Ismael Nuño Arana

Two additional cases are described with partial trisomy 4q, resulting from a de novo duplication of chromosome 4, involving segments q21-q28. This time a sibling is affected. The clinical manifestations are similar to other cases with de novo 4q duplication involving the same segments. Although a single distinctive phenotype has not been established, most reported cases of de novo duplication share a similar clinical spectrum depending on the specific duplicated segment of chromosome 4q. The major clinical manifestations are growth and psychomotor retardation, microcephaly, epicantic fold, antimongoloid slant of palpebral fissures, low-set and malformed auricles, high nasal bridge, long philtrum small mouth, micrognathia, short neck, additionally, one patient presented congenital heart disease, and both presented congenital pyloric hypertrophy stenosis, dorsal edema of the hands and feet, the hypertrichosis as the most important clinical manifestations. Diverse genes involved in neural, cardiovascular, acrorenal, and skeletal development—identified in molecular studies of the duplication—are reviewed; these genes are potentially responsible for the phenotypic anomalies reported in each chromosomal region. We reported the another family directly affected with the same de novo direct duplication in the literature of a rare chromosomal trisomy, as the second ovarian germline mosaicism case which was demonstrated through cytogenetic and molecular analysis, confirmed by fluorescent in situ hybridization (FISH) with a painting probe and microsatellites studies. Besides, deep in a clinical analysis of karyotype-phenotype correlation in each duplicated segment.

Backgrounds/Objectives: Allele frequencies of genetic variants associated with complex diseases can contribute to varying degrees to predisposition depending on the population’s genetic profile. The aim of this study was to analyze the genetic diversity of 15 relevant SNVs that could modulate bone and cartilage metabolism in underrepresented structured populations. Methods: In a sample of 130 Mestizos and 304 natives from 8 native Mexican populations, SNVs related to multifactorial diseases were genotyped using a SNaPShot Multiplex kit and analyzed via capillary electrophoresis using an ABI PrismTM 3130 Genetic Analyzer (Applied Biosystems, Waltham, MA, USA.), and genetic profiles for 15 SNVs were obtained using GeneMapper software v. 3.2. Allele frequencies were calculated by locus and population using Power Stats and Arlequin v.3.1 software, for which the EM algorithm was used to compare reference populations obtained from the dbSNV database of the International HapMap project. Population structure, paired comparisons, and genetic differentiation between native, admixed, and reference populations (p value) were estimated through Fst tests using the STRUCTURE v.2.3.2 and Arlequin v.3.1 software. Results: Haplotype frequency combinations grouped as profiles showed higher predominance in the allelic combination A/A/G for rs9340799 (ESR1), rs700518 (CYP19A1), and rs1800795 (IL6) genes, respectively. Conclusions: Allelic profiles could be useful as medical tools for preventing and managing individuals or populations. Mexican populations showed high genetic variability among allelic risk profiles for estrogen control and response, as well as high frequencies of variant combinations associated with an increased inflammatory response, potentially resulting in high osteoclastogenesis. This analysis advances our understanding of the complexity of bone and cartilage metabolism in highly stratified populations.

The Receptor Activator Nuclear of κB Ligand (RANKL) plays an important function in immune responses, activating osteoclast cells and unchanged bone resorption, which in turn leads to bone erosion and inflammation. Genetic variants in the promoter region of the RANKL gene could lead to a higher risk of rheumatoid arthritis (RA). Objective: To assess the association of rs9533155 (-693C>G) and rs9533156 (-643T>C) genetic variants with RA risk. Methods: A case–control study was carried out. A total of 94 patients with RA (RA group) and 134 subjects without any rheumatologic disease (control group) were included. Genetic DNA was extracted from peripheral white blood cells (leukocytes). Genetic variant rs9533155 (-693C>G) was screened by an approach based on Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP), while rs9533156 (-643T>C) was screened using quantitative polymerase chain reaction (qPCR) with TaqMan probes. RANKL serum levels were measured by ELISA. Results: For rs9533155 (-693C>G), the polymorphic homozygous genotype frequencies (CC) were higher in the RA group (p = 0.006). Individuals carrying the risk genotype presented higher levels of serum RANKL. Carriers of the polymorphic homozygous genotype in the dominant model (CC vs. CG + GG) had an increased risk of developing RA (OR: 1.8, 95% CI 1.04 to 3.1). No association between rs9533156 (-643T>C) and the haplotypes with RA risk was observed. Conclusion: The rs9533155 (-693C>G) genetic variant exhibits a potential role in RA risk. The studied population had no association with the rs9533156 (-643T>C) genetic variant.

