Genistein supplementation has no effects on vitamin D levels in healthy Spanish postmenopausal women.

Background: In vitro studies have shown that genistein inhibits the CYP240 enzyme, which is involved in the degradation of 1,25-dihydroxycholecalciferol and its precursor 25-hydroxycholecalciferol, and increases their plasma levels. However, no clinical studies have primarily assessed the synergistic effect of isoflavones on vitamin D levels. The aim of this study was to evaluate the possible additive effect of genistein supplementation on vitamin D levels, calcium metabolism and bone remodeling markers in healthy postmenopausal women during the spring-summer months. Patients and methods: We made a prospective, double-blind study with 150 healthy postmenopausal women that were randomized to three groups. One received placebo, another received calcium (1000 mg/day) and vitamin D (cholecalciferol, 800 U/day) and the third received calcium (1000 mg/day), vitamin D (cholecalciferol, 800 U/day) and genistein (90 mg/day). The study period was from May to September (spring-summer). Vitamin D, PTH, CTX and P1NP were determined by electrochemiluminescence at baseline and after 12 weeks. Results: Vitamin D levels increased in all groups: placebo (23±9 ng/ml vs. 29±10 ng/ml, p<0.05), calcium+vitamin D (26±10 ng/ml vs. 33±8 ng/ml, p<0.05) and calcium+vitamin D+genistein (24±9 ng/ml vs. 31±8 ng/l, p<0.05) without between-group differences. At study end, the percentage of women with vitamin D <20 ng/ml (11%) and <30 ng/ml (39%) had fallen without between-group differences. The effects on calcium metabolism and bone remodeling markers were similar between groups: rises in vitamin D were significantly linked to reductions in PTH, CTX and P1NP. Conclusion: Adding genistein to supplementation with calcium and vitamin D provided not additional changes in vitamin D levels, calcium metabolism or bone remodeling markers in healthy Spanish postmenopausal women during the spring-summer months.

Association between genetic variants in oxidative stress-related genes and osteoporotic bone fracture. The Hortega follow-up study.

The most widely accepted etiopathogenesis hypothesis of the origin of osteoporosis and its complications is that they are a consequence of bone aging and other environmental factors, together with a genetic predisposition. Evidence suggests that oxidative stress is crucial in bone pathologies associated with aging. The aim of this study was to determine whether genetic variants in oxidative stress-related genes modified the risk of osteoporotic fracture. We analysed 221 patients and 354 controls from the HORTEGA sample after 12-14 years of follow up. We studied the genotypic and allelic distribution of 53 SNPs in 24 genes involved in oxidative stress. The results showed that being a carrier of the variant allele of the SNP rs4077561 within TXNRD1 was the principal genetic risk factor associated with osteoporotic fracture and that variant allele of the rs1805754 M6PR, rs4964779 TXNRD1, rs406113 GPX6, rs2281082 TXN2 and rs974334 GPX6 polymorphisms are important genetic risk factors for fracture. This study provides information on the genetic factors associated with oxidative stress which are involved in the risk of osteoporotic fracture and reinforces the hypothesis that genetic factors are crucial in the etiopathogenesis of osteoporosis and its complications.

Association Between Bat Vitamin D Receptor 3' Haplotypes and Vitamin D Levels at Baseline and a Lower Response After Increased Vitamin D Supplementation and Exposure to Sunlight.

