The “flip-flop” of aldose reductase gene in diabetic retinopathy and nephropathy

Retinopathy and nephropathy - current view

The Kumamoto and UKPDS studies of type-2 diabetes demonstrated that high glucose mean faster worsening for both diabetic retinopathy and nephropathy. However, why so many type-2 diabetics develop nephropathy but no retinopathy? Why so many type-2 diabetics have severe retinopathy and little or no nephropathy? The answer may be genetic susceptibility.

Hypothesis: the “flip-flop” effect of aldose reductase gene

When the CC genotype (high aldose reductase expression) of the (−106) polymorphism of the aldose reductase gene was linked to enhanced retinal susceptibility to hyperglycemia, it was expected that it would also accelerate nephropathy. As the case was the opposite, we now hypothesize that in the kidney, higher aldose reductase activity reduces susceptibility to hyperglycaemia by means of shifting glucose away from the synthesis of Transforming Growth Factor-Beta (TGF-β), a stimulator of mesangial expansion - the landmark of diabetic nephropathy. As the CT & TT genotypes (lower expression of aldose reductase) have effects that are the opposite of those of CC genotype, i.e. retinopathy-protection & nephropathy proneness, we have coined the term “flip-flop”, an acronym taken from electronics, meaning a system that is bi-stable.

If the “flip-flop” was confirmed - what then?

Those diabetics who are retinopathy-protected & nephropathy-prone (CT & TT), should not be given aldose reductase inhibitors (which could worsen nephropathy) but the new breed of TGF-β inhibitors. This might be a first step towards “genetic individualization of diabetes therapy”.     

The APOE4 allele is associated with a decreased risk of retinopathy in type 2 diabetics

Background

Common polymorphisms within the apolipoprotein E (APOE) gene are suggested to be associated with the development of type 2 diabetes mellitus (T2DM), but the potential association with T2DM complications (nephropathy, neuropathy and retinopathy) remains unclear. We perform the case–control study to analyse the association between the APOE polymorphism and risk of T2DM and to analysed the potential relationship between the APOE and T2DM complications.

Methods and results

APOE variants (rs429358 and rs7412) were genotyped by TaqMan assay in T2DM patients (N?=?1274; N?=?829 with complications including retinopathy, neuropathy and nephropathy status) and with PCR–RFLP in healthy nondiabetic controls (N?=?2055). The comparison of subjects with genotypes associated with low plasma cholesterol (APOE2/E2 and APOE2/E3 carriers vs. others) did not show an association with T2DM (OR [95% CI]?=?0.88 [0.71–1.08). The differences remained insignificant after adjusting for diabetes duration, sex and BMI. Carriers of at least one APOE4 allele (rs429358) are protected against T2DM related retinopathy (OR [95% CI]?=?0.65 [0.42–0.99]. Protection against retinopathy is driven mostly by females (OR [95% CI]?=?0.50 [0.25–0.99]); and remains significant (P?=?0.044) after adjustment for diabetes duration and BMI.

Conclusion

Common APOE polymorphism was not associated with T2DM in the Czech population. Yet, APOE4 allele revealed an association with retinopathy. In particular, female T2DM patients with at least one APOE4 allele exhibit lower prevalence of retinopathy in our study subjects.

     

HLA-DPB1*04:01 allele is associated with non-obstructive azoospermia in Japanese patients

Azoospermia is defined by absence of sperm in the semen and can either be caused by obstruction of the seminal tract (obstructive azoospermia) or by defects in spermatogenesis (non-obstructive azoospermia, NOA). Previous studies reported that specific alleles and single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region were associated with NOA in East Asians. We attempt to expand upon previous findings by genotyping more HLA genes and to replicate SNP associations by focusing on Japanese NOA patients. HLA typing of six genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) was done on 355 NOA patients using SSO-Luminex assay while genotyping of two previously reported SNPs (rs498422 and rs3129878) was done on 443 patients and 544 fertile males using TaqMan assay. Association between the HLA alleles and SNP with NOA was assessed with Chi squared and logistic regression tests. We found that HLA-DPB1*04:01 [corrected p value, P _c 7.13 × 10^?6; odds ratio (OR) 2.52], DRB1*13:02 (P _c 4.93 × 10^?4, OR 1.97), DQB1*06:04 (P _c 8.94 × 10^?4, OR 1.91) and rs3129878 (p value 3.98 × 10^?4; OR 1.32) showed significant association with NOA, however, these loci are in linkage disequilibrium with each other. The conditional logistic regression tests showed that DPB1*04:01 is independently associated with NOA, confirming the involvement of the HLA region in the etiology of NOA in Japanese patients.     

