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. 2023 Sep 13;14(6):505–517. doi: 10.1007/s12687-023-00668-6

The Circassians and the Chechens in Jordan: results of a decade of epidemiological and genetic studies

Sara Abudahab 1,2, Nancy Hakooz 2, Laith Al-Etian 3, Kawkab Shishani 4, Adel Bashqawi 5, John Connolly 6, Joseph T Glessner 6,7,8, Hui-Qi Qu 6, Jingchun Qu 6, Hakon Hakonarson 6,7,8, Rana Dajani 9,✉
PMCID: PMC10725377  PMID: 37700208

Abstract

Circassians and Chechens in Jordan, both with Caucasian ancestry, are genetically isolated due to high rate of endogamous marriages. Recent interest in these populations has led to studies on their genetic similarities, differences, and epidemiological differences in various diseases. Research has explored their predisposition to conditions like diabetes, hypertension, and cancer. Moreover, pharmacogenetic (PGx) studies have also investigated medication response variations within these populations, and forensic studies have further contributed to understanding these populations. In this review article, we first discuss the background of these minority groups. We then show the results of a principle component analysis (PCA) to investigate the genetic relationships between Circassian and Chechen populations living in Jordan. We here present a summary of the findings from the 10 years of research conducted on them. The review article provides a comprehensive summary of research findings that are truly valuable for understanding the unique genetic characteristics, diseases’ prevalence, and medication responses among Circassians and Chechens living in Jordan. We believe that gaining deeper comprehension of the root causes of various diseases and developing effective treatment methods that benefit the society as a whole are imperative to engaging a wide range of ethnic groups in genetic research.

Keywords: Circassian, Chechen, Jordan, Epidemiology, Pharmacogenetics, Genetics

Introduction

Most genetic studies are focused on populations of European lineage, resulting in a bias in the scientific data and research performed (De La Vega and Bustamante 2018; Sirugo et al. 2019). This is particularly concerning as genetic diversity plays a critical role in disease susceptibility, response to treatments, and health outcomes. To gain a more comprehensive understanding of genetic factors, it is crucial to study diverse populations. In fact, focusing on minorities and underrepresented groups can have major advantages. For example, these populations may have a higher prevalence of certain genetic variations that can provide insights into disease susceptibility and treatment response. Additionally, studying diverse populations can help to identify genetic variations that may have been missed in previous research, leading to new discoveries (Bustamante et al. 2011; Borrell et al. 2021). This study presents a concise overview of the Circassians and Chechens in Jordan, elucidating the ethnic origins of these two groups hailing from the North Caucasus region of Eastern Europe. In this study, the genetic relationships between Circassian and Chechen populations living in Jordan were investigated using principal component analysis (PCA). Finally, the paper presents a summary of several studies that have investigated the Circassian and Chechen populations in Jordan, including epidemiological and genetic epidemiological studies, pharmacogenetic studies, and forensic studies. The aim of this review paper is to highlight the unique characteristics of these populations and their potential implications for healthcare and personalized medicine.

A brief history of the Circassians and Chechens in Jordan

The Caucasus is an ethnically, genetically, linguistically, and culturally diverse region, forming a mosaic of various cultures and ethnicities. Two of its largest ethnic groups are Circassians and Chechens, both of whom descend from indigenous nationalities of the North Caucasus in Eastern Europe. Despite having a common ancestor, these groups eventually split apart because of linguistic and geographical boundaries (Barbujani et al. 1994; Nasidze and Stoneking 2001; Nasidze et al. 2004). Individuals of the Caucasus who were displaced to the Ottoman Empire in the nineteenth century settled in Turkey and other parts of the empire such as the Balkans and the Levant (Held 2018). In Jordan, the newcomers from the Caucasus evolved and formed small communities, and even though more than 140 years have elapsed since their arrival, they were successful in preserving their ethnic identity, inherited culture, and traditions. Endogamous marriages have played a significant role in this preservation, as it has helped to maintain a distinct genetic profile within these communities. This makes them a great and unique candidate for population studies in terms of genetic research.

Circassians and Chechens ancestral roots

The North Caucasus is the ancestral homeland of the Circassian and Chechen peoples, with the region consisting of two distinct areas located in Southwest Russia. Throughout history, the Circassians resided mainly along the Black Sea coastline, while the Chechens primarily inhabited the Northern Caucasus mountains. These geographical disparities have played a significant role in shaping the distinct ethnic and linguistic identities of the Circassian and Chechen populations. Specifically, the Circassians speak the Adyghe language, while the Chechens speak the Vainakh/Wainakh languages. Additionally, Circassians identify themselves as Adyge (Aдыгэxэp) and Chechens identify as Nokhchi (Hoxчи), further emphasizing the distinction between the two populations (Dweik 2000; Rannut 2009). Currently, it is estimated that 100,000 Circassians and 8000 Chechens live in Jordan (Seteney 1994; Kailani 2002; Zhemukhov 2008).

