Margarita Valdés-Flores

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening

Osteoporosis (OP) is a common skeletal disorder characterized by low bone mineral density (BMD) and is a common health problem in Mexico. To date, few genes affecting BMD variation in the Mexican population have been identified. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) located in genes of the Wnt pathway with BMD variation at various skeletal sites in a cohort of postmenopausal Mexican women. A total of 121 SNPs in or near 15 Wnt signaling pathway genes and 96 ancestry informative markers were genotyped in 425 postmenopausal women using the Illumina GoldenGate microarray SNP genotyping method. BMD was measured by dual-energy X-ray absorptiometry in total hip, femoral neck, Ward’s triangle, and lumbar spine. Associations were tested by linear regression for quantitative traits adjusting for possible confounding factors. SNP rs752107 in WNT3A was strongly associated with decreased total hip BMD showing the highest significance under the recessive model (P = 0.00012). This SNP is predicted to disrupt a binding site for microRNA-149. In addition, a polymorphism of the Wnt antagonist DKK2 was associated with BMD in femoral neck under a recessive model (P = 0.009). Several LRP4, LRP5, and LRP6 gene variants showed site-specific associations with BMD. In conclusion, this is the first report associating Wnt pathway gene variants with BMD in the Mexican population.

Steroid sulfatase activity in leukocytes: a comparative study in 45,X; 46,Xi(Xq) and carriers of steroid sulfatase deficiency

The enzyme steroid sulfatase (STS) hydrolyses 3‐beta‐hydroxysteroid sulfates. The female‐male STS activity ratio is 1.04‐1.7:1 in several cell lines in adults and reaches 2…n1 in prepubertal subjects. In fibroblasts, STS values in X‐chromosome abnormalities show a partial positive correlation according to the number of X‐chromosomes. X‐linked ichthyosis (XLI) carriers, with only one copy of the STS gene, present lower STS levels than normal controls. This study analyzes the STS activity in leukocytes of 46,Xi(Xq); 45,X; XLI carriers and normal controls using 7‐[3H]‐dehydroepiandrosterone sulfate as substrate. X‐monosomy (1.07±0.18 pmol/mg protein/h), Xq isochromosome (1.02±0.12 pmol/mg protein/h) and normal females (1.03±0.11 pmol/mg protein/h) had similar STS values (p>0.05). XLI‐carriers and males showed the lowest STS levels (0.34±0.04 pmol/mg protein/h, p<0.001 and 0.82±0.14 pmol/mg protein/h, p<0.05, respectively). Female‐male STS activity ratio in leukocytes was 1.3…n1. These data indicate that a complex mechanism regulates the STS expression depending on each type of cell line.

Original articleCharacterization of a group unrelated patients with arthrogryposis multiplex congenitaCaracterização de um grupo de pacientes não relacionados com artrogripose múltipla congênita

OBJECTIVE Arthrogryposis multiplex congenita is a relatively rare neuromuscular syndrome, with a prevalence of 1:3000-5000 newborns. In this study, the authors describe the clinical features of a group of 50 unrelated Mexican patients with arthrogryposis multiplex congenita. METHODS Patients were diagnosed by physical and radiographic examination and the family history was evaluated. RESULTS Of the 50 cases, nine presented other features (pectum excavatum, cleft palate, mental retardation, ulnar agenesis, etc.). Environmental factors, as well as prenatal and family history, were analyzed. The chromosomal anomalies and clinical entities associated with arthrogryposis multiplex congenita were reported. No chromosomal aberrations were present in the cases with mental retardation. Three unrelated familial cases with arthrogryposis multiplex congenita were observed in which autosomal recessive, autosomal dominant and X-linked inheritance patterns are possible. A literature review regarding arthrogryposis multiplex congenita was also conducted. CONCLUSIONS It is important to establish patient-specific physical therapy and rehabilitation programs. A multidisciplinary approach is necessary, with medical, surgical, rehabilitation, social and psychological care, including genetic counseling.