Mutations upstream of fabI in triclosan resistant Staphylococcus aureus strains are associated with elevated fabI gene expression

Background

The enoyl-acyl carrier protein (ACP) reductase enzyme (FabI) is the target for a series of antimicrobial agents including novel compounds in clinical trial and the biocide triclosan. Mutations in fabI and heterodiploidy for fabI have been shown to confer resistance in S. aureus strains in a previous study. Here we further determined the fabI upstream sequence of a selection of these strains and the gene expression levels in strains with promoter region mutations.

Results

Mutations in the fabI promoter were found in 18% of triclosan resistant clinical isolates, regardless the previously identified molecular mechanism conferring resistance. Although not significant, a higher rate of promoter mutations were found in strains without previously described mechanisms of resistance. Some of the mutations identified in the clinical isolates were also detected in a series of laboratory mutants. Microarray analysis of selected laboratory mutants with fabI promoter region mutations, grown in the absence of triclosan, revealed increased fabI expression in three out of four tested strains. In two of these strains, only few genes other than fabI were upregulated. Consistently with these data, whole genome sequencing of in vitro selected mutants identified only few mutations except the upstream and coding regions of fabI, with the promoter mutation as the most probable cause of fabI overexpression. Importantly the gene expression profiling of clinical isolates containing similar mutations in the fabI promoter also showed, when compared to unrelated non-mutated isolates, a significant up-regulation of fabI.

Conclusions

In conclusion, we have demonstrated the presence of C34T, T109G, and A101C mutations in the fabI promoter region of strains with fabI up-regulation, both in clinical isolates and/or laboratory mutants. These data provide further observations linking mutations upstream fabI with up-regulated expression of the fabI gene.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1544-y) contains supplementary material, which is available to authorized users.     

Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey

The polymorphic methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms C677T and A1298C cause mild hyperhomocysteinemia, not only in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The aim of this study was to determine allelic frequencies of the polymorphic MTHFR gene C677T, A1298C. In this regard, we have investigated the allelic frequencies of C677T and A1298C polymorphisms of the MTHFR gene in 1684 randomized individuals around Turkey. DNA samples isolated from peripheral blood samples of randomized individuals were analysed. The study population consisted of 1004 females and 680 males. The frequency in Turkey of the C677T was 42.9 %; of C677C, 47.4 %; and of T677T, 9.6 %. The frequency in Turkey of A1298C was 43.7 %; of A1298A, 46.3 %; and of C1298C, 10.0 %. The allelic frequencies of the T allele of MTHFR 677 and the C allele of MTHFR 1298 were 33.34 and 33.16 %, respectively. The frequency of C677T/A1298C compound heterozygosity is highest in Turkey (21.6 %), as compared to Canada (15 %), the United States (17 %) and The Netherlands (20 %).     

Temporomandibular disorder is associated with a serotonin transporter gene polymorphism in the Japanese population

Background  

Selective serotonin-reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of depression and can be used as nonhormonal alternatives to manage hot flashes for women with a history of breast cancer and unable to take hormone replacement therapy. There are, however, few reports on the efficacy of SSRIs for the treatment of natural postmenopausal climacteric symptoms. In this pilot study, we evaluate the SSRI, fluvoxamine, for controlling climacteric symptoms and vasomotor symptoms, in particular.     

Studies on the association of NIDDM in Japanese patients with hyperthyroid Graves' disease.

We attempted to analyze the association of hyperthyroid Graves' disease with non-insulin-dependent diabetes mellitus (NIDDM). Forty-nine patients (23 males and 26 females; 7.6%) of a total of 647 patients with hyperthyroid Graves' disease had NIDDM, several years before or after Graves' disease was diagnosed. Only 1 patient had insulin-dependent diabetes mellitus. Compared with the general Japanese population (n = 9,133), the incidence of NIDDM (n = 348; 3.9%) in patients with Graves' disease was higher in all age groups. Only 4 patients (8.2%) of the 49 hyperthyroid patients with NIDDM had a history of being overweight (body mass index > 25). In contrast, 276 (79.9%) of the 348 diabetic patients were currently or previously overweight. Moreover, the incidence of a family history of diabetes (13 of the 49 hyperthyroid Graves' patients with NIDDM; 26.5%) was also lower in the patients with NIDDM in the general Japanese population (50% incidence). The male:female ration in patients with Graves' disease and NIDDM was 1:1.1; much different from that in the total Graves' disease population (1:4.1). Analysis of the HLA loci A, B, C, DR and DQ (35 determinations) in 35 hyperthyroid patients with NIDDM and in 386 subjects from the general population revealed a highly significant difference between them in the incidence of HLA-Cw4, -DR2, -DQw1, -DQw3 and -DQw4. This study suggests that there was an association of Graves' disease with NIDDM. A significant association of HLA-DR and -DQ loci was observed in hyperthyroid Graves' patients with NIDDM.