Objective: The aim of this study was to evaluate the relationship between vitamin D levels at baseline and after 12 weeks of supplementation/exposure to sunlight and VDR genotypes (BsmI, TaqI and ApaI) and haplotypes in a homogeneous population of postmenopausal women. Methods: We made a prospective study in which 151 women were randomized to two groups: One with 1000 mg of calcium and 800 IU vitamin D supplementation (102 women) and a placebo group with neither calcium or vitamin D supplementation (49 women). The follow-up was from May to September 2012.Vitamin D was determined by chemiluminescent immunoassay. Genotypes were determined using the Sequenomi Plexplatform and haplotypes using PHASE software. Results: Baseline (25 ± 10 ng/mlvs.23 ± 9 ng/ml, p > 0.05) and 12-week (32 ± 8 ng/mlvs.29 ± 10 ng/ml, p > 0.05) vitamin D levels were similar between the two groups. The genetic study was made in the total population. There were no differences in baseline and final levels of vitamin D in terms of genotypes and haplotypes, except for the Bat haplotype, whose baseline values were lower (25OHD: 21 ± 10 ng/mlvs. 21 ± 10 ng/ml, p = 0.038). The rate of nonresponders in this group was 15 % (p = 0.001), compared with 9 %, 2 % and 3 % in the other groups. Conclusions: The Bat haplotype was associated with lower baseline levels of vitamin D and a worse response to supplementation and, therefore, may be a risk factor for vitamin D deficiency.

Estrogen receptor genes polymorphisms determine serum lipid profile in healthy postmenopausal women treated with calcium, vitamin D, and genistein.

Cardiovascular risk increases in women after menopause. Unfavorable lipid-lipoprotein changes due to a lack of estrogens may have an important role in this context. Estrogen actions are mainly mediated by their binding to two estrogen receptors (ERs) whose signaling may be conditioned by different factors. Calcium, vitamin D, and genistein, among others, cause a beneficial effect on serum lipid profile by its modulation. Some genetic factors can also determine this signal. We determined the possible additive effect of genistein on calcium and vitamin D supplementation regarding serum lipid profile changes and whether ER polymorphisms may mediate in this effect. We performed a prospective, double blind study in which women were randomized in two groups: one group received calcium and vitamin D and the other group received calcium, vitamin D and genistein. Subsequently, we studied rs9340799, rs928554, and rs4986938 ER polymorphisms in both groups. Our results showed that being a carrier of the variant allele G of rs928554 polymorphism was associated with a greater decrease in triglyceride levels and that the homozygous AA genotype of rs9340799 polymorphism was associated with a greater decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels after calcium, vitamin D, and genistein supplementation. This is the first report showing an association between polymorphisms in ER genes and an improvement of the serum lipid profile after taking calcium, vitamin D, and genistein supplementation in postmenopausal women. It reinforces the hypothesis that genetic factors are crucial in ER signalling.

The Effect of Genistein Supplementation on Vitamin D Levels and Bone Turnover Markers during the Summer in Healthy Postmenopausal Women: Role of Genotypes of Isoflavone Metabolism.

AIMS: The objective of this study was to determine whether vitamin D and genistein supplementation had an additive beneficial effect on levels of vitamin D and bone markers and whether this effect was mediated by genes regulating isoflavone metabolism. MATERIALS AND METHODS: We carried out a prospective study in postmenopausal women randomized to calcium and vitamin D supplementation or calcium, vitamin D, and genistein supplementation. Vitamin D, parathyroid hormone (PTH), cross-linked C-telopeptide (CTX), and procollagen 1 N-terminal (P1NP) were determined by electrochemiluminescence. Three SNPs - rs2231142 (ABCG2), rs358231 (cytosolic ß-glucosidase [CBG]), and rs2273697 (ABCC2) - were determined. RESULTS: We included 102 women. The effects on bone remodeling were similar: rises in vitamin D were significantly associated with reductions in PTH, CTX, and P1NP. Pharmacogenomic analysis of the genotypes showed that, in AT heterozygotes of the CBG1368T>A polymorphism, CTX and P1NP were not reduced. CONCLUSION: Genistein added to calcium and vitamin D supplementation had no additional effect. The supplementation of individual AT heterozygotes of the CBG1368T>A polymorphism had no effect on markers of bone remodeling.

Genomic and Metabolomic Profile Associated to Clustering of Cardio-Metabolic Risk Factors.

