AUTHOR=Natae Shewaye Fituma , Kósa Zsigmond , Sándor János , Merzah Mohammed Abdulridha , Bereczky Zsuzsanna , Pikó Péter , Ádány Róza , Fiatal Szilvia 

TITLE=The Higher Prevalence of Venous Thromboembolism in the Hungarian Roma Population Could Be Due to Elevated Genetic Risk and Stronger Gene-Environmental Interactions

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.647416

DOI=10.3389/fcvm.2021.647416

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.</p><p><bold>Objective:</bold> To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.</p><p><bold>Methods:</bold> The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking].</p><p><bold>Results:</bold> Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher (<italic>p</italic> &gt; 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10<sup>−8</sup>). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0–1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; <italic>p</italic> &gt; 0.05) than for the general Hungarian population (OR = 1.5; <italic>p</italic> &gt; 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (β = 0.819, <italic>p</italic> = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (β = 0.389, <italic>p</italic> = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (β = 0.370, <italic>p</italic> &lt; 0.001) than for the general population (β = −0.042, <italic>p</italic> = 0.6). The VTE risk increased in the Roma population (β = 0.280, <italic>p</italic> = 0.001), but was higher in the general population (β = 0.423, <italic>p</italic> = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (β = 0.143, <italic>p</italic> = 0.046) but not for the general population (β = −0.329, <italic>p</italic> &lt; 0.001).</p><p><bold>Conclusions:</bold> rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.</p>