Genetic Markers of Therapeutic Efficacy of Methotrexate in Patients with Psoriasis.

We studied the effect of C677T and A1298C polymorphisms of the MTHFR gene and 2R/3R polymorphisms of the TYMS gene on the sensitivity to methotrexate in patients with psoriasis (n=139). It was shown that genotype 3R/3R TYMS (OR 8.86, 95%CI 2.00-39.22) and complex genotypes MTHFR1298:A;TYMS:3R (OR 8.20, 95%CI 2.36-28.48) and MTHFR677:C;TYMS:3R (OR 5.40, 95%CI 1.95-14.94) were associated with sensitivity to methotrexate, while genotype 2R/2R TYMS (OR 8.20, 95%CI 2.36-28.48) and complex genotypes MTHFR1298:C;MTHFR677:T;TYMS:2R (OR 0.18, 95%CI 0.06-0.56) and MTHFR1298:C;MTHFR677:T (OR 0.23, 95%CI 0.09-0.59) were associated with resistance to methotrexate. The results can be used for preventive assessment of the effectiveness of methotrexate treatment in patients with psoriasis.

[CARD15 and TLR4 genes polymorphisms in atopic bronchial asthma].

In order to investigate whether single nucleotide polymorphisms G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene contribute to atopic bronchial asthma we performed a comparative analysis of alleles and genotypes frequencies of these polymorphisms in Russian patients from Moscow. DNA samples from 283 patients with atopic bronchial asthma and 227 healthy donors were genotyped. There were associations neither of G(+2722)C and 3020insC in CARD15 gene and Asp299Gly in TLR4 gene with asthma nor of markers of CARD15 gene with asthma severity. Haplotype frequency analysis of CARD15 gene polymorphisms did not reveal significant difference between groups. However, a strong association was found between Asp299Gly and asthma severity. Allele Asp of this marker showed association with mild atopic bronchial asthma and allele Gl--with moderate/severe asthma = 0.47, 95% CI [0.24-0.93] i OR = 2.12, 95% CI [1.08-4.18] respectively).

[M31R and R335C polymorphic variants of the IL8RA gene in Russian and Buryat patients with atopic bronchial asthma].

To test the M31R and R335C polymorphisms of the Il8RA gene for association with atopic bronchial asthma (BA), the allele and genotype frequency distributions of the polymorphisms were studied in Russian patients from Moscow and Buryat patients from Ulan-Ude. The study involved two Russian groups, one including 291 DNA samples of patients with atopic BA, and the other, 266 DNA samples of healthy people. The two Buryat groups included 124 and 152 DNA samples from patients with atopic BA and healthy people, respectively. The M31R polymorphism proved to be associated with atopic BA in Russians. Allele Arg and genotype Met/Arg suggested a higher risk of BA (OR= 4.45, P = 0.003 and OR = 4.58, P = 0.003, respectively), while allele Met and genotype Met/Metwere associated with a lower risk (OR = 0.22, P = 0.003 and OR = 0.22, P = 0.003, respectively). The R335C polymorphism was not associated with atopic BA in Russians and was in Buryats. Allele Arg and homozygous genotype Arg/Arg suggested a higher risk of the disease (OR = 3.06, P = 0.030 and OR = 3.20, P = 0.027, respectively), while allele Cys and genotype Arg/Cys suggested a lower risk (OR = 0.33, P = 0.030 and OR = 0.31, P = 0.027, respectively). The results support the role of the IL8RA gene in atopic BA.

[Association of interleukin-13 gene polymorphisms with atopic bronchial asthma].

A comparative analysis of allele and genotype distribution of C(-1055)T and R130Q IL13 gene polymorphisms has been performed in Russian patients from the Moscow region. In the study, 283 DNA specimens of atopic bronchial asthma (BA) patients and 227 DNA specimens of healthy donors were used. No association of these markers with ABA development as well as with total IgE concentration has been found. Haplotype frequency analysis did not reveal significant difference between samples. However, significant association ofC(-1055)Tpolymorphism with the disease severity has been revealed (OR = 2.39, 95% confidence interval 1.44-3.98, p = 0.001). Therefore, C(-1055)T polymorphism was shown to be associated with atopic BA progression.

[Association of polymorphic markers of lipid metabolism genes with diabetic polyneuropathy in type 1 diabetes mellitus].