Principal component analysis (PCA) in genetic studies of minority populations allows researchers to investigate the genetic relationships between different populations and can provide insights into population migration and admixture. According to principal component analysis (PCA) by the Population Genomics Group (PGG) Population database (Zhang et al. 2018), both the Adyghe and the Chechens in North Caucasia are related to individuals from Northern and Western Europe, while both are more closely correlated to the Turkish population (Fig. 1a), rather than the Jordanian population (Fig. 1a–b). The PCA based on comparisons with other human populations from the 1000 Genomes Project (Siva 2008) confirms that the Circassians and the Chechens in Jordan are related to the European populations (Fig. 2a), while some differentiation from other European populations can also be seen (Fig. 2b). When introducing the third PC (PC3), a difference between the Circassians/Chechens in Jordan and the Northern/Western Europeans is evident, while a close correlation with Iberians in Spain and Toscani in Italy can be seen (Fig. 2c). The difference between the Circassians in Jordan and the Chechens in Jordan is highly correlated with PC5 (r = 0.714, P = 1.41 × 10−45) and PC6 (r =  − 0.728, P = 3.84 × 10−48) (Fig. 2d). The correlation between the difference of the Circassians and the Chechens in Jordan and the PCs in the PCA of the human populations in the 1000 Genomes Project is shown in Table 1. The first two PCs account for 70.4% of the overall variation between human populations represented by the 20 overall PCs, whereas both showed no differences between the Circassians in Jordan and the Chechens in Jordan.

Fig. 1.

Fig. 1

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The population structure of the Adyghe and the Chechens, a compared to other human populations and b Jordanians. The principal component data of population structure are from the PGG. Population database (Zhang et al. 2018). X-axis, PC1; Y-axis, PC2

Fig. 2.

Fig. 2

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The population structure of the Circassians and the Chechens in Jordan, compared to other human populations. Data on the other human populations are based on the 1000 Genomes Project (https://www.internationalgenome.org/). a Compared to the three major human populations (X-axis, PC1; Y-axis, PC2); b compared to other European populations (X-axis, PC1; Y-axis, PC2); c compared to other European populations (X-axis, PC3; Y-axis, PC2); d the Circassians and the Chechens in Jordan (X-axis, PC5; Y-axis, PC6). Abbreviations: ChJ, Chechens in Jordan; CiJ, Circassians in Jordan; CEU, Europeans from the Centre d’Etude du Polymorphisme Humain (CEPH); FIN, Finnish; GBR, British; IBS, Iberian, Spanish; TSI, Toscani

Table 1.

Correlation between Circassians and Chechens in Jordan and the PCs of the human populations in the 1000 Genomes Project, N = 284

Eigenvalues R P
PC1 181.33  − 0.066 0.267
PC2 104.61 0.100 0.091
PC3 30.14  − 0.254** 1.50 × 10−5
PC4 24.18  − 0.267** 4.91 × 10−6
PC5 8.523 0.714** 1.41 × 10−45
PC6 5.505  − 0.728** 3.84 × 10−48
PC7 4.938  − 0.241** 4.05 × 10−5
PC8 4.851  − 0.384** 2.13 × 10−11
PC9 4.164  − 0.216** 2.45 × 10−4
PC10 4.149  − 0.127* 0.032
PC11 3.914  − 0.140* 0.019
PC12 3.800  − 0.105 0.077
PC13 3.510  − 0.210** 3.62 × 10−4
PC14 3.431  − 0.086 0.15
PC15 3.373  − 0.041 0.491
PC16 3.329  − 0.047 0.426
PC17 3.277 0.000 0.997
PC18 3.166 0.063 0.293
PC19 3.056 0.002 0.974
PC20 2.943  − 0.057 0.335
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*P < 0.05; **P < 0.01

Comparative studies on the Circassian and Chechen populations in Jordan

Researchers in Jordan have become more interested in investigating the Circassian and Chechen populations in recent years, which has led to the publication of various studies comparing their similarities and differences. These studies have looked at a variety of topics, including pharmacogenetics and their genetic ancestry, as well as several health issues (Table 2 summarizes the findings of these studies). Investigating the genetic variations within those groups and conducting epidemiological studies that contrast those minorities with the general population can help to understand the differences in the prevalence of several medical conditions, such as diabetes, hypertension, and cancer, among various ethnic groups. Additionally, pharmacogenetic research can shed light on how certain populations respond to drugs differently, which may help develop tailored therapy for these groups. The objective of this review paper is to provide an overview of all research that have been conducted on the Circassian and Chechen communities in Jordan, highlighting their distinctive traits and any potential implications for medical care and individualized treatment.

Table 2.

