Genetic diversity of present-day populations reflects the historical, demographic and evolutionary events. Genetic specificities are especially present in isolated populations in which the gene flow is minimal (Jewish populations, the Saami, the Roma, Bask and Croatian island isolates) and rare or private mutations are more frequent. The Roma are an example of founder population in which the century-long socio-cultural isolation has left traces in the gene pool, visible in the notable genetic distinctiveness of the Roma compared to other populations.
ADME genes, responsible for the absorption, distribution, metabolism and excretion of drugs, show significant variations between populations. Despite their confirmed functional role, an insight into their distribution in isolated populations is very limited. Hence this project is aimed at investigating ADME gene polymorphisms by means of analysis of basic ADME markers and gene CYP2D6 and CYP1A2 in a sample of 300 people, members of three different Croatian Romani groups. The main objective of the project is to determine the variation in ADME genes in the Roma population in order to determine the impact of the multiple founder effect, bottleneck, isolation and endogamy on this important gene group. Both publicly available data on the Roma population and the data obtained from our longstanding extensive molecular-genetic and epidemiological studies of the Roma population indicate a specific demographic history, frequent endogamy and a high degree of isolation in the Roma population, which make the selected sample an informative model for this type of research.
To accomplish our goals we will genotype the genetic markers – single nucleotide polymorphisms (SNPs) and short In/Del loci, taken from a list of basic ADME genetic markers (available on www.pharmadme.org) and sequence CYP1A2 and CYP2D6 genes. Based on these data we will define the intra- and inter-population structure and determine the age of recently found mutations in order to obtain information on their temporal and spatial features. Furthermore, the new haplotypes and private variants will undergo in silico functional analysis.
We expect to find a specific distribution of alleles of the investigated ADME gene loci, genetic characteristics that reflect the Indian origin of the Roma, as well as indicators of gene flow between the Roma and other populations with whom they came into contact in the course of migration from India to Europe. The newly established ADME genetic profile characteristic of the Roma population will be important for everyday medical practice in the modulation of pharmacotherapy. In addition, the obtained results will contribute to completing the picture of pharmacogenetic variation in ADME genes in the Roma and will facilitate the application of this knowledge in the development of pharmacogenetic tests specific to this minority population which numbers more than 15 million people throughout the world. We expect that the results will highlight the population specificity of ADME genes and encourage the implementation of such research in other isolated populations.