The aim of this study was the search of association with diabetic polyneuropathy of the polymorphic markers epsilon2/epsilon3/epsilon4 of apolipoprotein E (APOE) and I/D of apolipoprotein B (APOB) genes in groups of type 1 diabetes patients with diabetic polyneuropathy (n = 86) and without its clinical signs (n = 94). We have not found significant association with diabetic polyneuropathy (DPN) of epsilon2/epsilon3/epsilon4 marker of APOE gene. However the comparison of allele and genotype frequencies of I/D marker of APOB gene showed that the carriers of I allele and II genotype had higher risk (OR = 1.66 and 2.01, relatively; p < 0.027), whereas the carriers of D allele had lower risk of DPN (OR = 0.60; p < 0.018). Our findings show that APOB gene, encoding one of the main components of lipid metabolism system, is involved into the diabetic polyneuropathy development in type 1 diabetes mellitus.

[Polymorphic markers of the NO synthase genes and genetic predisposition to diabetic polyneuropathy in patients with type 1 diabetes mellitus].

The allele and genotype frequencies of polymorphic markers of NOS1, NOS2 and NOS3 genes, encoding three types of NO synthases, were compared in type 1 diabetes patients with and without diabetic polyneuropathty. 180 type 1 diabetes patients (T1DM) of Russian or Eastern Slavonic origin, living in Moscow city, were divided into two groups using non-overlapping (polar) phenotypes. 86 patients had overt DPN and T1DM duration in this group was less than 5 years (DPN+ group) and 94 patients had no clinical DPN and T1DM duration was more than 10 years (DPN- group). We have not found the significant differences of allele and genotype frequencies of polymorphic markers (CA)n of NOS1 gene, (CCTTT)n of NOS2 gene, ecNOS4a/4b and Glu298Asp of NOS3 gene that indicates that all these markers are not associated with diabetic polyneuropathty. Only in the case of (CCTTT)n marker of NOS2 gene we have found a tendency for the association of 14 allele with DPN development. The carriers of this allele have the lower risk of DPN in T1DM.

[Polymorphic gene markers of lipid metabolism are associated with diabetic nephropathy in patients with type 1 diabetes mellitus].

In groups of type 1 diabetes mellitus patients with and without clinical signs of diabetic nephropathy (n = 62 and n = 68, respectively), a search was made for associations between diabetic nephropathy and the polymorphic marker epsilon2/epsilon3/epsilon4 of apolipoprotein E gene (APOE), I/D marker of apolipoprotein B gene (APOB), and Ser447Ter marker of lipoprotein lipase-encoding gene (LPL). The risk of diabetic nephropathy was higher in the carriers of allele epsilon3 and genotype epsilon3/epsilon3 of the polymorphic marker epsilon2/epsilon3/epsilon4 of APOE gene as well as in the carriers of allele 1 and APOB genotype/gene (OR = 2.08 and 2.16; 1.91 and 2.11, respectively). Conversely, the carriers of allele D showed a reduced risk of this complication (OR = 0.52). No significant differences in distribution of alleles and genotypes of the polymorphic marker Ser447Ter of LPL gene were found between the groups. Our results indicate that the genes encoding two major components of lipid metabolism are involved in the development of diabetic nephropathy in patients with type 1 diabetes mellitus.

[A search for association between the polymorphic markers of PON1 and PON2 genes and diabetic nephropathy in patients with type I diabetes mellitus].

Alleles and genotypes of polymorphic markers of paraoxonase 1 and paraoxonase 2 genes (PON1 and PON2) encoding enzymes of the body antioxidative defense were compared in type 1 diabetes mellitus patients with or without diabetic nephropathy. The patients with nonoverlapping ("polar") phenotypes constituted different groups. The first group contained patients with diabetic nephropathy (DN+, n = 62), clinical proteinuria (albuminuria above 300 mg per day), and at least 15-year disease duration. In control group, the patients had no diabetic nephropathy (DN-, n = 68), their albuminuria was below 200 mg per day, and disease duration was at least 20 years. Comparative analysis with exact Fisher's test revealed no significant differences in frequencies of alleles and genotypes of the PON1 gene polymorphic marker Gln192Arg and of PON2 gene polymorphic markers Ala148Gly and Cys311Ser. Our results suggest that the polymorphic markers studied are not associated with diabetic nephropathy among Russian patients in Moscow.

[Identification of the locus associated with diabetic nephropathy in type 1 diabetes mellitus]. / Identifikatsiia lokusa assotsiirovannogo s diabeticheskoi nefropatiei pri sakharnom diabete tipa 1.

