von Ahsen Nicolas, Tzvetkov Mladen, Karunajeewa Harin A, Gomorrai Servina, Ura Alice, Brockmöller Jürgen, Davis Timothy M E, Mueller Ivo, Ilett Kenneth F, Oellerich Michael
Int J Mol Epidemiol Genet. 2010 Aug 18;1(4):310-9.
A high frequency of previously unknown CYP2D6 alleles have been reported in Oceania populations. Genetic and functional properties of these alleles remain unknown.
We performed analyses of the genetic variability of CYP2D6 and CYP2C19 genes using AmpliChip genotyping in cohorts from two distinct Papua New Guinea (PNG) populations (Kunjingini, n=88; Alexishafen, n=84) focussing on the genetic characterisation of PNG-specific alleles by re-sequencing.
Previously unknown CYP2D6 alleles have population frequencies of 24% (Kunjingini) and 12% (Alexishafen). An allele similar to CYP2D61, but carrying the 1661G>C substitution, was the second most frequent CYP2D6 allele (20% Kunjingini and 10% Alexishafen population frequency). Sequencing suggests the CYP2D6 1661G>C allele originated from a cross-over between CYP2D6*1 and *2 and thus is predicted to confer fully active CYP2D6 enzyme. Two additional predicted full activity alleles [1661G>C;4180G>C] and 31G>A were found in the Kunjingini cohort (frequencies 3 c/c and 1%, respectively) and a novel predicted reduced activity allele [100C>T;1039C>T] was found in the Alexishafen cohort (frequency 2%). A high frequency of ultra-rapid (15%) and notably low frequencies of intermediate and poor CYP2D6 metabolizers (<5%) and a high frequency of poor CYP2C19 metabolizers were observed in PNG. Both CYP2D6 and CYP2C19 showed heterozygote excess that may be explained by exogamy and recent introduction of alleles by migration that are yet to reach HWE in relatively isolated populations.
The CYP2D61661 allele common in Oceania may be regarded as functionally equivalent to the full activity CYP2D61 allele.
据报道，大洋洲人群中先前未知的CYP2D6等位基因频率较高。这些等位基因的遗传和功能特性尚不清楚。
我们使用AmpliChip基因分型技术，对来自巴布亚新几内亚（PNG）两个不同人群（昆吉尼尼，n = 88；亚历克西哈芬，n = 84）队列中的CYP2D6和CYP2C19基因的遗传变异性进行了分析，重点是通过重新测序对PNG特异性等位基因进行遗传特征分析。
先前未知的CYP2D6等位基因在昆吉尼尼人群中的频率为24%，在亚历克西哈芬人群中的频率为12%。一种与CYP2D61相似但携带1661G>C替换的等位基因是第二常见的CYP2D6等位基因（昆吉尼尼人群频率为20%，亚历克西哈芬人群频率为10%）。测序表明，CYP2D61661G>C等位基因起源于CYP2D61和2之间的交叉，因此预计可产生完全活性的CYP2D6酶。在昆吉尼尼队列中发现了另外两个预测的完全活性等位基因[1661G>C;4180G>C]和31G>A（频率分别为3%和1%），在亚历克西哈芬队列中发现了一个新的预测的活性降低等位基因[100C>T;1039C>T]（频率为2%）。在PNG人群中观察到超快速代谢者的高频率（15%）、中间代谢者和慢代谢者的低频率（<5%）以及慢代谢CYP2C19者的高频率。CYP2D6和CYP2C19均显示杂合子过剩，这可能是由于异族通婚以及相对隔离人群中通过迁移新近引入的等位基因尚未达到哈迪-温伯格平衡所致。
在大洋洲常见的CYP2D61661等位基因在功能上可能等同于完全活性的CYP2D61等位基因。
