Low nucleotide variability of CYP51A1 in humans: meta-analysis of cholesterol and bile acid synthesis and xenobiotic metabolism pathways.

Lanosterol 14a-demethylase CYP51 is the most conserved cytochrome P450 (CYP) and is a part of hepatic cholesterol synthesis. Other liver CYPs contribute to cholesterol detoxification through bile acids or to xenobiotic detoxification (DM). To get novel insights into characteristics of the CYP51A1 locus that was so far not linked to human disorders we performed a meta-analysis of CYP51A1 gene polymorphisms in comparison to other liver CYPs and other genes of cholesterol synthesis. Cholesterol linked genes are generally less polymorphic than DM CYPs, with less coding variants, indicating differences in selection pressure between cholesterol and xenobiotic pathways. Among the studied liver CYPs, CYP51A1 has the lowest number of coding variants, and less common variants compared to average for cholesterol synthesis. We were not able to detect other functional molecules within the CYP51 gene (such as lincRNA or miRNA), so we looked into the entire gene locus. We found the AL133568 sequence that overlaps with the CYP51A1 promoter region. Our hypothesis was that the AL133568 transcript may have a role in regulating CYP51A1 expression, but we were unable to prove this experimentally. The reason for the low population variability of the human CYP51A1 thus remains uncertain.