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| 3’-UTR (G3673A; rs992323) - Low warfarin dose phenotype - 90% Asians and 40% Caucasians - AA genotype at the highest risk for warfarin-related adverse events |
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| intron 1 (C6484T; rs9934438) - low-dose warfarin phenotype |
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| 3′-UTR (G9041A; rs7294) - Associated with a higher warfarin dose - Generally not found in the same haplotypes as -1639G>A or 1173C>T |
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Some mutations in the VKORC1 gene are associated with familiar multiple coagulation factor deficiency type 2 and warfarin resistance in rats.
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VKORC1 haplotypes are the major contributor to warfarin dose variability (21−25%).
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Distribution of high and low dose haplotypes is different in Europeans, Africans, and Asians and may account for observed differences in average warfarin dose.
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Patients with the -1639A and 1173T allele require a lower warfarin dose (mean dose 24–26 mg/week) compared with 35 mg/week for the wild-type carriers. Patients with 3073A need a higher warfarin dose (mean dose 40 mg/week).
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Incorporating VKORC1 and CYP2C9 genotype information and clinical factors such as age and weight into the warfarin dosing equation holds great promise to select the optimal dose for the individual patient at the start of warfarin therapy. |
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| thiazolidinediones, NSAIDs, indoles. |
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| Response to Rosiglitazone PPAR-γ |
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The decrease in FPG and HbA1c is significantly greater in carriers with the Ala12 allele than WT.
•The response rate is greater in Pro12 Ala genotype group than WT. |
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| Response to Pioglitazone PPAR-γ |
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Definition
A total of 131 patients were treated with pioglitazone (45 mg o.d.) during a course of ≥26 weeks.
Response to the pioglitazone therapy was defined by either a >20% decrease in fasting plasma glucose or a >15% decrease in HbA1c values after 26 weeks of pioglitazone treatment.
The Pro12Ala and the Pro12Pro variants in the PPARG gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes. |
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| Edema Caused by Rapaglitazar PPAR-γ |
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At 26 wk, edema was recorded in 48 of the patients (14%) treated with ragaglitazar.
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Cox regression analyses identified the common Pro12Ala variant of the PPARG gene as the most important risk factor (hazard ratio 4.42) for edema.
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Other risk factors included female gender & weight change during treatment.
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Testing for the Pro12Ala of the PPARG gene in addition to the already identified clinical risk factors may become a useful tool to further reduce the risk of PPARγ agonist-induced fluid retention and edema in patients with type 2 diabetes. |
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Several SNPs have been identified in the PPARG gene. Of which, Pro12Ala has a frequency of 12% in Caucasians and 1-4% in Asians. This SNP appears to lead to a reduced risk of NIDDM.
Several clinical studies indicate that this SNP also enhance the clinical therapeutic efficacy to glitazone therapy; but negative results have been also reported.
Pro12Ala variant of the PPARG gene is also the most important risk factor for rapaglitazar-induced edema. |
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CFTR potentiator for wild-type and G551D-CFTR only. No effect for homozygous F508del mutation in CFTR.
Phase III study: a 10.6% mean absolute improvement in baseline lung function over 24 weeks.
Primarily metabolized by CYP3A; M1 (active) and M6 as major metabolites. |
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Definition
oGuanine nucleotide binding protein (G-protein).
oExpressed in airway smooth muscle and target for the β-agonists used in treating bronchospasm.
oExpressed in blood vessel walls and target for antihypertensives.
oMany SNPs have been found within the gene and its upstream regulatory regions.
oThese SNPs have been organized into a series of haplotypes.
ADRB2 Arg16Gly allele frequencies were 0.49 and 0.37 among blacks and whites.
Among black subjects with β-agonist use at baseline (n = 63), those with the Arg/Arg genotype had better baseline lung function than those with Arg/Gly or Gly/Gly genotypes.
No difference in lung function by genotype among white subjects with β-agonist use at baseline.
No difference in lung function by genotype among non-users of β-agonists of either race.
FEV1 = forced expiratory volume in 1 second. |
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| individuals improved during placebo use when albuterol use was limited. |
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individuals improved with regular albuterol use compared with placebo.
Gly/Gly homozygotes responded better than Arg/Arg homozygotes. |
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| ADRB2 Arg16Gly Polymorphism |
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Definition
β-Agonists are a mainstay of asthma treatment and are important for symptom control.
β-Agonist-induced activation of ADRB2 causes the dilatation of airway smooth muscle.
