Post by Admin on Jul 20, 2022 17:31:12 GMT
The clinically relevant CYP2C8*3 and CYP2C9*2 haplotype is inherited from Neandertals
Abstract
Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals.
Introduction
The admixture between Neandertals and modern humans that took place ~60,000 years ago introduced genetic variants into the gene pool of modern humans, many of which are still found at low frequencies among present-day people [1]. Prior to what is now estimated to be several admixture events between Neandertals and modern humans, these two groups evolved largely independently of each other for ~500,000 years [2]. During this time, both groups accumulated genetic variants that differed from the ancestral states seen in other primates. Whereas modern humans evolved on the African continent, Neandertals evolved in Eurasia. The different habitats of these two groups might have exerted different evolutionary pressures, leading to the fixation of genetic variants advantageous in the respective environments. Other variants, even slightly deleterious variants, reached fixation due to genetic drift, particularly in periods when population sizes were small. Genetic evidence suggests that the effective population size of Neandertals was considerably smaller than that of modern humans [3].
The CYP2C9 gene, which encodes the cytochrome P450 enzyme CYP2C9, is highly polymorphic in present-day humans. More than 20 single nucleotide polymorphisms (SNPs) affecting the enzymatic activity of CYP2C9 have been reported. Importantly, people with lower enzymatic activity are at risk of toxic reactions from standard doses of warfarin and phenytoin, which are substrates of the enzyme [4]. The most frequent CYP2C9 allele, CYP2C9*1, is present at a frequency of 88 % in European populations [5]. The variant CYP2C9*2 with a cysteine replacing an arginine at position 144 in the encoded protein (R144C) at a frequency of 12% in Europe [5]. Its enzyme activity is reduced by ~70% relative to the common CYP2C9*1 allele [6]. Thus, carriers of CYP2C9*2, particularly if homozygous, have been denoted “slow metabolizers” [6].
Approximately 50 kilobases upstream of the CYP2C9, is the gene CYP2C8, which encodes the cytochrome CYP2C8. This enzyme is a crucial part of the metabolism of several pharmacological agents [7] including antidiabetic drugs (e.g., pioglitazone), statins (e.g., cerivastatin), anti-inflammatory drugs (e.g., ibuprofen) and chemotherapeutic agents (e.g., paclitaxel). The most studied allele in CYP2C8 is CYP2C8*3, which is characterized by the replacement of an arginine by a lysine at position 139 and a lysine by an arginine at position 399 (R139K and K399R) in the encoded protein. The effect of these variants are substrate dependent, with increased metabolism of drugs such as pioglitazone but decreased metabolism of R-ibuprofen [7]. The two variants in CYP2C8, as well as the R144C variant in CYP2C9, differ not only from the most common alleles in humans but also from the alleles present in apes and humans indicating that they are “new”, i.e., “derived”, changes that occurred recently in evolutionary terms.
The two variant alleles CYP2C9*2 and CYP2C8*3 have previously been shown to frequently co-segregate in families [8]. However, the distance between the R144C variant (chr10:96,702,047_C>T, hg19), defining CYP2C9*2, and the variant K399R (chr10:96,798,749_T>C, hg19), one of the two variants defining the CYP2C8*3 allele, is 96.7 kilobases. Thus, if these variants co-segregate they are present on an unusually long haplotype. Some such long haplotypes have been introduced by gene flow from Neandertals [1]. Here we verify the co-inheritance of these two alleles in large databases and test the hypothesis that this long haplotype is inherited from Neandertals.
Abstract
Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals.
Introduction
The admixture between Neandertals and modern humans that took place ~60,000 years ago introduced genetic variants into the gene pool of modern humans, many of which are still found at low frequencies among present-day people [1]. Prior to what is now estimated to be several admixture events between Neandertals and modern humans, these two groups evolved largely independently of each other for ~500,000 years [2]. During this time, both groups accumulated genetic variants that differed from the ancestral states seen in other primates. Whereas modern humans evolved on the African continent, Neandertals evolved in Eurasia. The different habitats of these two groups might have exerted different evolutionary pressures, leading to the fixation of genetic variants advantageous in the respective environments. Other variants, even slightly deleterious variants, reached fixation due to genetic drift, particularly in periods when population sizes were small. Genetic evidence suggests that the effective population size of Neandertals was considerably smaller than that of modern humans [3].
The CYP2C9 gene, which encodes the cytochrome P450 enzyme CYP2C9, is highly polymorphic in present-day humans. More than 20 single nucleotide polymorphisms (SNPs) affecting the enzymatic activity of CYP2C9 have been reported. Importantly, people with lower enzymatic activity are at risk of toxic reactions from standard doses of warfarin and phenytoin, which are substrates of the enzyme [4]. The most frequent CYP2C9 allele, CYP2C9*1, is present at a frequency of 88 % in European populations [5]. The variant CYP2C9*2 with a cysteine replacing an arginine at position 144 in the encoded protein (R144C) at a frequency of 12% in Europe [5]. Its enzyme activity is reduced by ~70% relative to the common CYP2C9*1 allele [6]. Thus, carriers of CYP2C9*2, particularly if homozygous, have been denoted “slow metabolizers” [6].
Approximately 50 kilobases upstream of the CYP2C9, is the gene CYP2C8, which encodes the cytochrome CYP2C8. This enzyme is a crucial part of the metabolism of several pharmacological agents [7] including antidiabetic drugs (e.g., pioglitazone), statins (e.g., cerivastatin), anti-inflammatory drugs (e.g., ibuprofen) and chemotherapeutic agents (e.g., paclitaxel). The most studied allele in CYP2C8 is CYP2C8*3, which is characterized by the replacement of an arginine by a lysine at position 139 and a lysine by an arginine at position 399 (R139K and K399R) in the encoded protein. The effect of these variants are substrate dependent, with increased metabolism of drugs such as pioglitazone but decreased metabolism of R-ibuprofen [7]. The two variants in CYP2C8, as well as the R144C variant in CYP2C9, differ not only from the most common alleles in humans but also from the alleles present in apes and humans indicating that they are “new”, i.e., “derived”, changes that occurred recently in evolutionary terms.
The two variant alleles CYP2C9*2 and CYP2C8*3 have previously been shown to frequently co-segregate in families [8]. However, the distance between the R144C variant (chr10:96,702,047_C>T, hg19), defining CYP2C9*2, and the variant K399R (chr10:96,798,749_T>C, hg19), one of the two variants defining the CYP2C8*3 allele, is 96.7 kilobases. Thus, if these variants co-segregate they are present on an unusually long haplotype. Some such long haplotypes have been introduced by gene flow from Neandertals [1]. Here we verify the co-inheritance of these two alleles in large databases and test the hypothesis that this long haplotype is inherited from Neandertals.