Genotypes of the UCP1 gene polymorphisms and cardiometabolic diseases: A multifactorial study of association with disease probability.

Cardiometabolic diseases (CMDs) are complex disorders with a heterogenous phenotype, which are caused by multiple factors including genetic factors. Single nucleotide polymorphisms (SNPs) rs45539933 (p.Ala64Thr), rs10011540 (c.-112A>C), rs3811791 (c.-1766A>G), and rs1800592 (c.-3826A>G) in the UCP1 gene have been analyzed for association with CMDs in many studies providing controversial results. However, previous studies only considered individual UCP1 SNPs and did not evaluate them in an integrated manner, which is a more powerful approach to uncover genetic component of complex diseases. This study aimed to investigate associations between UCP1 genotype combinations and CMDs or CMD risk factors in the context of non-genetic factors. We performed multiple logistic regression analysis and proposed new methodology of testing different combinations of SNP genotypes. We found that probability of CMDs increased in presence of the three-SNP combination of genotypes with minor alleles of c.-3826A>G and p.Ala64Thr and wild allele of c.-112A>C, with increasing age, body mass index (BMI), body fat percentage (BF%) and may differ between sexes and between countries. The combination of genotypes with c.-3826A>G minor allele and wild homozygotes of c.-112A>C and p.Ala64Thr was associated with increased probability of diabetes. While combination of genotypes with minor alleles of all three SNPs reduced the CMD probability. The present results suggest that age, BMI, sex, and UCP1 three-SNP combinations of genotypes significantly contribute to CMD probability. Varying of c.-112A>C alleles in the genotype combination with minor alleles of c.-3826A>G and p.Ala64Thr markedly changes CMD probability.

Prevalence of uncoupling protein one genetic polymorphisms and their relationship with cardiovascular and metabolic health.

Contribution of UCP1 single nucleotide polymorphisms (SNPs) to susceptibility for cardiometabolic pathologies (CMP) and their involvement in specific risk factors for these conditions varies across populations. We tested whether UCP1 SNPs A-3826G, A-1766G, Ala64Thr and A-112C are associated with common CMP and their risk factors across Armenia, Greece, Poland, Russia and United Kingdom. This case-control study included genotyping of these SNPs, from 2,283 Caucasians. Results were extended via systematic review and meta-analysis. In Armenia, GA genotype and A allele of Ala64Thr displayed ~2-fold higher risk for CMP compared to GG genotype and G allele, respectively (p<0.05). In Greece, A allele of Ala64Thr decreased risk of CMP by 39%. Healthy individuals with A-3826G GG genotype and carriers of mutant allele of A-112C and Ala64Thr had higher body mass index compared to those carrying other alleles. In healthy Polish, higher waist-to-hip ratio (WHR) was observed in heterozygotes A-3826G compared to AA homozygotes. Heterozygosity of A-112C and Ala64Thr SNPs was related to lower WHR in CMP individuals compared to wild type homozygotes (p<0.05). Meta-analysis showed no statistically significant odds-ratios across our SNPs (p>0.05). Concluding, the studied SNPs could be associated with the most common CMP and their risk factors in some populations.

Effectiveness of doxycycline for the treatment of zoonotic cutaneous leishmaniasis in vivo.

There are available data on in vivo studies of monotherapy of zoonotic cutaneous leishmaniasis with some antibacterial drugs (doxycycline) and their comparison with meglumine antimoniate (glucantime). We used golden Syrian hamsters as a laboratory model. Experimental groups were formed, each of which was treated with one of the tested drugs. Infection of animals was carried out with Leishmania major promastigotes. We selected highly virulent strains of L. major culture isolated from human ulcers or rodents. Meglumine antimoniate monotherapy and doxycycline monotherapy are quite effective and do not differ by the 30th day of their use in such indicators as the average degree of local damage and the average number of Leishmania in the lesions. The main differences were recorded in terms of average body weight gain and average clinical recovery in favour of doxycycline. Leishmania in the lesion on the 60th day were completely absent in treatment with doxycycline. The experiment proved the effectiveness of doxycycline monotherapy: Leishmania in the lesions were absolutely absent by the end of the treatment.

Association of uncoupling protein (Ucp) gene polymorphisms with cardiometabolic diseases.

The hereditary aspect of obesity is a major focus of modern medical genetics. The genetic background is known to determine a higher-than-average prevalence of obesity in certain regions, like Oceania. There is evidence that dysfunction of brown adipose tissue (BAT) may be a risk factor for obesity and type 2 diabetes (T2D). A significant number of studies in the field focus on the UCP family. The Ucp genes code for electron transport carriers. UCP1 (thermogenin) is the most abundant protein of the UCP superfamily and is expressed in BAT, contributing to its capability of generating heat. Single nucleotide polymorphisms (SNPs) of Ucp1-Ucp3 were recently associated with risk of cardiometabolic diseases. This review covers the main Ucp SNPs A-3826G, A-1766G, A-112C, Met229Leu, Ala64Thr (Ucp1), Ala55Val, G-866A (Ucp2), and C-55 T (Ucp3), which may be associated with the development of obesity, disturbance in lipid metabolism, T2D, and cardiovascular diseases.