Summary of studies conducted on Circassians and Chechens in comparison with Jordanian-Arabs living in Jordan

Related disorder Focus Year Sample size Results Ref
Epidemiological studies
Hypertension Hypertension risk assessment 2011 792 Circassians and Chechens This study established baseline data on cardiovascular disease and relevant risk factors in Circassians and Chechens (family history, dyslipidemia, waist measurement, gender, and age). The overall prevalence rate of hypertension in Circassians and Chechens grouped together was 23.9%, which is lower than the prevalence in Jordanian-Arabs Shishani et al. (2013)
Metabolic syndrome Metabolic syndrome manifestations through a cross-sectional study 2013 3234 Jordanian-Arabs The prevalence of the metabolic syndrome and its individual components is relatively high in the three ethnic groups compared to other populations Dajani et al. (2013a, b)
436 Circassians
355 Chechens
Diabetes mellitus Diabetes mellitus prevalence 2012 437 Circassians In Circassians, the prevalence of impaired fasting glucose and the prevalence of diabetes were 18.5% and 9.6% and, in Chechens, 14.6% and 10.1%, respectively Dajani et al. (2012)
Nutrient intake, lifestyle factors, and diabetes status 2014 437 Circassians No difference was found between the intake of nutrients in participants with normal blood glucose from those who had impaired fasting glucose or diabetes in the two populations Tayyem et al. (2014)
Cancer Cancer risk and prevalence 2013 20,000 Circassian Cancer Registry Report for the years 2000–2001 was used for the identification of crude rates of different types of cancers. The results showed that breast cancer has higher rates in the Circassians and Chechens than in Jordanian-Arabs. Lung cancer was the most common cancer in the males of Jordanian-Arabs and Chechens. Colorectal cancer rates in Jordanian-Arabs and Chechens were similar and were twice as high in Circassians Fathallah and Dajani (2013)
10,000 Chechen
Genetic epidemiological studies
Blood clotting Methylenetetrahydrofolate reductase C677T SNP prevalence 2013 72 Circassians The prevalence of methylenetetrahydrofolate reductase (MTHFR) C677T mutation in Chechens was 27.5% (allele frequency 15%) and in Circassians was 50% (allele frequency 29.2%). When comparing the prevalence between the populations, Chechens have similar rates to Jordanian-Arabs, but it was higher in the Circassians Dajani et al. (2013a, b)
120 Chechens
Factor II and factor V Leiden SNPs 2013 104 Circassians In Circassians, factor II G20210A was prevalent by 12.2% and factor V Leiden by 7.7%. Using the Hardy–Weinberg equilibrium for both mutations, it was found that they are within the range of other ethnic groups Dajani et al. (2012)
Angiogenesis Vascular endothelial growth factor 2023 129 Chechens No significant difference in the allele frequencies of VEGF-634 between the Circassian population and the Jordanian-Arab population. Moreover, all three populations, including the Circassians, exhibited similar frequencies of VEGF-936
190 Circassians
150 Jordanian-Arabs
Diabetes Diabetes manifestations 2017 237 Jordanian-Arabs Jordanian-Arabs were generally more obese, whereas Circassians and Chechens had lower lipid control. Jordanian-Arabs had an inferior glycemic control than Circassians and Chechens with diabetes, having higher means of glycated hemoglobin (HbA1c) and higher fasting blood glucose Al-Eitan et al. (2017)
56 Circassians
54 Chechens
Novel copy number variation associated with type 2 diabetes 2015 140 Circassians (34 cases and 106 controls) A novel copy number variation (CNV) region was identified in protein tyrosine phosphatase receptor type D with significant association with type 2 diabetes (T2D), and 16 CNV regions associated with T2D were also identified that overlapped with gene exons Dajani et al. (2015)
144 Chechens (34 cases and 110 controls)
Novel loci of type 2 diabetes 2017 144 Chechens A novel type 2 diabetes locus at chr20p12.2 was identified through a genome-wide association study (GWAS) at a genome-wide significance (rs6134031). Another locus at chr12q24.31 that is also associated with type 2 diabetes was identified (rs4758690), and is significantly associated with methylation level in the MLXIP gene which involves cellular glucose response Dajani et al. (2017)
140 Circassians
Association of genetic variants with macronutrient intake 2018 34 Circassians with type 2 diabetes A genetic association through a genome-wide association study (GWAS) was found with the calorie intake in Chechens and an association of carbohydrate, calorie, vitamin B2, and caffeine in the Circassians. Within the Circassian group. the carbohydrate and calorie intake and type 2 diabetes (T2D) were associated with SNPs on histone deacetylase 9 gene and between vitamin B2 intake and SNPs on a second locus of potential interest on chromosome 11 near (101,928,989) and teneurin transmembrane protein 4. Caffeine intake was associated with significant SNPs unrelated to T2D. In the Chechen group, only the calorie intake was correlated with significant SNPs; however, none of them was related to T2D Dajani et al. (2018a, b)
34 Chechens with type 2 diabetes
Genome-wide association study (GWAS) The study investigated the genetic markers identified by GWAS study for association with cancer, schizophrenia, and type 2 diabetes 2018 144 Chechens (34 case and 110 controls)