Heavy β-agonist use may cause fatal asthma exacerbations, although this association remains controversial.
The Arg16Gly polymorphism of ADRB2 is associated with increased receptor down-regulation compared to WT (26% vs 41%).
Of the Arg16 allele is about 39−42% in whites and ∼49% in blacks.
Asthma patients with the Arg/Arg genotype may experience adverse effects from β-agonist use, including deterioration of lung function.
Arg16 allele is associated with clinically significant, unsatisfactory response to β-agonists and less survival.
The Gly16 allele predisposes to nocturnal asthma and asthma severity.
Growing evidence suggests that it plays an important role in β-agonist response. |
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Each of the 10 identified SERT SNPs is separately transfected into HeLa cells, and 5-HT transport activity is assessed.
Five variants (Thr4Ala, Gly56Ala, Ser293Phe, Leu362Met, and Ile425Val) displayed enhanced 5-HT transport activity relative to WT.
One variant (Pro339Leu) displayed markedly reduced uptake activity.
Ile425Val is associated with obsessive-compulsive disorder (OCD). |
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| SERT Promoter VNTR Polymorphism |
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Definition
common VNTR polymorphism in the promoter of the SERT gene.
SERT/SLC6A4 is expressed at higher levels if the 42 bp insertion ("long") is present (16 vs 14 repeat).
The "Short" allele increases risk of anxiety, depression, bipolar disorder, autistic disorder and violent suicide. |
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Both l/l and l/s subjects had significantly better scores than s/s starting from week 2 to 6 when treated with fluvoxamine alone.
In patients treated with fluvoxamine plus pindolol, no significant difference among genotype groups was observed − The addition of pindolol abolished the differences of response to fluvoxamine. |
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Solute carrier
Same as SERT |
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| summary on SERT/SLC6A4 Promoter VNTR Polymorphism |
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Definition
SSRIs are thought to act through inhibition of the 5-HT transporter, so a genetic variant that affects the expression of this protein could affect treatment response.
There is a common VNTR deletion/insertion polymorphism in the promoter of the SERT/SLC6A4 gene. SERT is expressed at a higher level if the “long" is present.
The “short” form of a polymorphism in the promoter region of SERT/SLC6A4 impaired the efficacy of fluvoxamine in a group of 53 patients with major depression. The same effect of the SERT/SLC6A4 long/short promoter polymorphism was reported in a study of 51 geriatric patients with major depression treated with paroxetine. Zanardi et al. confirmed this finding in a group of 60 paroxetine-treated depressed patients.
However, Minov et al. found no effect of the SLC6A4 promoter polymorphism on response in 104 patients receiving a variety of antidepressant treatment regimens.
Kim et al. studied 120 Korean patients treated with fluoxetine or paroxetine and found that the short variant of the SLC6A4 promoter was associated with a better treatment response. A similar result was obtained by Yoshida et al. with Japanese patients.
One explanation for these results may be that the effect of the SERT/SLC6A4 promoter is dependent on ethnics.
The effect of SERT/SLC6A4 promoter variant on SSRI treatment is the most robust antidepressant pharmacogenetic finding to date.SSRIs are thought to act through inhibition of the 5-HT transporter, so a genetic variant that affects the expression of this protein could affect treatment response.
There is a common VNTR deletion/insertion polymorphism in the promoter of the SERT/SLC6A4 gene. SERT is expressed at a higher level if the “long" is present.
The “short” form of a polymorphism in the promoter region of SERT/SLC6A4 impaired the efficacy of fluvoxamine in a group of 53 patients with major depression. The same effect of the SERT/SLC6A4 long/short promoter polymorphism was reported in a study of 51 geriatric patients with major depression treated with paroxetine. Zanardi et al. confirmed this finding in a group of 60 paroxetine-treated depressed patients.
However, Minov et al. found no effect of the SLC6A4 promoter polymorphism on response in 104 patients receiving a variety of antidepressant treatment regimens.
Kim et al. studied 120 Korean patients treated with fluoxetine or paroxetine and found that the short variant of the SLC6A4 promoter was associated with a better treatment response. A similar result was obtained by Yoshida et al. with Japanese patients.
One explanation for these results may be that the effect of the SERT/SLC6A4 promoter is dependent on ethnics.
The effect of SERT/SLC6A4 promoter variant on SSRI treatment is the most robust antidepressant pharmacogenetic finding to date. |
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