	Largest and most variable (170–900 kDa).
Antioxidant Activity	High; most effective.	Moderate.	Low; least effective.
Associated Health Risk	Generally protective against cardiovascular disease in diabetics.	Intermediate risk for cardiovascular disease in diabetics.	Higher risk of cardiovascular disease in diabetics; linked to inflammation.

The Clinical and Genetic Implications of Haptoglobin Types

The haptoglobin polymorphism has significant clinical relevance due to functional differences, particularly in handling oxidative stress from free hemoglobin, which is linked to various disease risks. The less efficient Hp 2-2 protein struggles with clearing hemoglobin-mediated oxidative damage, concerning in conditions with increased red blood cell breakdown or inflammation.

The efficient Hp 1-1 protein provides robust protection. Studies in diabetics show Hp 1-1 is linked to a lower risk of cardiovascular complications. Conversely, Hp 2-2 is a risk factor for coronary artery disease in diabetics, independently of other factors.

Beyond these three types, genetic variations include modified forms and congenital deficiency (ahaptoglobinemia), more common in certain populations. The Hpdel allele causing absent haptoglobin is more prevalent in East Asians and can cause transfusion reactions. Haptoglobin genotyping is important for accurate risk assessment and medical procedures. As an acute-phase protein, haptoglobin levels increase with inflammation, complicating interpretation without genotype information.

Conclusion

The haptoglobin polymorphism illustrates how a single genetic difference results in a spectrum of functional outcomes. The three types—Hp 1-1, Hp 2-1, and Hp 2-2—represent distinct capabilities in binding and neutralizing free hemoglobin. These differences influence susceptibility and outcome of inflammatory and oxidative stress-related diseases. Hp 1-1 offers greater protection, especially against vascular complications in diabetes, while Hp 2-2 confers less protection and is linked to higher disease risk. Studying haptoglobin's genetic variations and clinical consequences offers insights into health and disease, aiding personalized medicine. More clinical details are available in the Medscape reference database.

Frequently Asked Questions

The main function of haptoglobin is to bind to free hemoglobin that is released into the bloodstream when red blood cells break down (a process called hemolysis). This binding prevents the hemoglobin from causing oxidative damage and allows the liver to clear the complex from the body.

The existence of three types of haptoglobin is due to a genetic polymorphism at the HP gene locus, which results in two main alleles, HP1 and HP2. The combination of these two codominant alleles in an individual results in one of the three phenotypes: Hp 1-1 (homozygous HP1), Hp 2-1 (heterozygous), and Hp 2-2 (homozygous HP2).

Haptoglobin type Hp 1-1 is the most biologically efficient. Its smaller, more compact structure allows it to bind and clear free hemoglobin more effectively and provides superior antioxidant protection compared to the other two types.

Research suggests that the Hp 1-1 phenotype offers more protective benefits, particularly against complications of diabetes and oxidative stress. The Hp 2-2 phenotype is associated with a higher risk for cardiovascular diseases in diabetic patients due to its lower antioxidant capacity.

Yes, while the phenotype is fixed by genetics, the concentration of haptoglobin in the blood can change. It is an acute-phase protein, so its levels increase during inflammation, infection, and malignancy. Conversely, levels decrease with conditions causing increased red blood cell destruction, such as hemolytic anemia.

Haptoglobin type is typically determined using methods like gel electrophoresis or more advanced molecular methods like Polymerase Chain Reaction (PCR). Electrophoresis separates the protein based on its size and charge, showing the characteristic patterns for each of the three phenotypes.

Yes, some individuals are born with a genetic absence of haptoglobin, a condition called anhaptoglobinemia (Hp 0). This is more common in populations of African and East Asian descent and can result from increased consumption or a gene deletion.