Using the National Center for Biotechnology Information for all genes related to the annotated nominally significant single nucleotide polymorphisms, the results showed that 20 genes are associated with cancer (LPAR3 (rs10493757), DTL (rs2993549, rs4951436), ESRRG (rs2813703), BRE (rs11127131), BIRC6 (rs11124283), SCTR (rs2579600), TP63 (rs11708944), ERGIC1 (rs498221), BRAF (rs10487888), TTF1 (rs3739915), KIN (rs19808560), FRMD4A (rs11258848), STIM1 (rs3750996), CD82 (rs883752), LIMA1 (rs1044370), NTN4 (rs7139030), KLF12 (rs9318227), RORA (rs13329643, rs782918), NOL3 (rs2233456), PAK7 (rs16996073)) and 6 are associated with schizophrenia in Circassians (DAB1 (rs1341322, rs10789050), CSMD1 (rs2469358), ADRA1A (rs573514), NRG1-3 (rs1623372, rs4733130, rs17719687), SYN3 (rs7284103, rs7290713, rs11704261, rs4999923), MEGF10 (rs35524))

In Chechens, 2 genes are associated with cancer (DCC (rs4940189), CHSY1 (rs12148369)) and 7 are associated with schizophrenia (DAB1 (rs3768171), CSMD1 (rs17066250), NAV1 (rs504988), GRM7 (rs162782, rs162769, rs3804820), CNTNAP2 (rs10250801), GRIA4 (rs17391295), ZDHHC8 (rs175174))

 Dajani et al. (2018a, b)
Pharmacogenetics
Pharmacogenetics Phase 1 metabolism (Cyp2c8) 2022 93 Circassians, 88 Chechens, and 200 Jordanians The study found significant differences in the prevalence of CYP2C83 and CYP2C8 Abudahab et al. (2022)
Phase 2 metabolism (Ugt1a1) 2019 168 Jordanian-Arabs Circassians and Chechens and Jordanian-Arabs have similar frequencies of UGT1A1*28 Abudahab et al. (2019)
56 Circassians
54 Chechens
Phase 2 metabolism (Ugt1a7) 2019 94 Jordanian-Arabs Circassians and Chechens have higher allele frequencies of UGT1A7*2, UGT1A7*3, and UGT1A7*4 than the Jordanian-Arabs. When compared with other populations, Circassians, Chechens, and Jordanians all have high allele frequencies of UGT1A7*4. In Jordanian-Arabs, a novel SNP (T622A) was reported with a frequency of 0.07. In Circassians and Chechens, a novel SNP was reported (T682C) with frequencies of 0.36 and 0.41, respectively Abudahab et al. (2019)
56 Circassians
54 Chechen
Identification of the polymorphic distribution of very important pharmacogenes (VIPs) 2019 130 Circassians Eleven VIP variants within the thiopurine S-methyltransferase, ATP-binding cassette, sub-family B, member 1, and vitamin D receptor genes were genotyped, and the results showed that Circassians differ from other populations in terms of their allelic frequencies Al-Eitan et al. (2019)
Genetic polymorphisms of pharmacogenes 2020, 2020 128 Circassians and 166 Chechen Fifty-six SNPs of several pharmacogenes were analyzed and compared with other ethnic groups by using two databases (Genome 1000 and eXAC). Rare variants were detected in Circassians and Chechens, and some alleles’ frequencies were different when compared to other ethnic groups Al-Eitan et al. (2020); AL-Eitan et al. (2020)
Forensic studies
Maternal lineage landscape through mitochondrial DNA (mtDNA) 2019 112 Circassians A total of 102 mtDNA haplogroups were identified; their distribution frequencies showed disparity and significant differences between the three groups with significant variations in the distribution of maternal genetic ancestries, mainly between Jordanian-Arabs and Circassians/Chechens Al-Eitan et al. (2020)
100 Chechens
81 Jordanian-Arabs
GlobalFiler loci for forensic parameters 2019 150 Circassians The forensic efficiency parameters of 21 highly polymorphic autosomal STR loci were evaluated; the results showed that SE33 locus is the most informative and polymorphic STR marker while TPOX was the least informative and that allele 8 of TPOX was the most common in all 21 loci AL-Eitan et al. (2020)
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Epidemiological studies

Hypertension prevalence and risk factors

Due to its link to cardiovascular disease, the primary cause of adult mortality, hypertension is a significant public health concern in Jordan (Khader et al. 2019). The frequency of hypertension and associated risk factors in Jordan’s minority populations, including the Circassians and Chechens, has drawn the attention of researchers. For example, a descriptive cross-sectional study in 2011 included 792 Circassians and Chechens to determine the prevalence and risk factors of hypertension in these populations. The overall prevalence rate was 23.9% and risk factors included presence of hypertension in family history, being a female, dyslipidemia, an above normal waist measurement, and older age. Hypertension prevalence rates in these subpopulations were lower compared to the general Jordanian-Arab population (32%) (Shishani et al. 2013). Khader et al. found that hypertension among the general population in Jordan was associated with large waist circumference, concurrent diabetes, dyslipidemia, and smoking, while no correlation between smoking and hypertension was found in the minorities groups (Khader et al. 2019). Finally, hypertension is an important modifiable risk factor for cardiovascular morbidity and mortality, and as mentioned earlier cardiovascular diseases are the leading cause of adult mortality in Jordan (Dababneh et al. 2015). Therefore, we need to understand the underlying factors that contribute to hypertension in minority populations, such as the Circassians and Chechens in Jordan, so that it can help in establishing focused public health initiatives and programs that might benefit the health of these communities.

