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Biomedical subjects

María T Zarrabeitia

Publications and source records attributed to María T Zarrabeitia.

12 recordsLinked to original sources
PubMed2006

Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis.

CONTEXT: Osteoporosis has a significant genetic component. The aromatase-dependent conversion of androgenic precursors is the main source of estrogens in postmenopausal women. OBJECTIVE: The objective of the investigation was to study the relationship of a set of single nucleotide polymorphisms (SNPs) of the aromatase gene with osteoporosis and determine their functional influence on gene transcription. DESIGN, PARTICIPANTS, AND METHODS: This was a case-control study including 135 women with vertebral fractures due to postmenopausal osteoporosis and 312 controls. Alleles at four SNPs situated between exons I.2 and 3 were determined by Taqman assays. Total aromatase RNA and differential allelic-specific expression were studied by RT-real time PCR in adipose tissue samples taken from 50 individuals. RESULTS: The SNPs studied were in strong linkage disequilibrium. A common haplotype, present in about half of the population, was identified as being associated with an increased risk of fractures (odds ratio 1.8, 95% confidence interval 1.2-2.8, P = 0.006). There was evidence of differential allelic expression. In heterozygous individuals, transcripts bearing T alleles at rs700518 SNP (which were included in the risk haplotype) were less abundant than those with the alternative C alleles (P < 0.001). Total aromatase expression was four times lower in fat samples from individuals who were homozygotes for the unfavorable alleles than in the opposite homozygotes (P = 0.007). CONCLUSIONS: A common haplotype of aromatase associated with gene expression is also associated with the risk of osteoporotic vertebral fractures in postmenopausal women. These data are in line with the hypothesis that the aromatase-dependent synthesis of estrogens plays an important role in bone homeostasis in postmenopausal women.

Adult↗
PubMed2006

Association of the F352V variant of the Klotho gene with bone mineral density.

Klotho gene codes for a protein with glucuronidase activity and is thought to influence bone and vascular homeostasis. We studied the relationship of a common T/G polymorphism, resulting in a phenylalanine (F) to valine (V) substitution at aminoacid position 352, with bone mineral density (BMD) and osteoporotic fractures. The study group comprised 914 Spanish women, including 438 control subjects, 190 patients with osteoporosis, 198 with hip fractures, and 88 patients with severe osteoarthritis. BMD was measured by DEXA in 540 women from the control and osteoporosis groups. Allele frequencies were 86% and 14%, for the F and V alleles, respectively. In comparison with the most common FF genotype, postmenopausal women with FV/VV genotypes had higher hip BMD (femoral neck: 0.673 +/- 0.011 vs. 0.644 +/- 0.006 g/cm(2); P = 0.02; total hip: 0.807 +/- 0.014 vs. 0.774 +/- 0.008 g/cm(2); P = 0.03). Klotho alleles explained about 1.5% of BMD variance, but were not associated to the risk of osteoporotic spine or hip fractures. The Klotho genotype was not associated to BMD in premenopausal women. In conclusion, the F352V Klotho polymorphism is associated with BMD in postmenopausal women, suggesting that Klotho gene variants influence skeletal aging.

Adult↗
PubMed2006

A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density.

OBJECTIVE: The aromatization of androgenic precursors is the main source of estrogens in postmenopausal women. We tested the hypothesis that allelic variants of the genes coding for aromatase and estrogen receptors (ER) could interact to determine the estrogenic signals on the bone tissue and, consequently, bone mineral density (BMD). DESIGN: Cross-sectional study including 331 postmenopausal women. METHODS: BMD was measured by dual energy x-ray absorptiometry. A CG polymorphism of the aromatase gene as well as three polymorphisms of ERalpha (a TA repeat in the promoter region, a C T single nucleotide polymorphism (SNP) in intron 1 and an AG SNP in exon 8) and a CA repeat polymorphism of ERbeta were studied. RESULTS: Age, body weight and the aromatase genotype were associated with BMD. Allelic variants of ERbeta and the exon 8 of ERalpha did not show a significant association with BMD. The polymorphisms located on the promoter and intron 1 of ERalpha interacted strongly with aromatase. Thus, in women TT homozygous for the ERalpha gene, there was a marked influence of aromatase genotypes on BMD: spine BMD was 0.724 +/- 0.027 g/cm2 in women with CC aromatase alleles and 0.926 +/- 0.032 g/cm2 in those with GG alleles (P < 0.001). Hip BMD in women with CC and GG aromatase genotypes was 0.722 +/- 0.020 and 0.842 +/- 0.026 g/cm2 respectively (P = 0.002). On the contrary, there were no aromatase-related differences in BMD in women with CT/CC alleles of ERalpha. Similarly, aromatase-related differences in BMD were found in women with short alleles at the promoter region of ERalpha, but not in those with long alleles. Both ERalpha polymorphisms were in strong linkage disequilibrium (P < 0.001). CONCLUSION: These results suggest that the interaction between polymorphisms of genes involved in estrogen synthesis and estrogen signaling exerts an important influence on BMD in postmenopausal women, thus helping to explain, in part, its heritable component. Nevertheless, further studies are warranted to confirm this gene-to-gene interaction in other populations.

