Table 2
The physical coverage of CYP2C8. CYP2D6 and CYP3A pharmacogenetic variants by genotyping chips
|
Omni 1S
|
Omni 2,5S
|
Omni 2,5
|
Omni 5
|
Axiome
|
Physical coverage
|
1/34
2.94%
|
4/34
11.76%
|
5/34
14.71%
|
8/34
23.53%
|
18/34
52.94%
|
As shown in the previous table, from the genotyping technologies, we see that the Axiom and the Omni 5.0 has the best coverage of the Core list.
We took into consideration the coverage that can be achieved by LD with the variants of the ADME lists (Table 3).
Table 3
The coverage of CYP2C8. CYP2D6 and CYP3A pharmacogenetic variants by genotyping chips when considering LD
|
Omni 1S
|
Omni 2.5S
|
Omni 2.5
|
Omni 5
|
Axiome
|
COVERAGE WIth ld
|
2/34
5.88%
|
14/34
41.18%
|
10/34
29.41%
|
20/34
58.82%
|
30/34
88.24%
|
As shown in the table, even by taking into consideration the SNPs of Omni platforms which are in LD with the variants of ADME list, the coverage rates increase only slightly, and therefore stays sub-optimal. Concerning the Axiome platform, the coverage taking into account the LD increases significantly up to 88.24%, that is to say a coverage of 30 among the 34 variants of our genes of interest. Even by taking into consideration the markers that are in LD, this list’s coverage rate has not reached 100% (Fig. 1).
Moreover, even by combining the five platforms, and taking LD into consideration, we will never be able to cover the two variants rs72549353 and rs72549357 (Table 4).
Table 4
Summary table of genotyping platforms coverage
For enrichment platforms, we relied on probes contained in these lists.
The coverage rates of the ADME genes by HaloPlex and SureSelect enrichment platforms are recorded in the following summary tables (Tables 5–6).
Table 5
coverage rate of CYP2C8. CYP2D6 and CYP3A pharmacogenetic variants by HaloPlex
Target ID
|
Regions
|
Coverage
|
High Coverage
( > = 90%)
|
Low Coverage
(< 90%)
|
CYP2C8
|
5
|
100%
|
5
|
0
|
CYP2D6
|
20
|
85%
|
17
|
3
|
CYP3A4
|
4
|
75%
|
3
|
1
|
CYP3A5
|
5
|
100%
|
5
|
0
|
Table 6
coverage rate of CYP2C8. CYP2D6 and CYP3A pharmacogenetic variants by SureSelect
Target ID
|
Regions
|
Coverage
|
High Coverage
( > = 90%)
|
Low Coverage
(< 90%)
|
CYP2C8
|
5
|
100%
|
5
|
0
|
CYP2D6
|
20
|
95%
|
19
|
1
|
CYP3A4
|
4
|
100%
|
4
|
0
|
CYP3A5
|
5
|
100%
|
5
|
0
|
As we can infer, from enrichment lists previously described, the SureSelect platform allows the best coverage of the ADME variants, up to 33 among the 34 variants of our genes of interest (97.05%), wich is sufficiently to conduct pharmacogenomics studies with this tool.
Due to technological limitations, complex genomic regions, including certain ADME genes, are generally excluded from high-throughput genotyping and sequencing chips [18].
Although the quality of clustering is generally good for the vast majority of genetic variants present on such commercial platforms, it is not uncommon for clustering to function poorly in highly homologous genomic regions such as those of several ADME genes, including, but not limited to, CYP2C8, CYP2D6, CYP3A4 or CYP3A5 [8].
Previous studies have shown the limitations of genome-wide methods for pharmacogenomic testing. Gamazon et al. [19] focused on one set of genes most important in pharmacogenomics and personalized medicine, using only genotyping platforms. Their results demonstrated that even taking into account the SNPs that are in LD, the rate of coverage of these genes by genotyping platforms is sub-optimal.
In another study [7], they also evaluated the sequencing platforms. The HaloPlex enrichment platform enabled the best coverage of ADME variants. But this coverage remains for all of the ADME genes.
There are also chips marketed with targeted pharmacogenetic content, such as the DMET panel (Enzymes and transporters metabolizing metabolics of Affymetrix) or the iPLEX PGx Pro panel from Agena, which provide targeted coverage of the most difficult pharmacogenetic variants. However, these panels have not been examined here since they do not offer genomic coverage, but they could possibly be used as complementary tests in addition to a genomic set in the context of pharmacogenomic studies [20].