Metabolic syndrome

Metabolic syndrome is a major risk factor for a variety of metabolic and cardiovascular disorders. It is linked to obesity, hypertension, type 2 diabetes, and lipid metabolism abnormalities. Due to lifestyle changes, metabolic syndrome prevalence is rising worldwide, including sedentary lifestyles, increased consumption of processed foods with added sugar and unhealthy fats, and decreased physical activity that characterizes modern lifestyles (Saklayen 2018). In Jordan, a cross-sectional study was conducted to estimate and compare the prevalence of metabolic syndrome between three ethnic populations in Jordan (Dajani et al. 2013a, b). The study included 3234 Jordanian-Arabs, 436 Circassians, and 355 Chechens living in Jordan. Metabolic syndrome prevalence was 38%, 32%, and 34% in Jordanian-Arabs, Circassians, and Chechens, respectively. Circassian and Chechen groups had lower mean BMIs, fasting blood glucose, total cholesterol, and triglycerides than Jordanian-Arabs. However, the mean of high-density lipoprotein and low-density lipoprotein was the highest among Circassians compared with the other two groups. Overweight and obesity were less common among Circassians and Chechens compared with Jordanian-Arabs. All in all, compared with populations worldwide, the prevalence of metabolic syndrome and its components is relatively high in the three ethnic groups (Dajani et al. 2013a, b).

Diabetes

Diabetes is a major public health issue worldwide, including Jordan (Ajlouni et al. 2008). In 2012, a study investigated diabetes in two ethnic populations, Circassians and Chechens. The purpose was to determine if those ethnic populations have higher or lower prevalence of diabetes. The study found that 18.5% of Circassians and 14.6% of Chechens in Jordan had impaired fasting glucose. The prevalence rate of diabetes in Circassians and Chechens was 9.6% and 10.1%, respectively. Moreover, this study identified no significant socio-demographic, anthropometric, or clinical differences between the groups. This study also found lower diabetes prevalence in Circassians and Chechens in comparison to the Jordanian general population, suggesting that ethnicity may predispose or protect against diabetes. In addition, this research revealed that more than half of those diagnosed with diabetes did not have their condition effectively managed.

In a subsequent investigation, lifestyle variables including nutrient consumption were examined among individuals with and without diabetes within the Circassian and Chechen communities (Tayyem et al. 2014). The findings of this study showed that dietary factors do not appear to play a significant role in the development of diabetes within the Circassian and Chechen ethnic populations, as there were no differences observed in the consumption of macro- or micro-nutrients between the two groups. However, the study did identify that higher levels of education could be considered a significant contributing factor in the prevention of diabetes within these populations.

The study also found that individuals presenting with impaired fasting glucose (IFG) or diabetes manifested notably heightened values across an array of variables encompassing body mass index (BMI), body weight, waist circumference, triglyceride levels, cholesterol levels, HbA1c levels, diastolic blood pressure (DBP), and systolic blood pressure (SBP), when compared to participants with normal blood glucose levels.

The study suggests that Circassians and Chechens in Jordan may have lower rates of diabetes compared to the general population. Additionally, individuals with impaired fasting glucose or diabetes exhibited significant deviations in various health parameters, emphasizing the need for targeted interventions to manage and prevent diabetes within these populations.

Cancer prevalence

Using information from the National Cancer Registry for the years 1996 to 2005, cancer prevalence rates were compared among Circassians, Chechens, and Jordanian-Arabs in Jordan (Fathallah and Dajani 2013). This study discovered significant ethnic differences in cancer frequency. For example, breast cancer was the most prevalent cancer type in women, and Circassian and Chechen ethnicities had higher crude rates of breast cancer compared to Jordanian-Arab population. Moreover, when compared to Jordanian-Arabs, Circassians had an odds ratio (95% confidence intervals) of 2.1 (1.48–2.72) and Chechens had an odds ratio of 1.81 (1.16–2.85). With a crude rate of 8.0 per 100,000, lung cancer was the most prevalent type of cancer among Chechen men. For Circassians, the crude rate of lung cancer was 6.5 per 100,000. Crude rates of colorectal cancer were similar among Jordanian-Arabs and Chechens at 6.2 and 6.0 per 100,000, respectively, while twice as high among Circassians (Fathallah and Dajani 2013). In summary, this study showed that there were significant ethnic differences in cancer frequency among Circassians, Chechens, and Jordanian-Arabs in Jordan. These findings highlight the importance of considering ethnic differences in cancer prevalence rates, in cancer prevention and in control programs.

