016P Brighton
Winter Meeting December 2008

Genetic variability in PXR, MDR-1, CYP3A4 and CYP2B6 in HIV infected Caucasian and sub-Saharan African patients - benefits from a cohort approach

Jenny Svard1, Paul Spiers1, Fiona Mulcahy2, Martina Hennessy1

1Trinity College, Dublin, Ireland, 2St James’s Hospital, Dublin, Ireland

Despite research advances, antiretroviral (ARV) drug interactions and toxicities remain unpredictable. ARVs increase expression of CYP450 enzymes by activation of nuclear receptors PXR and CAR, altering drug metabolism. Genetic variation in the regulatory genes and their targets may further enhance this effect. The Dublin HIV cohort encompasses 1200 patients, predominantly Caucasians (C) and first generation Sub-Saharan Africans (SSA) - the latter group being underrepresented in clinical and genetic studies and often limited by small study sizes. This study comprehensively investigates the frequency distribution of a range of potentially functional and clinically relevant SNPs in PXR, MDR-1, CYP3A4 and CYP2B6 in HIV infected patients.

750 patients (37% SSAs) were included. DNA was isolated from blood and genotyped for 34 SNPs in the PXR (15), CYP3A4 (9), CYP2B6 (5) and MDR-1 (5) promoter and coding regions, chosen based on association with altered expression/activity or ARV plasma drug levels. Differences in allele frequencies between ethnic groups were compared by the χ2 test.

The frequency distributions of 21 SNPs were significantly different (p<0.05) between C and SSA patients (presented in Table 1), 4 previously unreported in SSAs (*).

Table 1PXRC/SSAMDR-1C/SSACYP3A4C/SSACYP2B6C/SSA
Promoter -25564(G/A) 0.02 / 0.002 -129(T/C)* 0.04 / 0.13 insTGT* 0.04 / 0.00
-25385(C/T) 0.39 / 0.24 -392(A/G) 0.04 /0.74
-24756(G/A) 0.008 / 0.37
-24381(A/C) 0.40 / 0.88
Introns 0.003 / 0.12 0.03 / 0.002
79(C/T)
Exons 106(G/A) 0.39 / 0.96 61(A/G)* 0.10 / 0.004 683(C/T) 0.001/0.05 516(G/T) 0.23 / 0.39
7635(A/G) 0.19 / 0.40 1199(G/A)* 0.02 / 0.00 785(A/G) 0.28 / 0.41
8055(C/T) 0.19 / 0.51 2677(G/T) 0.45 / 0.05 983(T/C) 0.14 / 0.24
11156(A/C) (3’UTR) (3’UTR) 3435(C/T) 0.56 / 0.13 1459(C/T) 0.14 / 0.007

The results strengthen data from smaller studies of comparable groups. Importantly, over half the SNPs related to PXR and CYP2B6 had higher frequencies in SSAs compared to Caucasians. Given 2B6 induction is mainly mediated by PXR, multiple mutations in these genes may partly explain increased predisposition to toxicity in this group. Furthermore, some significant differences in allele frequency were noted between our SSA patients and mixed African American groups (c/w published literature). This requires further consideration. Our results provide a foundation on which functional studies of genetic variability related to drug disposition in distinct ethnic groups can be designed.