The -112G>A polymorphism of the secretoglobin 3A2 (SCGB3A2) gene encoding uteroglobin-related protein 1 (UGRP1) increases risk for the development of Graves' disease in subsets of patients with elevated levels of immunoglobulin E.
The human secretoglobin 3A2 (SCGB3A2) gene encoding secretory uteroglobin-related protein 1 (UGRP1) resides on the chromosome region 5q31-33 that harbors a susceptibility locus to several autoimmune and inflammatory diseases, including asthma and Graves' disease (GD). Recently, association between the marker rs1368408 (-112G?>A), located in the promoter region of the SCGB3A2 gene, and susceptibility to GD was found in Chinese and UK Caucasians. The study aim was to evaluate whether this polymorphism confers GD susceptibility in a large population cohort comprising 1,474 Russian GD patients and 1,619 controls. The marker rs1368408 was studied using a TaqMan allele discrimination assay. Serum levels of UGRP1 and immunoglobulin E (IgE) were assessed using enzyme-linked immunosorbent assay (ELISA) analyses. Association between the allele A of SCGB3A2 and a higher risk of GD (odds ratio [OR] = 1.33, P = 2.9 × 10(-5)) was shown. Both affected and non-affected carriers of the higher risk genotype A/A had significantly decreased levels of serum UGRP1 compared to the subjects homozygous for G/G (93 ± 37 pg/ml vs. 132 ± 45 pg/ml, P = 0.0011 for GD patients; 77 ± 28 pg/ml vs. 119 ± 33 pg/ml, P = 0.0019 for controls). Serum IgE levels were significantly higher in non-affected subjects homozygous for A/A compared to control individuals homozygous for G/G (153 ± 46 IU/ml vs. 122 ± 40 IU/ml, P = 0.0095). Our data suggest that the carriage of the SCGB3A2 -112A/A variant increases the risk for GD in subsets of patients with elevated levels of IgE, a hallmark of allergic asthma. Therefore, the SCGB3A2 -112G?>A polymorphism may be considered as a likely marker linking susceptibility to allergy/asthma and GD on chromosome 5q31-33.
Atrial fibrillation (AF) renders individual patients at risk for development of an atrial thrombus. The aim of this study was to determine clinical and echocardiographic factors influencing the risk of left atrial thrombosis (LAT) in patients with persistent nonvalvular AF. Genetic variants encoding haemostatic factors have been also assessed for putative association with LAT. In the cross-sectional study, a total of 212 patients (132 males and 80 females) with nonvalvular persistent AF (duration range 48 h-90 days) have been selected. LAT was visualized by transesophageal echocardiography. The FGB G(-455)A, PAI-1 4G/5G, F5 C(-224)T, and F5 R506Q genetic markers were tested using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. To reveal independent factors contributing to the thromboembolic risk in AF, a multivariate logistic model was applied. LA thrombi were found in 44 out of 212 subjects (21%). LAT was more frequently observed in patients at age >75 years (P 75 years, LVEF
Abnormalities in lipid metabolism and enhanced oxidative stress are considered as major risk factors for coronary atherosclerosis. Functional genetic variations in genes whose products are involved in lipid metabolism and antioxidant defense could therefore modulate risk of coronary artery disease (CAD). In this study, we evaluate whether the PPARGC1A Gly482Ser, PPARG3 (-681)C/G, PPARD +294T/C, and CYBA +242C/T gene variants confer the risk of CAD in a Russian population. A total of 313 CAD patients and 132 controls with no clinical sign of CAD were studied. The polymorphic markers were tested using a TaqMan assay. Allele and genotype frequencies in CAD patients and controls were compared using the Yates chi(2) test. Association of the genetic markers with metabolic risk factors of arterial atherosclerosis was studied using the analysis of variance test and then adjusted for conventional risk factors in the multiple regression analysis. For CYBA +242C/T, both the allele T and genotype T/T showed significant association with higher risk of CAD (odds ratio =1.49 and 3.89, respectively). The allele C and genotype C/C of the +294T/C marker of PPARD were associated with increased risk of CAD providing an odds ratio of 2.12 and 2.78, respectively. The risk variants of CYBA +242C/T and PPARD +294T/C markers were associated with higher low-density lipoprotein cholesterol and increased total serum cholesterol, respectively. In conclusion, the CYBA +242C/T and PPARD +294T/C variants modulate risk of CAD through their associations with atherogenic serum lipid profiles.