Genetic epidemiological studies

Methylenetetrahydrofolate reductase

Methylenetetrahydrofolate reductase (MTHFR) mutation (C677T SNP) is a major inherited risk factor of venous thromboembolism. One hundred and twenty unrelated Chechens and 72 Circassians participated in a study to evaluate the prevalence of MTHFR variants in these two ethnic groups. Circassians and Chechens were found to have prevalence rates of 50% and 27.5%, respectively. Although it is more common in the Circassian population, the prevalence among Chechens is comparable to that in Jordanian-Arabs and other populations (Dajani et al. 2013a, b). The incidence of the two other variants, factor II G20210A and factor V Leiden, which are known to be risk factors for the pathophysiology of arterial and venous thrombosis, was also investigated in Circassians. Analysis of 104 Circassians revealed prevalence rates of 12.2% and 7.7%, respectively, for factor II G20210A and factor V Leiden single nucleotide polymorphisms (SNPs). When compared to other populations, Circassians had a comparatively high incidence of factor II G20210A, whereas the prevalence of factor V Leiden mutation was within the expected range for European populations (Dajani et al. 2012).

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is a signaling protein that promotes the growth of new blood vessels in vasculogenesis and angiogenesis, and it plays a significant role in diseases that involve blood vessels, such as tumor angiogenesis, age-related macular degeneration (AMD), and diabetic retinopathy (DR) (Apte et al. 2019). A study in 2023 involved the genotyping of 319 healthy individuals from the Circassian and Chechen populations for VEGF-936 and VEGF-634 using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques (Al-Daghastani et al. 2023). According to this study, there was no significant difference in the allele frequencies of VEGF-634 between the Circassian population and the Jordanian-Arab population. Additionally, all three populations, including the Circassians, exhibited similar frequencies of the VEGF-936 allele.

Diabetes

A genome-wide association study (GWAS) in 2017 found two unique loci determinants for type-2 diabetes that were not detected in previous literature in Circassians and Chechens (Dajani et al. 2017). Another study has identified several SNPs and copy number variations (CNV) associated with diabetes in Circassians and Chechens. The CNV analysis included 34 diabetes cases and 110 controls from Chechens and 34 diabetes cases and 106 controls from Circassians. It identified a CNV region in protein tyrosine phosphatase receptor type D and other 16 CNV regions associated with type-2 diabetes which overlapped with gene exons (Dajani et al. 2015). The previous studies suggest a distinct genetic factor for type-2 diabetes in the two populations.

In addition, a comparative study between diabetes patients of Arab descent and diabetes patients of Circassian/Chechen descent was conducted in 2017 (Al-Eitan et al. 2017). It showed some differences in the disease manifestations; Jordanian-Arabs were proportionately more likely to have hypertension comorbidity with diabetes versus Circassians/Chechens. Jordanian-Arabs were also generally more obese, whereas Circassians/Chechens had inferior lipid control. Jordanian-Arabs had less adequate glycemic control versus Circassians/Chechens with diabetes, and also had higher levels of glycated hemoglobin (HbA1c) and fasting blood sugar.

Tayyem et al. showed that risk factors for diabetes were not correlated with health outcomes in those two ethnic groups. Chechens had lower current smoking rates (19% versus 25%) and higher quit rates (45% versus 38%) in comparison to Caucasians (Tayyem et al. 2014). Levels of physical activity reported by both groups were aligned with the American Heart Association recommendations. Moreover, Awad et al. reported in their national study that smoking and physical inactivity are risk factors for diabetes among Jordanians (Awad et al. 2020). The fat intake of Chechens and Circassians was also consistent with the American Diabetes recommendations (Tayyem et al. 2014). Arabs with diabetes were more obese, had hypertension, and had unsatisfactory glycemic control in comparison to Chechens and Circassians with diabetes. Additionally, a high percentage of Chechens and Circassians with diabetes reported that they adhered to a diabetic diet.

The aforementioned secondary analyses of risk factors for hypertension and diabetes, as detailed by Tayyem et al. (2014) and Awad et al. (2020), demonstrate that (1) hypertension and diabetes prevalence rates in Chechens and Circassians are lower compared to the general Jordanian-Arab population and (2) differences in behavioral risk factors for hypertension and diabetes are observed in the Chechen and Circassian groups compared to the Jordanian-Arab population. Chechens and Circassians living in Jordan were more physically active than Jordanian-Arabs, smoked less, were less obese, and followed dietary recommendations more closely, and thus had fewer chronic health conditions.

