The two SNPs rs rs presented above are
The two SNPs rs4818-rs4680 presented above are part of the haploblock (rs6269, rs4633, rs4818, rs4680) presenting the 3 major haplotypes which influence the enzymatic activity of COMT. This activity is inversely related to the sensitivity of pain in a chronic pain syndrome; so the haplotype (GCGG) has a high activity associated with low pain sensitivity (LPS), the haplotype (ATCA) has an intermediate activity with average pain sensitivity (APS); while the haplotype (ACCG) which has a low enzymatic activity, is considered associated with high pain sensitivity (HPS) (Diatchenko et al., 2005; Nackley et al., 2006).
Haplotype activity can be predicted according to a classification found in the pharmacogenomics database PharmGKB (https://www.pharmgkb.org/haplotype/PA165947990), this classification was based on previous studies (Nackley et al., 2006; Bitsios and Roussos, 2011).
Moreover, micro-haplotypes from COMT gene are very powerful forensic markers since the SNPs that constructed them are very close with an extremely low recombination rate, which makes it possible to distinguish between human groups and justifies their major utility in genetic anthropology (Kidd et al., 2013; Kidd et al., 2017). Haplotypes from the COMT gene have been used already as micro-haplotypes in a panel developed by the Kidd Lab (Kidd et al., 2014) and they can be found in the ALFRED database (https://alfred.med.yale.edu/alfred/microhaps.asp). The distance between the two SNPs rs4818-rs4680 is 65 bp and their micro-haplotype name is mh22KK-060. These haplotypic markers give more informative results than those found by the use of single SNPs.
There is very little data about the COMT gene polymorphism in North African populations, only one recent work done on Tunisian patients with cancer studied the effect of rs4680 of the COMT gene on Mu opioid vadadustat function and the clinical efficacy of morphine without finding any association (Chatti et al., 2016; Chatti et al., 2017).
Materials and methods
Discussion The SNP allelic haplotypic frequencies analysis according to PCA and to distance from centroid and the heterozygosity displayed three main features on North African populations. First, similarities among most of the North African populations is revealed. Second the level of heterozygosity suggested the great level of admixture of the North African populations. Third, the allelic and haplotypic frequencies of the North African populations are similar to those of Europe and Southwest Asia but are very distinct from Sub-Saharan Africans and East Asians. Our results are in agreement with those found by Mukherjee et al. (2010) though deriving from different haplotype combinations of the COMT gene (Mukherjee et al., 2010).They are also consistent with previous studies using other markers (Elkamel et al., 2017; Frigi et al., 2017; Hajjej et al., 2017; Elkamel et al., 2018) and in agreement with the settlement history of these populations. Since North Africa has a complex human demographic history, many waves of migrations have colonized pepsinogen region from Africa, Europe and the Middle East (Cherni et al., 2016) during pre-historic and modern times. In this work, clustering of populations according to their geographic origin was more clearly visualized using haplotypic frequencies than the Fst distance matrix data based on individual SNP frequencies which shows the greater informativity of using haplotypes to distinguish between populations of different ethnicity or geographic origin. The distinctive geographical clustering of populations from different continental regions is quite impressive considering that these results are based on variation of only 4 SNPs at one gene. Such results usually are not seen until one includes data from many, often dozens, of independent polymorphisms. Since other studies have also shown that COMT gene frequencies differ according to ethnicity (Palmatier et al., 1999; DeMille et al., 2002; Mukherjee et al., 2010; Gonzalez-Castro et al., 2013) in populations sampled worldwide. COMT gene polymorphism could be useful for forensic studies.