SNP Shot: Genomic Insights

Thiopurine S-methyltransferase (TPMT) deficiency is characterized by a significant decrease in the activity of the TPMT enzyme. This enzyme is crucial for processing thiopurines, a class of drugs that includes 6-thioguanine, 6-mercaptopurine, and azathioprine. These drugs suppress the immune system and are used to treat autoimmune diseases like Crohn's disease and rheumatoid arthritis, as well as certain cancers like leukemias and lymphomas. They are also used in organ transplant recipients to prevent organ rejection.

A major risk associated with thiopurine drugs is damage to the bone marrow, known as hematopoietic toxicity. While anyone taking these drugs can experience this, individuals with TPMT deficiency are at a higher risk. Bone marrow is responsible for producing red blood cells (oxygen carriers), white blood cells (infection fighters), and platelets (blood clotting). When bone marrow is damaged, it leads to myelosuppression, a condition where the bone marrow doesn't produce enough of these cells. This can result in anemia (low red blood cells), causing paleness, weakness, shortness of breath, and fatigue; neutropenia (low white blood cells), leading to frequent and potentially serious infections; and thrombocytopenia (low platelets), causing easy bruising and bleeding.

To mitigate these risks, healthcare providers often recommend testing a patient's TPMT activity before prescribing thiopurine drugs. If reduced enzyme activity is detected, the medication may be administered at a much lower dosage, or alternative medications may be considered to minimize the risk of hematopoietic toxicity.

TPMT deficiency itself doesn't appear to cause any health issues except those related to thiopurine drug treatment.

Inheritance:

TPMT enzyme activity is inherited in an autosomal codominant manner. This means that both versions of the TPMT gene that a person inherits are active and contribute to their TPMT enzyme activity level. The TPMT gene is classified as either low-activity or high-activity. Low-activity genes produce less TPMT enzyme, while high-activity genes produce normal amounts. Since everyone has two copies of the TPMT gene, a person can have two low-activity genes, one low-activity gene and one high-activity gene, or two high-activity genes. Individuals with two low-activity genes have TPMT deficiency and are at the highest risk of hematopoietic toxicity from standard doses of thiopurine drugs. Those with one high-activity and one low-activity gene have moderately reduced enzyme activity and an increased risk as well. People with two high-activity genes have normal TPMT activity and are not at increased risk of hematopoietic toxicity from thiopurine drug treatment.