Summary
Background
Raloxifene is a selective oestrogen receptor modulator with effects on bone and breast cancer and cardiovascular disease risk. The aim of this study was to examine the influence of ...raloxifene treatment on surrogate markers of atherosclerosis and the correlation of these markers with raloxifene serum concentrations.
Methods
A prospective clinical trial on 53 postmenopausal osteoporotic women treated with raloxifene was performed. Surrogate markers of atherosclerosis (flow-mediated vasodilatation, glyceryltrinitrate-induced vasodilatation of the brachial artery, carotid intima-media thickness (c-IMT), inter-cell adhesion molecule-1, vascular-cell adhesion molecule-1 and E-selectin) were measured before and after 6 months of treatment. Serum concentrations of raloxifene and raloxifene metabolites were assessed after 12 months of treatment. The tested markers were correlated with measured serum concentrations of raloxifene species.
Results
Among the tested surrogate markers of atherosclerosis c-IMT, E-selectin and ICAM changed significantly during treatment. A negative correlation of the non-metabolized raloxifene serum levels with the percentage change of c-IMT during treatment (r = − 0.315,
p
= 0.048) was found. Likewise, the sum of the levels of three raloxifene metabolites, raloxifene-6-b-glucuronide (M1), raloxifene-4'-b-glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3) in serum showed a negative correlation with the percentage change of c-IMT during treatment (r = − 0.375,
p
= 0.017). For the other tested parameters, no correlation with raloxifene serum levels was found.
Conclusions
To the best of our knowledge, this is the first study correlating raloxifene species serum concentrations with changes in the surrogate markers of atherosclerosis. A greater decrease of c-IMT in patients with higher raloxifene concentrations could contribute to a lower risk of cardiovascular events in these patients.
Background and Aims N-acetyltransferase 2 (NAT2) is a drug-metabolizing enzyme, which is genetically variable in human populations. Polymorphisms in the NAT2 gene have been associated with drug ...efficacy and toxicity as well as disease susceptibility. Recently, an association of NAT2 gene variation with risk of type 2 diabetes mellitus (T2DM) has been suggested. This is the first study performed in a population from Bosnia and Herzegovina (BH) in which the frequency of two common NAT2 polymorphisms, 341T>C ( NAT2∗ 5) and 590G>A ( NAT2∗6 ) was determined in diabetic patients. Methods The frequency of the NAT2∗5 (341T>C) and NAT2∗6 (590G>A) polymorphisms was analyzed by employing TaqMan SNP Genotyping Assays (Applied Biosystems) in a group of 63 patients with T2DM and 79 nondiabetic subjects. Results Our data demonstrated that the frequencies of NAT2∗5 (341T>C) and NAT2∗6 (590G>A) polymorphisms in BH population were in line with the Caucasians genotype data. The NAT2∗5 and NAT2∗6 alleles were in high linkage disequilibrium (D′ = 0.969). Strinkingly, there was a significant difference in genotype frequencies for NAT2∗5 ( p <0.05) and NAT2∗6 ( p <0.001) polymorphisms between diabetic and nondiabetic subjects. NAT2∗5 polymorphism was associated with 2.4-fold increased risk for developing T2DM (adjusted OR = 2.40, 95% CI = 1.10–5.25, p = 0.028). On the contrary, NAT2∗6 variant significantly decreased by 5-fold susceptibility to the disease (adjusted OR = 0.20, 95% CI = 0.09–0.43, p <0.001). Conclusions Our data demonstrated that NAT2 genetic variation appeared to be an important risk factor in development of T2DM.
Cathepsin K is a cysteine protease that plays an essential role in organic bone matrix degradation. The aim of our study was to seek correlation of serum cathepsin K levels and a change in bone ...mineral density (BMD) over a 3-year period in a population of healthy nonosteoporotic women. The secondary end points were the correlations of serum cathepsin K with cross-sectional BMD and with other serum bone turnover markers and age.
In 43 healthy women aged 42 to 57 years, blood samples for determination of cathepsin K, osteocalcin, bone alkaline phosphatase, C-terminal cross-linking telopeptide of type I collagen, osteoprotegerin, and nuclear factor kappaB ligand were collected at the time of the first BMD measurement. BMD measurements were repeated after 3 years.
We found a moderate negative correlation of serum cathepsin K levels with change in femoral neck BMD, but none with change in spinal BMD. There were no significant correlations between cross-sectional BMD of the spine or femoral neck and serum levels of cathepsin K. Serum levels of cathepsin K were not significantly correlated with any bone turnover markers studied or with age.
Serum cathepsin K does not seem to represent a surrogate for bone turnover markers used at present, but it might be useful as a predictor of cortical bone loss.
Polymorphisms in HSD11B1, the gene encoding 11β-hydroxysteroid dehydrogenase type 1 enzyme, have been associated with obesity, metabolic syndrome, and type 2 diabetes. In this study, we present an ...optimized high-resolution melting (HRM) method for genotyping two common polymorphisms of the HSD11B1 gene: rs846910: G>A and rs45487298: insA.
One hundred DNA samples from patients with polycystic ovary syndrome and healthy controls were genotyped by HRM. The results were compared with those obtained with classic polymerase chain reaction followed by restriction fragment length polymorphism analysis.
Various approaches were used during HRM specificity optimization. With the optimized method, genotyping accuracy of 100% was achieved.
HRM analysis is a fast, simple, and cost-effective method compared with the alternative genotyping approaches. The work required for optimizing the method (improvement of specificity) is minor compared to the advantages.