Family-based studies and segregation analyses suggest that inherited factors play a significant role in susceptibility to diabetic nephropathy (DN). Moczulski et al. [Diabetes 47 (1998) 1164-1169] found a susceptibility locus for DN in type 1 diabetes covering a 20cM region on chromosome 3q, with a peak of linkage close to the angiotensin II type 1 receptor (AT1) gene. We examined eight polymorphic markers (D3S1512, D3S1550, D3S1557, D3S1744, D3S2326, D3S3599, D3S3694, and a (CA)(n) dinucleotide repeat polymorphism in the 3' flanking region of the AT1 gene) spanning about 6.2 megabases (Mb) in the region of maximal linkage with DN on chromosome 3q23-q24. The markers were used to genotype a total of 381 Russian type 1 diabetic subjects, 195 of whom had DN and 186 had no clinical nephropathy. Four of the markers tested, D3S1512, D3S1550, D3S2326, and D3S3599, showed an association with DN in type 1 diabetes mellitus. These markers are located within a 1.0Mb interval that starts about 4.4Mb centromeric to the AT1 gene. Thus, our results suggest the existence of the DN susceptibility locus previously described by Moczulski et al. on chromosome 3q.
Type 1 diabetes (T1D) susceptibility locus, IDDM8, has been accurately mapped to 200 kilobases at the terminal end of chromosome 6q27. This is within the region which harbours a cluster of three genes encoding proteasome subunit beta 1 (PMSB1), TATA-box binding protein (TBP) and a homologue of mouse programming cell death activator 2 (PDCD2). In this study, we evaluated whether these genes contribute to T1D susceptibility using the transmission disequilibrium test of the data set from 114 affected Russian simplex families. The A allele of the G/A1180 single nucleotide polymorphism (SNP) at the PDCD2 gene, which was significant in its preferential transfer from parents to diabetic children (75 transmissions vs. 47 non-transmissions, chi2=12.85, P corrected=0.0038), was found to be associated with T1D. G/A1180 dimorphism and two other SNPs, C/T771 TBP and G/T(-271) PDCD2, were shown to share three common haplotypes, two of which (A-T-G and A-T-T) have been associated with higher development risk of T1D. The third haplotype (G-T-G) was related to having a lower risk of disease. These findings suggest that the PDCD2 gene is a likely susceptibility gene for T1D within IDDM8. However, it was not possible to exclude the TBP gene from being another putative susceptibility gene in this region.
Graves' disease (GD) is a polygenic autoimmune thyroid syndrome. Some of the genes implicated in its pathogenesis may encode thyroid-stimulating hormone receptor (TSHR) and estrogen receptors 1 (ESR1) and 2 (ESR2). We examined dinucleotide repeat polymorphisms in the ESR1 and ESR2 genes and D727E amino acid substitution in the TSHR gene for possible association with GD in a Russian population.
The polymorphic regions of the target genes were amplified by polymerase chain reaction (PCR) on the basis of genomic DNA isolated from blood of 78 unrelated Russian patients with GD and 93 control subjects. To detect the D727E TSHR polymorphism, the PCR product was additionally digested with Eco72I restriction endonuclease. The genotype and allele frequencies in the groups studied were compared by c2 test. The odds ratios and 95% confidence intervals (CI) were calculated to assess the strength of the relationship between the polymorphisms tested and GD.