A systematic review of major risk factors for CVD and CVD burden in the 83 regions of the Russian Federation found that CVD mortality rates were lowest in several regions including the Republic of Chechnya (Chechens) and Republic of Cherkessia (Circassians) (Kharlamov 2017). Moreover, according to Kharlamov et al., people in the Caucasus tend to be more physically active (Kharlamov 2017). The climate zone in the Caucasus is conducive to a prolonged growing season (200–240 days/year), allowing abundance of grain, nuts, fruits and vegetables to be grown. Therefore, it can be concluded that the Caucasian dietary lifestyle is similar to the Mediterranean diet. This type of diet is associated with significant health benefits including lower risk of CVD and metabolic conditions; lower plasma lipids, blood pressure, and body mass index; counteracting effect of stress on inflammatory biomarkers; and modulation of DNA repair (Martini 2019). The previous findings align with the data from Russia, which suggested that the health behaviors of Chechens and Circassians may contribute to positive health outcomes specifically in CVD.

Pharmacogenomic studies

Pharmacogenomics (PGx) is a relatively new area of science that investigates the correlation between genetics and the response to medication. It has been demonstrated that genetic factors and interindividual variability affect the metabolism of medications (pharmacokinetics) and their mode of action (pharmacodynamics). Genetic variations occur when one or more of the nucleotides are mutated: deleted, switched, or inserted. Accordingly, extrapolation and understanding the genetic variation in a patient’s genetic makeup will help to direct drug selection to get an effective therapeutic potential and decrease the adverse effects of the drug. The US Food and Drug Administration (FDA) presently supplies about 280 genetic biomarkers in more than 200 medications, with several boxed alerts recommending PGx testing prior to starting treatment. PGx has been implicated in many fields including oncology (Dj et al. 2020), cardiovascular diseases (Ibdah et al. 2021), autoimmune diseases (Ross et al. 2007), psychological diseases (Alavez-Rubio and Juarez-Cedillo 2019), and many other diseases.

Very important pharmacogene (VIP) variants are defined as clinically relevant single nucleotide polymorphisms that have been screened and investigated extensively in various genes within various ethnic populations (Risch et al. 2002). These VIPs include more than 120 variants in more than 40 genes that code for drug receptors, drug transporters, and drug-metabolizing enzymes (Evans and Johnson 2001). Several clinically significant VIPs have been studied in the isolated Circassian population. The data has revealed both differences and commonalities. For example, a study in 2021 investigating phase I drug metabolism focused on the cytochrome P450 2C8 (CYP2C8) gene. A total of 200 Jordanians, 93 Circassians, and 88 Chechens were examined, and the study revealed that the prevalence of CYP2C8*3 and *4 alleles among the three populations were significantly different. The mutant CYP2C8*3 (416A) allele was only detected in the Jordanian-Arab population with an allele frequency of 0.082, while the mutant allele CYP2C8*4 (792G) was detected with frequencies of 0.065, 0.122, and 0.017 in Jordanian-Arabs, Circassians, and Chechens, respectively (Abudahab et al. 2022). Another study in 2019 investigating the phase II drug-metabolizing gene UDP-glucuronosyltransferase (UGT) examined 110 unrelated Circassian and Chechen participants. It found that Circassians and Chechens have significantly higher allele frequencies of UGT1A7*2, UGT1A7*3, and UGT1A7*4 in comparison to the Jordanian-Arab population (Abudahab et al. 2019).

Other VIP genes include the potassium voltage-gated channel subfamily H member 2 (KCNH2). The frequency of rs3807375 SNP within the KCNH2 gene was 0.68 among Circassian, which differed from other populations’ frequencies (Al-Eitan et al. 2020b, d). On the other hand, the frequencies of both SNPs rs1051266 and rs1131596 of the solute carrier family 19 member 1 (SLC19A1) were the same in Circassians and among other populations. Another study that was conducted on the Chechens population in Jordan had shown that several SNPs such as the alternative allele (T) frequency of rs1229984 allele in the ADH1B gene were less frequent compared to other populations such as European Finnish, European non-Finnish, South-Asian, Latino, and Africans (Al-Eitan et al. 2020b, d). This genotype (TT) of rs1229984 was shown to correlate with the elevation Vmax of ethanol in healthy individuals when compared to the (CT) and (CC) genotypes (Seng et al. 2013). The frequency of the minor allele (G) of rs1042714 among the ADRB2 gene was also shown to be lower when compared to other ethnic populations (Al-Eitan et al. 2020b, d).

A broader study of very important pharmacogenes (VIPs) compared data from Circassians with VIP variants from 18 populations. Circassians were found to resemble African, Chechen, European (Finnish), European (non-Finnish), and South-Asian populations (Al-Eitan et al. 2019). Furthermore, fifty-six SNPs within 28 genes of several pharmacogenes were analyzed and compared with other ethnic groups using two databases (Genome 1000 and eXAC). Rare variants were detected in Circassians; some allele frequencies were different when compared to other ethnic groups (Al-Eitan et al. 2020b, d). Another study focusing on Chechens only found that several single nucleotide variants within the CYP450 genes have been reported as clinically significant (Al-Eitan et al. 2020b, d).