BACKGROUND: To identify metabolomic and genomic markers associated with the presence of clustering of cardiometabolic risk factors (CMRFs) from a general population. METHODS AND FINDINGS: One thousand five hundred and two subjects, Caucasian, > 18 years, representative of the general population, were included. Blood pressure measurement, anthropometric parameters and metabolic markers were measured. Subjects were grouped according the number of CMRFs (Group 1: <2; Group 2: 2; Group 3: 3 or more CMRFs). Using SNPlex, 1251 SNPs potentially associated to clustering of three or more CMRFs were analyzed. Serum metabolomic profile was assessed by 1H NMR spectra using a Brucker Advance DRX 600 spectrometer. From the total population, 1217 (mean age 54±19, 50.6% men) with high genotyping call rate were analysed. A differential metabolomic profile, which included products from mitochondrial metabolism, extra mitochondrial metabolism, branched amino acids and fatty acid signals were observed among the three groups. The comparison of metabolomic patterns between subjects of Groups 1 to 3 for each of the genotypes associated to those subjects with three or more CMRFs revealed two SNPs, the rs174577_AA of FADS2 gene and the rs3803_TT of GATA2 transcription factor gene, with minimal or no statistically significant differences. Subjects with and without three or more CMRFs who shared the same genotype and metabolomic profile differed in the pattern of CMRFS cluster. Subjects of Group 3 and the AA genotype of the rs174577 had a lower prevalence of hypertension compared to the CC and CT genotype. In contrast, subjects of Group 3 and the TT genotype of the rs3803 polymorphism had a lower prevalence of T2DM, although they were predominantly males and had higher values of plasma creatinine. CONCLUSIONS: The results of the present study add information to the metabolomics profile and to the potential impact of genetic factors on the variants of clustering of cardiometabolic risk factors.

Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study.

Atraumatic subtrochanteric and diaphyseal (atypical) femoral fractures are a rare, but important adverse event in patients treated with potent anti-resortive agents. The mechanisms involved are unknown and particularly the association with genetic variants has not been explored. The aim of the study was to identify rare genetic variants that could be associated with the occurrence of these fractures. We performed a genome-wide analysis of up to 300,000 variants, mainly distributed in gene coding regions, in 13 patients with atypical femoral fractures and 268 control women, either healthy or with osteoporosis. Twenty one loci were more frequent in the fracture group, with a nominal p value between 1 × 10(-6) and 2.5 × 10(-3). Most patients accumulated two or more allelic variants, and consequently the number of risk variants was markedly different between patients and controls (p = 2.6 × 10(-22)). The results of this pilot study suggest that these fractures are polygenic and are associated with the accumulation of changes in the coding regions of several genes.

Genomic and metabolomic profile associated to microalbuminuria.

To identify factors related with the risk to develop microalbuminuria using combined genomic and metabolomic values from a general population study. One thousand five hundred and two subjects, Caucasian, more than 18 years, representative of the general population, were included. Blood pressure measurement and albumin/creatinine ratio were measured in a urine sample. Using SNPlex, 1251 SNPs potentially associated to urinary albumin excretion (UAE) were analyzed. Serum metabolomic profile was assessed by 1H NMR spectra using a Brucker Advance DRX 600 spectrometer. From the total population, 1217 (mean age 54 ± 19, 50.6% men, ACR>30 mg/g in 81 subjects) with high genotyping call rate were analysed. A characteristic metabolomic profile, which included products from mitochondrial and extra mitochondrial metabolism as well as branched amino acids and their derivative signals, were observed in microalbuminuric as compare to normoalbuminuric subjects. The comparison of the metabolomic profile between subjects with different UAE status for each of the genotypes associated to microalbuminuria revealed two SNPs, the rs10492025_TT of RPH3A gene and the rs4359_CC of ACE gene, with minimal or no statistically significant differences. Subjects with and without microalbuminuria, who shared the same genotype and metabolomic profile, differed in age. Microalbuminurics with the CC genotype of the rs4359 polymorphism and with the TT genotype of the rs10492025 polymorphism were seven years older and seventeen years younger, respectively as compared to the whole microalbuminuric subjects. With the same metabolomic environment, characteristic of subjects with microalbuminuria, the TT genotype of the rs10492025 polymorphism seems to increase and the CC genotype of the rs4359 polymorphism seems to reduce risk to develop microalbuminuria.