For polymorphic dinucleotide microsatellites at ESR1 and ESR2, no significant difference was observed in allele frequencies between affected and nonaffected patients. For the D727E TSHR polymorphism, the E allele and the DE genotype were significantly more frequent (p
The long-term stress of high blood pressure levels increases the risk of a variety of macro- and microvascular complications of type 2 diabetes (T2D). The etiology of essential hypertension (EH) has been explored in depth, but the pathophysiology is multifactorial, complex, and poorly understood. Recent findings showed a role of inherited mutations in mitochondrial DNA (mtDNA) in maternally inherited forms of hypertension. However, an impact of somatic mtDNA mutations in the development of EH is significantly less investigated. In this study, we examined whether the level of heteroplasmy for the 15059G>A mutation in the mitochondrial cytochrome b gene is associated with EH in T2D.
The heteroplasmy level in mtDNA isolated from blood of 189 diabetic participants randomly selected from general population (124 of whom had EH) was quantified using a real-time PCR.
The 15059G>A heteroplasmy exceeding 39% was found to be significantly associated with a higher risk of EH (odds ratio 1.96; P (Fisher) 0.032).
There is the first evidence reporting association between the mtDNA 15059G>A mutation heteroplasmy and EH in T2D.
Poly(ADP-ribose) polymerase-1 (PARP-1) is an ubiquitous DNA-binding protein involved in the cellular response to various genotoxic agents. Excessive PARP-1 activation is known to lead to the depletion of intracellular NAD+ and ATP pools and hence to threat cell survival. Therefore, PARP-1 could be involved in neuronal death and contribute to the development of diabetic polyneuropathy (DPN). This study addressed the association of Leu54Phe and Val762Ala polymorphisms of PARP-1 with DPN in Russian type 1 diabetic (T1D) patients. Eighty-six T1D patients with severe DPN and 93 T1D patients with no clinical signs of DPN have been studied by a polymerase chain reaction restriction fragment length polymorphism approach. Using Fisher's exact test revealed the association of the Phe54 and Val762 variants of PARP-1 (odds ratio (OR), 1.66 and 2.88, respectively) with increased risk of DPN in T1D. These results suggest that the PARP1 gene is involved in the pathogenesis of diabetic neuropathy in a Russian population. Additionally, a logistic regression analysis revealed a significant association between the neurological variances such as vibration detection threshold (OR, 2.08), vibration and temperature perception thresholds (OR, 1.32 and 1.67, respectively), and sensory and motor nerve conduction velocities (OR, 2.34 and 2.58, respectively), with DPN.
Melanoma differentiation-associated 5 (MDA5), a product of the IFIH1 gene, is responsible for sensing double-stranded viral double-stranded RNA (RNA). In this study, we showed a significant association of two rare IFIH1 variants, rs35744605 (E627X) and rs35667974 (I923V), with decreased risk of type 1 diabetes (T1D) in a Russian population (for the allele X627, odds ratio [OR] = 0.39, 95% confidence interval [95% CI] = 0.22-0.69, p = 0.0015; for the allele V923, OR = 0.45, 95% CI, 0.30-0.66, p = 5.4 × 10(-5)). We detected a 3.5-fold greater frequency of enteroviral RNA in T1D subjects compared with controls (p
The mucopolysaccharidoses (MPSs) are rare genetic disorders caused by mutations in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). In this study, we analyzed a total of 48 patients including MPSI (n=6), MPSII (n=18), MPSIIIA (n=11), MPSIVA (n=3), and MPSVI (n=10).
In MPS patients, urinary GAGs were colorimetrically assayed. Enzyme activity was quantified by colorimetric and fluorimetric assays. To find mutations, all IDUA, IDS, SGSH, GALNS, and ARSB exons and intronic flanks were sequenced. New mutations were functionally assessed by reconstructing mutant alleles with site-directed mutagenesis followed with expression of wild-type and mutant genetic variants in CHO cells, measuring enzymatic activity, and Western blot analysis of protein expression of normal and mutated enzymes in cell lysates.
A total of five novel mutations were found including p.Asn348Lys (IDUA) in MPSI, p.Tyr240Cys (GALNS) in MPSIVA, and three ARSB mutations (p.Gln110*, p.Asn262Lysfs*14, and pArg315*) in MPSVI patients. In case of mutations p.Asn348Lys, p.Asn262Lysfs*14, and p.Gln110*, no mutant protein was detected while activity of the mutant protein was