Human Genetic Variation of CYP450 Superfamily

Table 1.  Significant CYP450 SNPs and their F-statistics.

ID (rs)	Gene	HBP	FST	FST p-value	FCT	FCT p-value
rs12141009	CYP4X1	0.515	0.275	0.009	0.259	0.004
rs1393667		0.482	0.298	0.005	0.251	0.006
rs9793471		0.458	0.292	0.004	0.241	0.006
rs2065996	CYP4B1	0.308	0.010	<0.001	0.001	0.002
rs4646487		0.293	0.018	<0.001	0.006	0.009
rs2855658	CYP1B1	0.474	0.328	0.002	0.304	0.002
rs9349367	CYP39A1	0.277	0.027	0.001	0.006	0.009
rs9349368		0.256	0.043	0.008	0.000	0.007
rs4646437	CYP3A4	0.446	0.359	0.001	0.290	0.001
rs10225908	CYP3A43	0.259	0.363	0.002	0.320	0.002
rs472660		0.348	0.455	<0.001	0.417	<0.001
rs585071		0.305	0.488	<0.001	0.432	<0.001
rs678040		0.260	0.364	0.002	0.321	0.002
rs4646450	CYP3A5	0.509	0.384	0.001	0.337	0.001
rs776746		0.442	0.313	0.002	0.242	0.004
rs1557967	TBXAS1	0.358	0.030	<0.001	0.000	0.009
rs4726473		0.360	0.014	<0.001	0.003	0.004
rs4737681	CYP7B1	0.416	0.338	0.002	0.308	0.002
rs7916649	CYP2C19	0.655	0.390	<0.001	0.014	0.010
rs1329149	CYP2E1	0.404	0.281	0.009	0.270	0.004
rs915906		0.456	0.285	0.004	0.251	0.004
rs2060793	CYP2R1	0.453	0.009	<0.001	0.001	0.001
rs4646537	CYP27B1	0.054	0.007	0.001	0.001	0.008
rs12435918	CYP46A1	0.443	0.029	<0.001	0.004	0.004
rs7157032		0.492	0.016	<0.001	0.004	0.006
rs508757	PTGIS	0.395	0.284	0.009	0.262	0.005

F_CT: Fixation index among defined groups; F_ST: Fixation index among populations; H_BP: Heterozygosity between populations.

Authors and Disclosures

Renato Polimanti*¹, Sara Piacentini¹, Dario Manfellotto² & Maria Fuciarelli<sup>1

1</sup>Department of Biology, University of Rome, "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy
²Clinical Pathophysiology Center, "San Giovanni Calibita" Fatebenefratelli Hospital – Associazione Fatebenefratelli per la Ricerca, Isola Tiberina, Rome, Italy

Financial & competing interests disclosure
This work was supported by the RSA Grant 2009 –University of Rome 'Tor Vergata' to M Fuciarelli and by the PRIN 2009 grant (prot. n. 200975T9EW). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

*Author for correspondence
Tel.: +39 067 259 4310 Fax: +39 062 023 500 renatopolimanti@alice.it

Sidebar

Executive Summary

Background

• The CYP450 superfamily plays a key role in the metabolism of both endogenous and exogenous molecules, such as steroids, fatty acids, carcinogens, toxins and 90% of drugs currently in use.

• A vast literature details the effects of CYP450 gene variation in different medical care areas, such as disease-causing variants and variants associated with drug response.

• To the best of our knowledge, although several studies have investigated ethnic differences in different CYP450 genes, none have provided an analysis of the entire CYP450 superfamily.

Materials & Methods

• A computational analysis of genetic and functional differences of the 57 CYP450 genes using the Human Genome Diversity Project and HapMap data was performed.

Results

• Our results highlighted that ethnicity is an influencing factor in CYP450 variability. In particular, we identified 26 CYP450 SNPs with F-statistics significantly different compared with the general distribution. Some showed high differentiation among human populations, whereas the others showed low differentiation.

• Among the highly-differentiated SNPs, some are associated with important health aspects: rs4646437 with cyclosporine response, rs472660 with olanzapine response, rs4646450 with warfarin response, rs776746 with calcineurin inhibitor response, rs1329149 with colorectal cancer and rs915906 with nasopharyngeal carcinoma.

• The analysis of Integrated Haplotype Score in SNPs with significant F-statistics highlighted that some CYP450 genes ( TBXAS1 and genes in CYP3A cluster) may be involved in selection processes.

Conclusion

• The present study highlights how the population history affects human CYP450 variation and how this variation may influences human health, identifying health aspects strongly differentiated among individuals with different ethnic origins.