STAT4 plays an important role in disease activity in SLE patients. STAT4 particles have the capacity to activate the transcription of genes associated with the production of TH1 and Th17 lymphocytes, with a greater predominance on the production of IFN-γ and IL-17A. The presence of variants in STAT4 genes has a major impact on the generation of autoimmunity. However, there are few studies evaluating the impact of these variants on the production of proinflammatory cytokines such as IFN-γ and IL-17A. Methods—A case–control study was carried out with 206 Mexican mestizo patients residing in Western Mexico with a diagnosis of SLE and a group of 80 patients without autoimmune diseases was captured to determine the cut-off point for high IFN-γ levels. In this study, SLE patients with high IFN-γ levels were considered as cases (cut-off > 15.6 pg/mL), and SLE patients with normal IFN-γ levels were considered as controls (cut-off ≤ 15.6 pg/mL). Disease activity was identified from the systemic lupus erythematosus disease activity index (SLEDAI). For the determination of levels of cytokines IFN-γ, IL-12, and IL17A, commercial ELISA kits were used. Genotyping of STAT4 rs7574865 (G > T) was performed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. Results—The patients with SLE had a median age of 45 years with a range of disease duration from 4 years to 18 years; 45.6% were identified as having disease activity. In this sample, we identified a high IFN-γ prevalence of 35.4%. The levels of IFN-γ were higher in the patients with genotype TT than GG. We found that TT genotype conferred a higher risk of high IFN-γ when compared to the GG and GT genotypes. Conclusions—In this study, we identified that the polymorphic genotype TT of the STAT4 gene rs7574865 polymorphism is associated with increased levels of IFN-γ. However, its strength of association was weak, so complementary studies are needed to evaluate its impact on SLE patients.

Background: Postmenopausal osteoporosis is a multifactorial disease. Genetic factors play an essential role in contributing to bone mineral density (BMD) variability, which ranges from 60 to 85%. Alendronate is used as the first line of pharmacological treatment for osteoporosis; however, some patients do not respond adequately to therapy with alendronate. Aim: The aim of this work was to investigate the influence of combinations of potential risk alleles (genetic profiles) associated with response to anti-osteoporotic treatment in postmenopausal women with primary osteoporosis. Methods: A total of 82 postmenopausal women with primary osteoporosis receiving alendronate (70 mg administered orally per week) for one year were observed. The bone mineral density (BMD; g/cm²) of the femoral neck and lumbar spine was measured. According to BMD change, patients were divided into two groups: responders and non-responders to alendronate therapy. Polymorphic variants in CYP19, ESR1, IL-6, PTHR1, TGFβ, OPG and RANKL genes were determined and profiles were generated from the combination of risk alleles. Results: A total of 56 subjects were responders to alendronate and 26 subjects were non-responders. Carriers of the G-C-G-C profile (constructed from rs700518, rs1800795, rs2073618 and rs3102735) were predisposed to response to alendronate treatment (p = 0.001). Conclusions: Our findings highlight the importance of the identified profiles for the pharmacogenetics of alendronate therapy in osteoporosis.

Alendronate are used as the first line of pharmacological treatment for osteoporosis; however, some of them do not respond adequately to therapy with alendronate. The aim of this study was to investigate the influence of combinations of potential risk alleles (genetic profiles) associated with the response to antiosteoporotic treatment in a cohort consisting of 82 postmenopausal women with primary osteoporosis receiving alendronate (70 mg administered orally per week) for one year. Bone mineral density (BMD; g/cm2) of the femoral neck and lumbar spine was measured. According to BMD change patients were divided in two groups: responders and non-responders to alendronate therapy. Polymorphic variants in CYP19, ER, IL-6, PTHR1, TGFβ, OPG and RANKL genes were determined and profiles generating from the combination of risk alleles. Results: 56 subjects were responders to alendronate and 26 subjects were non-responders. The carriers of A-C-T-C profile (constructed from rs700518, rs1800795, rs2073618, and rs3102735) were predisposed to response to alendronate treatment (P= 0.001). Our findings highlight the importance of identified profiles for pharmacogenetics of alendronate therapy in osteoporosis.