Absorptiometry, Photon↗
PubMed2005

Interaction between CYP19 aromatase and butyrylcholinesterase genes increases Alzheimer's disease risk.

Biological evidence supports a role of aromatase and butyrilcholinesterase (BCHE) enzymes in the disruption of the cholinergic neurotransmission observed in Alzheimer's disease (AD). Estrogens may reduce the risk of AD through enhancing or preserving cholinergic neurotransmission, and aromatase, the product of the CYP19 gene, is a critical enzyme in the peripheral synthesis of estrogens. BCHE is a hydrolytic enzyme associated with acetylcholine synaptic degradation, and the BCHE K genetic variant confers some protective effect for AD by reducing the activity of the enzyme. We investigated whether a 5'-UTR CYP19 polymorphism and the BCHE K variant might be responsible for susceptibility to AD by studying a clinically well-defined group of 187 sporadic AD patients and 172 control subjects from a Spanish population. We have shown that the CYP19 C/C genotype is overrepresented in AD patients who carry the BCHE non-K allele when compared with controls (OR=1.85, p=0.03). Our findings suggest that the CYP19 and BCHE polymorphisms may interact in determining the risk of AD.

Aged↗
PubMed2005

Aromatase gene and osteoporosis: relationship of ten polymorphic loci with bone mineral density.

Aromatase activity appears to be important for bone homeostasis in postmenopausal women. In fact, therapy with aromatase inhibitors is associated with bone loss and fractures. A common biallelic A/G polymorphism in the 3'-untranslated region (UTR) of CYP19-aromatase gene has been associated with differences in gene transcription and the risk of estrogen-responsive tumors. We explored the relationship of such a polymorphism and other 9 polymorphisms situated within or near CYP19 gene with bone mass. The study group comprised 286 postmenopausal women. DNA was isolated from peripheral blood. Biallelic and insertion/deletion polymorphisms were analyzed with exonuclease assays using TaqMan probes. A microsatellite polymorphism in intron 4 was studied by capillary electrophoresis. Bone mineral density (BMD) was determined by DXA. In this cross-sectional study, the postmenopausal decrease in bone mass appeared to be slower in women with AA genotype in the 3'UTR, than in those with AG or GG genotypes. Consequently, there were significant genotype-related differences in BMD. In women after age of 60, hip T-scores were: AA -1.3 +/- 0.1, AG -1.3 +/- 0.2, GG -1.9 +/- 0.1 (P = 0.002). Lumbar spine T-scores were: AA -1.9 +/- 10.2, AG -2.2 +/- 0.1, GG -3.0 +/- 0.2 (P = 0.001). Moreover, GG genotype showed a trend for lower free estrogen levels. This polymorphism was strongly linked to a tetranucleotide repeat in intron 4, as well as to other biallelic polymorphisms situated between 3'UTR and I.2 promoter regions. They all were associated with BMD. However, biallelic polymorphisms in the extreme 5' region of CYP19 and two polymorphisms in neighbor genes were not associated with BMD. In conclusion, common variations of CYP19-aromatase are associated with differences in BMD that seem to be important from an individual as well as from a population perspective.

Aromatase↗
PubMed2004

Age-related influence of common aromatase gene polymorphisms on bone mass of healthy men.

Androgens and estrogens are critical factors for bone homeostasis; hence, polymorphisms of genes involved in the metabolism and activity of sex steroids are likely candidates to influence bone mass. Therefore, we studied the association of two of those microsatellite polymorphisms, situated in intron 4 of CYP19-aromatase and exon 1 of androgen receptor, with bone mass in a group of 324 healthy men of a wide age range (mean age 49, range 22-75). CYP19 and androgen receptor alleles were typed by capillary electrophoresis after PCR amplification. Bone mass was measured by dual X-ray absorptiometry at the hip and the spine. No association was found between androgen receptor variation and bone mass. However, among the 184 subjects aged more than 45 years, a significant association was found between CYP19 alleles and bone mass at the lumbar spine (P = 0.001) and total hip (P = 0.01). Individuals with long alleles had higher bone mass, even after adjusting for body weight, height, or calcium intake. Mean spine Z scores were -0.1 (95% CI, -0.3 to 0.2), -0.1 (-0.4 to 0.2), and 0.6 (0.3 to 0.9) for individuals with short, intermediate, and long alleles, respectively. Total hip Z scores were 0.4 (0.2 to 0.6), 0.4 (0.2 to 0.6), and 0.8 (0.5 to 1.0), respectively. Longer CYP19 alleles were also associated with higher free estradiol index. These results suggest that common variations in CYP19-aromatase gene may have an important influence on the maintenance of male skeleton after peak bone mass is reached.

