Genetic basis for personalized medicine in asthma

Figures & data

Figure 1. Targets of current asthma medication.

Corticosteroids cross the cell membrane and bind to receptors that are stabilized by regulatory proteins. The glucocorticoid receptor (GR) then crosses the nuclear membrane, binds to a response element and modulates transcription. β₂-adrenergic receptor agonists bind to the β₂-adrenergic receptor and mediate smooth muscle relaxation via PKA and regulate various genes via the transcription factor CREB. The cysteinyl leukotrienes in Figure 1 LTC₄, LTD₄ and LTE₄,and dihydroxy leukotriene LTB₄ are synthesized from arachidonic acid in a series of steps via an enzymatic cascade as depicted. Following translocation into the extracellular space, cysteinyl leukotrienes activate their cognate GPCRs (including CYSLTR1) and mediate a variety of effects such as smooth muscle contraction.

AC: Adenylcyclase; ALOX5: Arachidonate 5-lipoxygenase; β₂AR: β₂-adrenergic receptor; cAMP: Cyclic adenosine monophosphate; cysLTR: Cysteinyl Leukotriene receptor; CREB: Cyclic AMP response element-binding; DAG: Diacyl glycerol; GC: Glucocorticoid; GPCR: G-protein-coupled receptor; GR: Glucocorticoid receptor; IP3: Inositol-triphosphate; LTA₄: Leukotriene A₄; LTB₄: Leukotriene B₄; LTC₄: Leukotriene C₄; LTD₄: Leukotriene D₄; LTE₄: Leukotriene E₄; LTC4S: Leukotriene C4 synthase; LTA4H: Leukotriene A4 hydrolase; LTSI: Leukotriene synthesis inhibitor; LTRA: Leukotriene receptor antagonist; PKA: Cyclic-AMP dependent protein kinase; PKC: Protein kinase C; PLC: Phospholipase C.

Table 1. Recently identified pharmacogenetic effects on current asthma therapies.

Gene	Key polymorphism	Pharmacogenetic effect in asthma
β2-adrenergicreceptor agonists (e.g., salbutamol and salmeterol)
ADRB2	Arg16GlyGln27GluPolyC (3´UTR)	Mixed reports (see text)Mixed reports (see text)Counteracts ADRB2 downregulation
ARG I	rs2781659 (5´ region)	Haplotypes increase ARG1 transcription, leading to improved response to β2AR agonist
GSNOR	rs1154400(5´ region)	Differential response to β2AR agonistGSNOR haplotypes determine GSNOR transcription
Leukotriene modifiers (e.g., montelukast, zarfirlukast and zileuton)
ALOX5	rs2115189 (intronic)rs4987105 (Thr120Thr)rs4986832 (5´ region)	Causes a differential response to zileuton and montelukast therapy (FEV1 change)Cause differential response to montelukast therapy (FEV1 change)
LTC4S	A-444Crs272431 (intronic)	Associated with LTRA and LTSI response (FEV1 change) in some but not all studiesCauses a differential response to zileuton therapy (FEV1 change)
CYSLT2	rs91227 (3´ UTR)rs912278 (3´ UTR)	Associated with morning PEF in subjects taking montelukast
MRP1	rs119774 (intronic)	Causes a differential response to zileuton and montelukast therapy (FEV1 change)
OATP2B1	rs12422149 (Arg312Gln)	Reduced morning plasma concentrations of montelukast, resulting in lack of clinical benefit
Corticosteroids (e.g., prednisolone and beclomethasone)
CRHR1	rs242941 (intronic)	Associated with corticosteroid response (FEV1 change)
TBX21	rs224001 (His33Gln)	Improvements in BHR with corticosteroid treatment
NK2R	rs7703891 (Gly231Glu)	Improved asthma control with corticosteroid treatment
STIP1	rs4980524 (intron 1)rs6591838 (intron 1)rs2236647 (intron 5)	Associated with corticosteroid response (FEV1 change)
DUSP1	rs881152 (5´ region)	Associated with bronchodilator response and asthma control in the presence of corticosteroids
FCER2	rs28364072 (intronic)	Associated with asthma exacerbations in the presence of corticosteroids
GLCCI	rs37972 (5´ region)	Associated with corticosteroid response (FEV1 change); potential transcriptional mechanism

β₂AR: β₂-adrenergic receptor; BHR: Bronchial hyper-responsiveness; FEV₁: Forced expiratory volume in 1 s; LTRA: Leukotriene receptor antagonist; LTSI: Leukotriene synthesis inhibitor; PEF: Peak expiratory flow; UTR: Untranslated region.

Table 2. Asthma susceptibility genes recently identified by genome-wide association studies.

Gene/region	Chromosome	Function	Ref.
IL6R	1q21	Regulatory T-cell function, T-cell differentiation	[9]
DENND1B	1q31	Memory T cell functions	[8]
IL1RL1	2q11	IL-33 receptor, recruitment/activation of inflammatory cells	[5,7]
PDE4D	5q12	Modulates cAMP, role in cell signaling, inflammation and airway smooth muscle function	[6]
TSLP	5q22	Activates dendritic cells, role in Th2 immune responses	[5]
HLA-DQ	6p21	Cell membrane alloantigens, T-cell responses	[5]
IL-33	9p24	Produced by airway structural cells, recruitment/activation of inflammatory cells	[5,7]
LRRC32	11q13	Regulatory T-cell function	[9]
SMAD3	15q22	TGFβ signalling intermediate, fibrosis	[5]
ORMDL3/GSDMB	17q21	Sphingolipid synthesis (ORMDL3), cell apoptosis? (GSDMB)	[4,5,8]
IL2RB	22q12	Binds IL-2/IL-15, lymphoid cell differentiation	[5]

Genes focused on those meeting conventional genome-wide significance (p < 10^-8) and/or independent replication.

Ferreira MA, Mcrae AF, Medland SE et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur. J. Hum. Genet.19(4), 458–464 (2011).

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