Pharmacogenomics in Asthma,

Immunology, Transplantation, and Vaccines

Lecture 12
 Pharmacogenomics of B2-agonist in
Asthma
• Thirteen polymorphism have been identified in B2AR gene. Two of them are of great interest
and shown dawn-regulation of receptor (β16, β27)
• Β16 : (Arg  Gly)
• B27 : (Gln  Glu) Glutamine  Glutamic Acid

 Bronchodilator response was significantly higher in subjects homozygous for Arg16 than
homozygous for Gly16.
 Subjects who are homozygous for Gln27 responded much better than those who are
homozygous for Glu27.

 Maximum response was observed in subjects who are:

1. Homozygous Arg16 Gln27 compared to
2. Heterozygous Arg16Gln27/Gly16Glu27 followed by
3. Homozygous Gly16Glu27 (lowest response)
 Genetic Variations and Glucocorticoids
• They are the most potent anti-inflammatory drugs used in asthma. 5-10 % of asthmatics may
have a reduced response to glucocorticoids ( in severe asthma it could reach 25%).

• The variation in response has been observed over 3 main mutations:

1. Mutations in the glucocorticoids receptor gene (NR3C1):
 Four mutations have been identified. They are missense mutations leads to decreased affinity
for the steroid and an impaired ability to activate gene transcription
 On the other hand (rs6195) polymorphism was associated with an increased response to
glucocorticoids.

2. Corticotropin releasing hormone receptor 1 (CRHR1):

 It mediate the regulation of cortisol level. Gene variation in CRHR1 gene was associated with an
increased pulmonary function response to inhaled corticosteroids

3. Histone deacetylase enzymes (HDAC):

 Activation of this enzyme is needed for the action of glucocorticoids. So, polymorphisms in the
(HDAC) gene may contribute to variation of response to glucocorticoids.
 Pharmacogenomics of Leukotrienes
inhibitors
 They inhibit the formation of cysteinyl leukotrienes by inhibiting the enzyme 5-
lipooxygenase (ALOX5) which will lead to reduction in bronchospasm and improve
asthma control (montelukast, zafirlukast, pranlukast and zileuton).

 ALOX5 gene is highly polymorphic with tandem repeats (GGGCGG). Commonly, 5

repeats is the wild-type allele.

More or fewer copies from this tandem repeat will result in diminished ALOX5 activity
(due to diminished transcription of ALOX5)
↓
Subjects with ALOX5 polymorphism will produce less leukotrienes
↓
so, they will not respond well to leukotrienes inhibitors
 Human Leukocyte Antigen (HLA)
• The HLA genes are located on chromosome 6, and each individual has HLA
genes for Class I “HLA-A, HLA-B and HLA-C” and for class II “HLA-DRB, HLA-
DQA, HLA-DQB, HLA-DPA and HLA-DPB”.

• The function of HLA is to present peptides from pathogens to T cell

receptors to initiate an immune response.

• Rheumatoid arthritis serves as an example of an autoimmune disease with

a well-established connection to HLA polymorphisms.

• Patients with HLA-DRB gene polymorphisms have been associated with

rheumatoid arthritis in several ethnic groups . About one third of the risk
for rheumatoid arthritis can be attributed to HLA-DRB gene
polymorphisms.
 Polymorphic Metabolism of
Immunosuppressant drugs
• Example:
• Mycophenolic acid is metabolized primarily by glucuronidation.
Polymorphisms in UGT1A9 and UGT2B7 genes result in variability in enzyme
expression.

• Individuals with high UGT genotypes have significantly lower mycophenolic

acid exposure. Lower exposure to mycophenolic acid increases the risk of
acute organ rejection.

• Diarrhea is a common and dose-limiting adverse event with mycophenolic

acid use. UGT1A8 gene polymorphism, which is expressed in the intestinal
mucosa, has been identified as a target gene.
 Pathogen Genome for Antigen Identification

• Serogroup B Neisseria meningitides sequence represents a good example

of the use of the pathogen's genome to explore vaccine development.

• Although serogroup B causes approximately one third of all cases of

invasive N. meningitides infections, the meningococcal conjugate vaccine in
clinical use covers only for serogroups A, C, Y, and W135.

• Serogroup B Meningococcal Vaccines (MenB)

• Two serogroup B meningococcal vaccines (Bexsero® and Trumenba®) have
been licensed by the Food and Drug Administration (FDA).

• These vaccines are recommended routinely for people 10 years or older

who are at increased risk for serogroup B meningococcal infections.
 Measles Vaccine / Influenza Vaccine

• Pharmacogenomics can also be used to predict which individuals may be

likely to have a poor response to a vaccine.

• Both HLA class I and class II alleles were associated with measles vaccine
responses.

• Class I HLA-B8, HLA-B13, and HLA-B44 alleles and class II HLA-DRB1*03 and
HLA-DQA1*0201 are associated with low measles antibody responses.

• Antibody responses to influenza A/H1N1 have been associated with HLA-A

gene polymorphisms. HLA-A*1101 and HLA-1*6801 are associated with
higher H1N1 influenza antibody production.