Polymorphic tetranucleotide microsatellites D3S1512, D3S1744, D3S1550, and D3S232 were used to study the association of chromosome region 3q21-q25 neighboring the angiotensin II receptor type 1 gene (AT2R1) with diabetic nephropathy (DN) in diabetes mellitus type 1 (DM1). Allele and genotype frequencies were compared for DM1 patients with (N = 39) or without (N = 62) DN. Fisher's exact test with Bonferroni's correction revealed significant differences in frequencies of two D3S2326 alleles, one D3S1512 allele, and one allele and one genotype of D3S1550. No significant difference was observed with D3S1744. Thus, region 3q21-q25 proved tightly associated with DN in ethnic Russians with DM1 from Moscow.

[Polymorphic markers of endothelial NO-synthase and angiotensin II vascular receptor genes and predisposition to ischemic heart disease]. / Polimorfnye markery genov éndotelial'noi NO-sintazy i sosudistogo retseptora angiotenzina II i predraspolozhennost' k ishemicheskoi bolezni serdtsa.

Allele and genotype frequency distribution patterns of the polymorphic regions at the genes for human endothelial NO-synthase (NOS3) (the ecNOS4a/4b VNTR and the Glu298Asp substitution) and the angiotensin II type 1 receptor (AT1)(the A1166C substitution) were compared in 83 unrelated healthy individuals and 88 patients with ischemic heart disease (IHD). In the group of patients statistically significantly higher frequencies of the NOS3 allele 4a (45.5 versus 19.3%), as well as the 4a/4a (15.9 versus 2.4%) and 4a/4b (59.1 versus 33.7%) genotypes were observed. Frequencies of the allele 4b (54.5% versus 80.7%) and the 4b/4b homozygotes (25.0 versus 63.9%) were statistically significantly lower in the group of IHD patients than in healthy individuals. The IHD patients were statistically significantly different from the healthy subjects also in the distributions of the AT1 genotypes. In the former group, a significantly decreased frequency of the AA homozygotes (51.1 versus 65.1%) and an increased frequency of AC heterozygotes (40.9 versus 27.7%) were observed. Thus, in the Moscow population the ecNOS4a/4b VNTR of the NOS3 gene and the A1166C polymorphism of the AT1 gene are associated with the IHD development. Furthermore, the correlation with the IHD revealed was much stronger for the NOS3 VNTR locus.

[Association of the complex of polymorphic markers of ACE genes, aldosteron synthetase and endothelial synthetase of nitric oxide with progression of chronic glomerulonephritis]. / Assotsiatsiia kompleksa polimorfnykh markerov genov angiotenzinprevrashchaiushchego fermanta, sintazy al'dosterona i éndotelial'noi sintetazy okisi azota s progressirovaniem khronicheskogo glomerulonfrita.

AIM: To study association of the complex of polymorphic markers of ACE genes (ACE complex), aldosteron synthetase gene (CYP11B2) and endothelial synthetase of nitric oxide (NOS3) with onset, course and progression of chronic glomerulonephritis (CGN). MATERIAL AND METHODS: 117 CGN patients were examined. Genetic predisposition to CGN development was studied by comparison of distributions of alleles and genotypes of polymorphic markers of genes ACE, CYP11B2 and NOS3 in CGN patients and controls (n = 80) free of renal diseases and arterial hypertension (AH). The course of CGN was analysed with consideration of the following factors: AH severity, proteinuria persistence, nephritic level for 6 months and longer, immunosuppressive therapy and response to it, therapy with ACE inhibitors and/or blockers of antiotensin II receptors (ARB). CGN progression rate end point was doubling of initial blood creatinine level. RESULTS: Significant differences in the incidence of the above alleles and genotypes in the patients and controls were not found. The patients were divided into two groups: group 1 consisted of 25 patients carrying the combination of alleles D+C+4a, group 2 consisted of the rest 92 patients. The groups did not differ by CGN course parameters, but renal survival was significantly lower in carriers of the allele combination D+C+4a. Cox's mono- and multifactorial regression analysis has shown that carriage of the allele combination D+C+4a is an independent riskfactor of renal survival deterioration. CONCLUSION: No association was detected between polymorphic markers of genes ACE, CYP11B2 and NOS3 and onset of CGN. Carriage of D+C+4a allele combination is an independent factor of risk for fast progression of chronic renal failure.

[The use of SNP markers for estimation of individual genetic predisposition to diabetes mellitus types 1 and 2].

Single nucleotide polymorphisms (SNPs) are now considered as the most perspective and convenient markers for research of genetic bases of multifactorial diseases. Fast development of technologies for exact screening of great volume of genetic information, construction of genomic maps of SNP-markers promotes development of innovative diagnostic systems on the basis of significant SNP for an estimation of individual genetic risk of development of various diseases. In this review the basic aspects of genetics of a diabetes of type 1 and 2 and an opportunity of use SNP as markers for an estimation of individual genetic predisposition to the given diseases are considered.