Aim
To investigate association of two LPIN1 gene variations with main traits of metabolic syndrome (MS) (waist circumference,
body mass index, blood pressure, triglycerides, HDL-cholesterol and ...fasting glucose levels) in population from Bosnia and Herzegovina.
Methods
This study included 43 patients with metabolic syndrome and 43 healthy controls from General Hospital in Tešanj, Bosnia and Herzegovina. Subjects were genotyped for two LPIN1 gene variations (rs11693809: C>T and rs2716610: C>T) by real
time PCR method.
Results
In control subjects LPIN1 polymorphism, rs2716610: C>T, was significantly associated with a lower body mass index
(BMI) (p=0.008) and waist circumference (p=0.008). The second analyzed rs11693809: C>T polymorphism was associated with lower blood HbA1c levels (p=0.048) in a group of MS patients.
Conclusion
Results of our study suggest that rs2716610: C>T polymorphism of LPIN1 gene could have a protective effect against development of metabolic syndrome, while rs11693809: C>T might affect a glucose control in patients with MS.
Uvod. Osteogenesis imperfecta (OI) je vzročno heterogena bolezen, katere značilnost je osteoporoza v otroštvu. Pri vseh opisanih bolnikih s podtipom OI tipa V je vzrok bolezni ista mutacija c.-14C>T ...gena IFITM5. Kljub temu med bolniki obstaja izrazita fenotipska variabilnost v klinični sliki, toda opisan je le dober odgovor na zdravljenje z bisfosfonati.
Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. ...Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good.
Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed.
In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452.
The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.
Introduction. Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 ...gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good.
Methods. Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed.
Results. In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452.
Conclusions. The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism.
Uvod. Osteogenesis imperfecta (OI) je vzročno heterogena bolezen, katere značilnost je osteoporoza v otroštvu. Pri vseh opisanih bolnikih s podtipom OI tipa V je vzrok bolezni ista mutacija c.-14C>T gena IFITM5. Kljub temu med bolniki obstaja izrazita fenotipska variabilnost v klinični sliki, toda opisan je le dober odgovor na zdravljenje z bisfosfonati.
Metode. Oba bolnika z OI tipa V sta imela ponavljajoče se zlome kosti s hipertrofičnimi kalusi, skoliozo in zakostenelo membrano med podlahtnico in koželjnico. Opravili smo sekvenčno analizo gena IFITM5 in genotipizacijo variant rs2297480 gena za farnesil difosfat sintazo (FDPS) in rs3840452 gena za geranilgeranil difosfat sintazo 1 (GGPS1), ki sta vpletena v presnovo bisfosfonatov.
Rezultati. Pri bolniku 1 se je ob zdravljenju z bisfosfonati mineralna kostna gostota povečala do normalnih vrednosti in ostala nespremenjena štiri leta po prenehanju zdravljenja. Pri bolniku 2 kljub pet let trajajočemu zdravljenju z bisfosfonati ni prišlo do izboljšanja mineralne kostne gostote, še naprej so se pojavljali zlomi kosti in hipertrofični kalusi. Pri obeh bolnikih smo ugotovili znano mutacijo c.-14C>T v genu IFITM5 v heterozigotni obliki. Oba imata v homozigotni obliki prisotno tudi varianto rs2297480 gena FDPS in v heterozigotni obliki varianto rs3840452 gena GGPS1.
Zaključek. V članku je predstavljen kratek pregled osteoporoze v otroštvu s posebnim poudarkom na OI tipa V pri dveh bolnikih. Pri obeh bolnikih z OI tipa V, ki sta imela različno klinično sliko in potek bolezni, smo ugotovili mutacijo c.-14C>T v genu IFITM5. Z analizo genov encimov, vpletenih v presnovo bisfosfonatov, nismo mogli pojasniti neuspešnega zdravljenja z bisfosfonati pri enem od bolnikov.
The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of the hormonally inactive cortisone to active cortisol, thus facilitating glucocorticoid receptor ...activation in target tissues. Increased expression of 11beta-HSD1 in adipose tissue has been associated with obesity and insulin resistance. In this study, we investigated the association of two 11beta-HSD1 gene (HSD11B1) polymorphisms with the metabolic syndrome (MetS) and its characteristics in the Bosnian population.
The study included 86 participants: 43 patients diagnosed with MetS and 43 healthy controls. Subjects were genotyped for two HSD11B1 gene polymorphisms: rs846910: G > A and rs45487298: insA, by the high resolution melting curve analysis. Genotype distribution and an influence of genotypes on clinical and biochemical parameters were assessed.
There was no significant difference in the mutated allele frequencies for the two HSD11B1 gene polymorphisms between MetS patients and controls. In MetS patients, no significant associations between disease-associated traits and rs45487298: insA were found. Regarding rs846910: G > Avariant, heterozygous patients (G/A) had significantly lower systolic (P = 0.017) and diastolic blood pressure (P = 0.015), lower HOMA-IR index (P = 0.011) and higher LDL-cholesterol levels (P = 0.049), compared to the wild-type homozygotes. In the control group, rs45487298: insA polymorphism was associated with lower fasting plasma insulin levels (P = 0.041), lower homeostasis model assessment insulin resistance (HOMA-IR) index (P = 0.041) and lower diastolic blood pressure (P = 0.048). Significant differences between rs846910: G > A genotypes in controls were not detected. Haplotype analysis confirmed the association of rs45487298: insA with markers of insulin resistance in the control subjects.
Our results indicate that a common rs45487298: insA polymorphism in HSD1181 gene may have a protective effect against insulin resistance.
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