Adult↗
PubMed2003

A Windows-based software for common paternity and sibling analyses.

A new Windows-based freeware for kinship analysis from DNA data is presented. This software can be used to calculate likelihood ratios and probabilities of paternity in trio and motherless cases, as well as in cases when a parent is lacking but there are data from the grandparents. It can also be used to compute the probability of two subjects being full-brothers or half-brothers.

DNA Fingerprinting↗
PubMed2003

Spanish population data and forensic usefulness of a novel Y-STR set (DYS437, DYS438, DYS439, DYS460, DYS461, GATA A10, GATA C4, GATA H4).

DNA typing of 8 recently described STRs on the Y chromosome was carried out by means of 2 multiplex amplification reactions for 134 unrelated males from Cantabria, a region in northern Spain. Multiplex 1 included loci DYS460 (GATA A7.1), GATA A10, GATA H4 and DYS439; multiplex 2 included DYS461 (GATA A7.2), GATA C4, DYS437 and DYS438. Haplotype diversity was found to be 99.36%, similar to that obtained with the standard 9-STR set ("minimal haplotype") of the European Y-user group (99.35%). The 13-locus haplotype resulting from the combination of the standard minimal haplotype and the 4-locus multiplex 1 showed a 99.89% diversity. Further inclusion of the 4 loci in multiplex 2 resulted in a haplotype diversity of 99.93%. The combination of the "minimal haplotype" and the multiplex 1 in the present study may be an efficient way of increasing the power of discrimination in forensic cases.

Alleles↗
PubMed2003

Significance of micro-geographical population structure in forensic cases: a bayesian exploration.

We studied the influence of population structure at the microgeographical level on the analysis of forensic cases. A total of nine autosomal STRs and seven Y-STRs were analyzed in the general mixed population and in two relatively isolated valleys of Cantabria, a region in Northern Spain. Statistically significant differences existed in the frequency distribution of four autosomal STRs, with an overall Fst value of 0.3%. A simulation of virtual trio cases revealed that it did not have a practical influence on the analysis of paternity disputes. Significant differences also existed in most Y-STRs, with an overall Fst value of 3%. Thus, using the general database instead of the specific valley database resulted in 5-fold or higher overestimation of the likelihood ratio of matching in up to 30% of cases. A bayesian analysis revealed that this had a significant impact on the estimation of the probability of identity in scenarios of low "a priori" odds of suspicion.

Alleles↗
PubMed2002

A new pentaplex system to study short tandem repeat markers of forensic interest on X chromosome.

A new method has been optimised to amplify five X chromosome short tandem repeat (STR) markers of interest in forensic medicine: human phosphoribosyl transferase (HPRTB), DXS101, androgen receptor (ARA), DXS7423 and DXS8377. Markers were conveniently amplified in a single PCR reaction with fluorochrome-labelled primers, which allowed the analysis of fragment sizes after injection into a capillary electrophoresis system. The most common alleles of each locus were sequenced and used in a control ladder to type unknown samples.

Adult↗
PubMed2002

Sequence structure and population data of two X-linked markers: DXS7423 and DXS8377.

DXS7423 and DXS8377 are two microsatellite markers located in the q28 band of chromosome X. We developed a protocol to amplify both markers in a single reaction, sequenced the most common alleles and studied allele frequencies in a Spanish population sample. DXS7423 allele variability was due to different numbers of (TCCA) repeats and five different alleles were found with apparent sizes between 181 and 197 bp. The probability of discrimination (PD) was 87% for female samples, and the expected probability of exclusion (PE) was 71%. DXS8377 appeared as a highly polymorphic marker with variable numbers of (CTC), (TCC) and (TTC) repeats. We found 18 alleles of different sizes (204-258 bp) and the PD and PE were 99% and 93%, respectively. These data suggest that DXS7423 and DXS8377 can be very useful markers for genetic forensic studies.

Chromosomes, Human, X↗