The history and biochemical nature of the H antigen is entangled with that of the ABO and Lewis blood group systems. The recognition of the Hh blood group probably begins with the discovery by Bhende et al. (1952) of the first three individuals who completely lacked A and B antigens but were not group O. This null phenotype was named "Bombay" after the city where it was found. Although the Bombay phenotype is extremely rare in most populations, a number of examples have been found in India over the years. Early suggestions were that this type was due to a new allele at the ABO locus, but others suggested an inhibitor gene and finally the possibility of a genetically independent but related gene. We now know that the Bombay phenotype is due to a recessive gene at the H locus; ie. h and is therefore referred to as O_h. Subsequently, intermediate form of the H gene have been found and these individuals are called "para-Bombays".

Understanding of the biochemical nature of the A,B,O, H and Lewis antigens came from the laborious work of Kabat, Morgan and Watkins. They found that the corresponding genes code for carbohydrate (sugar) transferases which are added in a stepwise manner to a backbone protein or lipid. The H gene is a alpha (1,2) fucosyl transferase which must first put a fucose in place before the A or B specific transferases can act. Persons with the rare Bombay phenotype do not have the H gene and hence cannot make the fucosyl (H) transferase. Without this structure the A and B gene products have no foundation to build upon and no A or B antigen can be made.

The gene that makes the fucosyl transferase is called FUT1 and is located on chromosome 19 at q13. A mutation at position 316 from a tyrosine to a stop codon leads to the O_h phenotype. In secretions such as saliva and tears, the H antigen is made by the related gene FUT2 and is known as the secretor (Se) gene. This gene product is important for the formation of Lewis antigens which are later absorbed onto the red blood cell.

Patients with the Bombay phenotype can have severe transfusion reactions if transfused with "normal" group O blood. This is because their serum contains a potent anti-H antibody.

Changes in A,B and H antigens have been associated with disease states. In 20-30% of patients diagnosed with acute leukemia, there will be a depression of the A, B or H antigens. Serum H-transferase level is reduced in patients having acute myelogenous leukemia but is increased in those with chronic granulocytic leukemia.