Characterization of a group unrelated patients with arthrogryposis multiplex congenita

OBJECTIVE Arthrogryposis multiplex congenita is a relatively rare neuromuscular syndrome, with a prevalence of 1:3000-5000 newborns. In this study, the authors describe the clinical features of a group of 50 unrelated Mexican patients with arthrogryposis multiplex congenita. METHODS Patients were diagnosed by physical and radiographic examination and the family history was evaluated. RESULTS Of the 50 cases, nine presented other features (pectum excavatum, cleft palate, mental retardation, ulnar agenesis, etc.). Environmental factors, as well as prenatal and family history, were analyzed. The chromosomal anomalies and clinical entities associated with arthrogryposis multiplex congenita were reported. No chromosomal aberrations were present in the cases with mental retardation. Three unrelated familial cases with arthrogryposis multiplex congenita were observed in which autosomal recessive, autosomal dominant and X-linked inheritance patterns are possible. A literature review regarding arthrogryposis multiplex congenita was also conducted. CONCLUSIONS It is important to establish patient-specific physical therapy and rehabilitation programs. A multidisciplinary approach is necessary, with medical, surgical, rehabilitation, social and psychological care, including genetic counseling.

Genetic Diseases Related with Osteoporosis

Primary osteoporosis is the disease’s most common form and results from the progressive loss of bone mass related to aging and unassociated with other illness, a natural process in adult life; its etiology is considered multifactorial and polygenic. This form currently represents a growing worldwide health problem due in part, to the contemporary environmental condi‐ tions of modern civilization. Risk factors that are considered as “modifiable” also play an important role and include physical activity, dietary habits and eating disorders. Furthermore, there is another group of associated risk factors that are considered “non-modifiable”, including gender, age, race, a personal and/or family history of fractures that in turn, indirectly reflect the degree of genetic susceptibility to this disease [2-4]. Secondary osteoporosis encompasses a large heterogeneous group of primary conditions favoring osteoporosis development. Table 1 summarizes some of the disease entities associated to primary and secondary osteoporosis.

The RANKL rs12585014 polymorphism is associated with age at menarche in postmenopausal women with hip fracture

Abstract The RANK/RANKL/OPG signaling is important in the regulation of bone turnover. The aim of the present work was to analyze the rs3018362 and rs12585014 polymorphisms in the RANK and RANKL genes, as well as risk factors in postmenopausal women. Women with hip fracture, with femoral neck osteoporosis and controls (n = 646) were recruited. From these, 303 women who fulfill the inclusion criteria were genotyped using real-time PCR with TaqMan probes. There were no associations of the rs3018362 and rs12585014 with osteoporosis or fracture. When women were divided by age at menarche, the rs12585014 GG genotype was strongly associated with age at menarche >13 years [p = .00774, OR = 6.429 (1.907–21.103)] in women with hip fracture. Significant differences in risk factors such as body mass index, age at menopause, use of estrogens, the presence of hypertension, and diabetes mellitus were found. Carrying the GG genotype of rs12585014 entails a higher risk of having menarche later (>13 years), which could involves a greater risk of fractures. The rs3018362 and rs12585014 do not seem to be associated with hip osteoporosis or hip fracture in Mexican women. 摘要 RANK/RANKL/OPG 信号通路在骨转换的调控中非常重要。本研究的目的是分析rs3018362 和 rs12585014的多态性和危险因素。本研究纳入髋部骨折的女性646人, 包括股骨颈骨质疏松组和对照组。303例符合纳入标准的病例使用 TaqMan探针实时PCR分析基因型。 rs3018362 和 rs12585014与骨质疏松或骨折无关。按初潮年龄分组后, 发现rs12585014与绝经后髋部骨折患者的初潮年龄>13岁相关性明显[p=.00774, OR=6.429 (1.907–21.103)] 。体质数、绝经年龄、应用雌激素、合并高血压、糖尿病也是影响因素。携带 rs12585014基因导致初潮年龄>13岁, 骨折的风险会增加。在墨西哥女性中 rs3018362 和 rs12585014似乎与髋部骨质疏松或骨折无关。

Serum miRNAs miR-140-3p and miR-23b-3p as potential biomarkers for osteoporosis and osteoporotic fracture in postmenopausal Mexican-Mestizo women