Several studies demonstrate the effect of genetic variation among the Circassians and Chechens and their association with different diseases (Table 1). For example, genetic variations in genes associated with type 2 diabetes have been shown to correlate with other diseases (Dajani et al. 2018a, b). About 20 of these genes were associated with cancer and 6 genes were associated with schizophrenia in the Circassian population. Meanwhile, 7 genes were associated with schizophrenia and 2 genes were associated with cancer in the Chechen. The genetic biomarkers implicated in the macronutrient and micronutrient intake associated with type 2 diabetes in Circassian and Chechen populations were studied (Dajani et al. 2018a, b). In the Circassian population, there was a statistically significant association between vitamin B2 intake and SNPs on a second locus of potential interest on chromosome 11 near LOC101928989 and teneurin transmembrane protein 4 gene, as well as between carbohydrate and calorie intake and T2D-associated SNPs on the histone deacetylase 9 gene (Dajani et al. 2018a, b). Additionally, the use of caffeine was linked to important SNPs unrelated to T2D. However, no significant SNPs were connected to T2D among Chechens, and only calorie intake was tied with their incidence (Dajani et al. 2018a, b).

Mitochondrial and forensic genetic studies

In 2020, a study examined mitochondrial DNA (mtDNA) haplotype diversity in 293 unrelated individuals from the Jordanian population, including Circassians, Chechens, and the original inhabitants of Jordan. MtDNA is widely used in several fields, such as medical genetics, forensic sciences, genetic genealogy, and evolutionary anthropology (Al-Eitan et al. 2020a, c). The study identified and analyzed a total of 102 mtDNA haplotypes among the three populations, revealing significant differences in the distribution of haplotype frequencies. Only six haplogroups were common between the three populations (U4a, U5a, M41a, H2a, K, and T), and Chechen and Circassian were shown to be more closely related to each other than to the Jordanian population (Al-Eitan et al. 2020a, c).

Another study in 2020 aimed to determine the allelic frequencies and evaluate the forensic efficiency of 21 highly polymorphic autosomal STR loci among the Circassian subpopulation in Jordan (Al-Eitan et al. 2020a, c). The researchers amplified the GlobalFiler loci using DNA extracted from whole blood samples of 150 Circassians. The SE33 locus was found to be the most informative and polymorphic STR marker, while TPOX was the least informative. Moreover, allele 8 of the TPOX gene was the most common among all the 21 loci investigated in Circassians. The study also calculated the combined matching probability (CMP) and combined power of discrimination (CPD) as 5.02 × 10−24 and 0.99, respectively. The identification of the most informative and least informative STR markers in the Circassian subpopulation in Jordan can have significant implications for forensic genetic investigations in other regions as well.

Understanding the genetic diversity and allele frequencies of different populations is essential for accurate and reliable forensic analyses of genetic evidence. This study provides valuable information that can guide the selection of appropriate genetic markers for forensic analyses in diverse populations. Such information can help forensic analysts to enhance the sensitivity and specificity of genetic profiling and contribute to better accuracy in forensic investigations. Therefore, the findings of this study can be useful not only in the Circassian subpopulation in Jordan but also in other countries as well.

Conclusion and future directions

The study of ethnic populations is important to addressing the lack of diversity in the genetic datasets worldwide and is potentially important to elucidating biological mechanisms in disease development and progression from an individualized perspective. The examination of these populations may reveal new genetic factors that contribute to disease development. Such discoveries will not only expand our knowledge but also reduce the global burden of diseases. The findings of 10 years of investigating the ethnic populations in Jordan suggest that the Circassian and Chechen minority populations show lower prevalence rates of hypertension and diabetes compared to the general Jordanian population. On the other hand, metabolic syndrome is relatively high in all three ethnic groups (Circassians, Chechens, and Jordanian-Arabs). Moreover, cancer frequency shows significant ethnic differences, with higher rates observed in Circassians and Chechens compared to Jordanian-Arabs. Pharmacogenomic studies indicate potential differences in medication response, and further research in this area can aid in personalized treatment strategies.

Minority studies are limited worldwide; nevertheless, it is important to highlight studies on ethnic groups to enrich and expand the genetic datasets for future advances in science and technology. Future projects should explore the Chechen and Circassian population in longitudinal studies rather than cross-sectional studies and investigate the effects of the environment on genetics. A natural follow-up is to explore if the epigenetic signatures of the environment are transferred across generations.

Author contribution

Writing—original draft, S.A. and R.D.; writing—review and editing, S.A., N.H., L.A., K.S., A.B., R.D.; conceptualization, R.D., N.H.; formal analysis and visualization, J.C., J.T.G., H.Q., J.Q., H.H.; supervision, R.D.

Declarations

Conflict of interest

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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