Petra Lukasova

Role of D327N sex hormone-binding globulin gene polymorphism in the pathogenesis of polycystic ovary syndrome.

SHBG (sex hormone-binding globulin) is a transport protein specific for dihydrotestosterone, testosterone and estradiol. The missense mutation in exon 8 (GAC-->AAC) causing the amino acid exchange Asp-->Asn in codon 327 (D327N) correlates according to the published data with increased SHBG levels. We studied possible association of this polymorphism with polycystic ovary syndrome (PCOS) and anthropometric and biochemical parameters in 248 PCOS patients and 109 healthy control women. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). For statistical evaluation chi(2) test, Mann-Whitney test, ANCOVA, ANOVA (NCSS 2004, Statgraphics Plus v.5.1, USA) were used. There was no significant difference in genotype distribution between PCOS and controls (chi(2)=1.03, p=0.59). Moreover, we did not find an association of the variant allele with plasma SHBG level, steroid hormones, or screened parameters of lipid and glucose metabolism. In conclusion, the D327N polymorphism of the SHBG gene does not influence susceptibility to PCOS.

MTNR1B Genetic Variability Is Associated with Gestational Diabetes in Czech Women.

The gene MTNR1B encodes a receptor for melatonin. Melatonin receptors are expressed in human β-cells, which implies that genetic variants might affect glucose tolerance. Meta-analysis confirmed that the rs10830963 shows the most robust association. The aim of the study was to assess the rs10830963 in Czech GDM patients and controls and to study relations between the SNP and biochemical as well as anthropometric characteristics. Our cohort consisted of 880 women; 458 were diagnosed with GDM, and 422 were normoglycemic controls without history of GDM. Despite similar BMI, the GDM group showed higher WHR, waist circumference, abdominal circumference, and total body fat content. The risk allele G was more frequent in the GDM group (38.3 versus 29.4% in controls, OR 1.49 CI95% [1.22; 1.82]; P OR = 0.0001). In spite of higher frequency, the G allele in the GDM group was not associated with any markers of glucose metabolism. In contrast, controls showed significant association of the allele G with FPG and with postchallenge glycemia during the oGTT. Frequency analysis indicates that rs10830963 is involved in gestational diabetes in Czech women. However, the association of the SNP with glucose metabolism, which is obvious in controls, is covert in women who have experienced GDM.

Associations of polymorphisms in the candidate genes for Alzheimer’s disease BIN1, CLU, CR1 and PICALM with gestational diabetes and impaired glucose tolerance

Alzheimer’s disease (AD) is the most common type of dementia, with a prevalence that is rising every year. AD is associated with type 2 diabetes mellitus (T2DM) and insulin resistance, and is therefore sometimes called “type 3 diabetes mellitus”. The aim of this study was to examine whether the variants of some candidate genes involved in the development of AD, namely BIN1 (rs744373), CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179), are related to several disorders of glucose metabolism—gestational diabetes (GDM), T2DM and impaired glucose tolerance (IGT). Our study included 550 women with former GDM and 717 control women, 392 patients with T2DM and 180 non-diabetic controls, and 117 patients with IGT and 630 controls with normal glucose tolerance. Genotyping analysis was performed using specially-designed TaqMan assays. No significant associations of the genetic variants rs744373 in BIN1, rs11136000 in CLU, or rs3818361 in CR1 were found with GDM, T2DM or IGT, but rs3851179 in PICALM was associated with an increased risk of GDM. The frequency of the AD risk-associated C allele was significantly higher in the GDM group compared to controls: OR 1.21; 95% CI (1.03–1.44). This finding was not apparent in T2DM and IGT; conversely, the C allele of the PICALM SNP was protective for IGT: OR 0.67; 95% CI (0.51–0.89). This study demonstrates an association between PICALM rs3851179 and GDM as well as IGT. However, elucidation of the possible role of this gene in the pathogenesis of GDM requires further independent studies.

SHBG Genetic Variability and Glucose Tolerance in T2DM Patients, Gestational Diabetics, and Women with PCOS in Comparison with the Control Czech Population Sample

Background: Sex hormone-binding globulin (SHBG) belongs to the factors contributing to the pathophysiology of type 2 diabetes mellitus (T2DM). We determined genotypic frequencies of the single nucleotide polymorphisms (SNPs) rs6259 and rs6257 in T2DM patients, offspring of T2DM patients, gestational diabetics, patients suffering from polycystic ovary syndrome (PCOS), and in healthy adult Czechs. 1687 volunteers entered the study. The aim was to compare genetic constellation between the groups and to study the possible association of the SNPs with biochemical and anthropometric markers of insulin sensitivity. Methods: TaqMan (LC480, Roche) was used for genotyping, statistical evaluation was carried out using Statgraphics Centurion version XVI and NCSS 2007. Results: The SNPs distribution was similar between the groups. We found lower SHBG concentrations in diabetics and PCOS patients. The rs6259 SNP was associated with SHBG levels: in the NN carriers, the concentration was significantly higher in comparison with DD and DN. Unexpected results were observed when association of the rs6259 SNP with insulin sensitivity was assessed. In spite of higher SHBG concentration, which is considered to be protective factor, the NN homozygotes exhibited systematically higher stimulated glucose levels during the 3-hour oral glucose tolerance test and lower Cederholm index of insulin sensitivity. Conclusions: Genetic analysis confirmed the association between rs6259 NN genotype and higher SHBG levels. Furthermore, the NN genotype showed higher stimulated glycemia and lower insulin sensitivity. This observation seems intriguing considering established protective effect of higher SHBG levels in relation to T2DM and should be verified on a larger group of probands.