Osteoporosis is a metabolic bone disorder characterized by low bone mineral density and decreased bone strength, leading to an increased risk of fractures with a consequent increase in morbidity and mortality. The current methods to estimate the fracture risk are very limited. microRNAs (miRNAs) have been considered as good biomarkers for many pathological processes, including osteoporosis. Some circulating miRNAs are associated with regulation of bone formation and differentiation of bone cells. The aim of this study, was to analyze the expression of miRNAs in serum of patients with osteoporosis (n = 20) and healthy controls (n = 20). Expression of 754 miRNAs was analyzed through quantitative real time RT-PCR arrays. Seven miRNAs showed significant differences between groups. The microRNAs miR-23b-3p, miR-140-3p and miR-885-5p were selected based on fold change and p-values (40.5, p = 0.038, 20.7, p = 0.045, and 2.2, p = 0.002; respectively) for validation in independent serum samples from patients with osteopenia (n = 28), osteoporosis (n = 26) and osteoporotic hip fracture (n = 21). After validation, we confirm differences across the groups for miR-23b-3p and miR-140-3p. Our data pointed miR-140-3p and miR-23b-3p as potential biomarkers candidates for osteoporosis in postmenopausal women.

Association of the IL6 rs1800796, but not of the IL6 rs1800795, IL6R rs4845617 and rs2228145 polymorphisms with hip fracture in elderly Mexican women

Background and aimsPolymorphisms in Interleukin-6 (IL6) and its receptor (IL6R) have been associated with bone mineral density. In this work, the G-174C and G-572C polymorphisms in IL6, G-208A, and Asp358Ala in IL6R were analyzed in Mexican women with hip fracture.MethodsPostmenopausal Mexican women (60 years or over) with hip fragility fracture (77.97 ± 8 years) and without hip fracture (70.5 ± 7.02 years) were genotyped by real-time PCR.ResultsThe rs1800796 GG genotype was associated with low risk of fracture (p = 0.05), while GC genotype was associated with high risk of fracture [p = 0.047, OR 2.3 (95% CI 1.013–5.2)]. The AA genotype of the rs2228145 SNP (IL6R) was significantly different [p = 0.033, OR 1.94 (95% CI 1.01–3.75)], but when data were adjusted by age and body mass index, there were no differences (p = 0.9).ConclusionOur results suggest that the IL6 rs1800796 SNP is a good marker for hip fracture risk in Mexican women.

Dermochondrocorneal dystrophy (Francois syndrome) in a Mexican patient and literature review

Dermochondrocorneal Dystrophy (OMIM 221800) is a very rare disease first described by Francois in 1949. It is characterized by the appearance of skin nodules, osteochondral deformities, and corneal opacities during childhood. Only a few cases have been reported. There is uncertainty about the inheritance pattern and no gene or genes have been associated to this disease. We report a patient from Mexican mestizo origin with the classic manifestations of Dermochondrocorneal Dystrophy. We perform a multidisciplinary assessment in order to contribute to the knowledge of the clinical presentation of this uncommon condition. Among the few documented patients, this is the third patient of Mexican ancestry reported with this syndrome.

Association of a (TTTA)n microsatellite and a TCT del/ins polymorphisms in the aromatase gene (CYP19) with hip fracture risk in Mexican postmenopausal women.

Abstract A (TTTA)n polymorphism in the aromatase gene has been studied in relation to bone mineral density (BMD). The low number of TTTA repeats has been associated with low BMD and fracture risk. The aim of this study was to search for associations of TTTA copy number with hip fracture and lumbar spine osteoporosis in Mexican peri and postmenopausal women. The allele with seven repeats was present in the two reported versions, with or without a TCT deletion upstream of the microsatellite (A1 and A2, respectively). After adjustment by confounders, the A1 allele and the A1A1 genotype were significantly associated with an elevated risk of fracture (p = 0.034, OR = 3.2 [95% CI, 1.09–9.41] and p = 0.019, OR = 2.26 [95% CI, 1.14–4.49], respectively) and the A2 allele was associated with protection of hip fracture (p = 0.04, OR = 0.48, [95% CI, 0.22–1.05]) as the A2A2 genotype (p = 0.048, OR = 0.29 [95% CI, 0.06–1.16]). The analysis allowed us to defining the usefulness of the (TTTA)n polymorphism in the aromatase gene as an indicator of hip fracture risk in Mexican population.