Annotation of rs3814058

Genotype CC is associated with decreased metabolism of repaglinide in men as compared to genotype TT.

Comparisons are between groups that are classified by their genotypes at TWO SNPs: rs2276706 AND rs3814058. These results are for volunteers who received repaglinide and placebo. The study was randomized, in two-phase and crossover with a 2-week washout period. Volunteers received placebo or flucloxacillin 2 times daily for 6 days. On day 7 volunteers were given repaglinide and a meal 3 hours later. Venous blood samples were collected before and after repaglinide at multiple time points.The only significant difference was when comparing Group A, the homozygous wild type genotypes (rs2276706 AA/ rs3814058 TT) to Group D, the homozygous variant genotypes (rs2276706 TT/ rs3814058 CC).

From Publication

PXR polymorphisms and their impact on pharmacokinetics/pharmacodynamics of repaglinide in healthy Chinese volunteers. European journal of clinical pharmacology. 2013. Du Qing-qing et al.
PMID:23807564(opens in new window) DOI:10.1007/s00228-013-1552-2(opens in new window)

Gene

NR1I2

Variant

rs3814058

Phenotype Category

Metabolism/PK

Association Significance

The study reports this association is significant

PharmGKB ID

1184754529

Score
More info on scoring

1.5

Evidence for Clinical Annotations

This annotation has been used as evidence for the following clinical annotations.

    Study Parameters

    1.

    Study type

    cohort

    Study size

    24

    Association p-value

    = 0.014

    Allele frequency

    C=0.49; T=0.51

    Biogeographical group
    More info on groups

    East Asian

    Population description

    men

    Drug: repaglinide; the half life of repaglinide was significantly longer for Group D (rs2276706 GG and rs3814058 CC) compared to Group A (rs2276706 AA and rs3814058 TT).

    2.

    Study type

    cohort

    Study size

    24

    Association p-value

    = 0.026

    Allele frequency

    C=0.49; T=0.51

    Biogeographical group
    More info on groups

    East Asian

    Population description

    men

    Drug: repaglinide; the AUC for repaglinide was significantly higher for Group D (rs2276706 GG and rs3814058 CC) than it was for Group A (rs2276706 AA and rs3814058 TT).

    3.

    Study type

    cohort

    Study size

    24

    Association p-value

    = 0.041

    Allele frequency

    C=0.49; T=0.51

    Biogeographical group
    More info on groups

    East Asian

    Population description

    men

    Drug: repaglinide; Group D (rs2276706 GG and rs3814058 CC) had a significantly lower oral clearance (a high dose/AUC ratio) when compared to Group A (rs2276706 AA and rs3814058 TT).

    Note: Alleles in PharmGKB are mapped to the positive chromosomal strand. Therefore, variants in genes on the "minus" strand (eg. VKORC1) are complemented in PharmGKB annotations.

    History

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