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The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.
Berner, D, Hoja, U, Zenkel, M, Ross, JJ, Uebe, S, Paoli, D, Frezzotti, P, Rautenbach, RM, Ziskind, A, Williams, SE, et al
Human molecular genetics. 2019;(15):2531-2548
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Abstract
LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
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INSIG2 gene polymorphism is associated with higher blood pressure and triglyceride levels in Brazilian obese subjects.
Nicoletti, CF, Azevedo, RG, Pinhel, MAS, Delfino, HBP, Nonino, CB
Nutricion hospitalaria. 2019;(3):604-610
Abstract
Objective: this study aimed to evaluate the association between polymorphisms of INSIG, PCSK9 and FTO genes with anthropometric, biochemical characteristics and presence of metabolic syndrome in patients with severe obesity. Material and methods: the present study enrolled 150 patients with grade II or III obesity, who were submitted to nutritional assessment, blood pressure measurement and peripheral blood collection. INSIG2 (rs75666605), PCSK9 (rs505151), and FTO (rs9939609) polymorphisms were genotyped using TaqMan Pre-Designed SNP Genotyping Assays probes in real time polymerase chain reaction (PCR). The experimental data are processed in SPSS Statistics 22.0 (p < 0.05). Results: in this study, 72.2% of obese subjects had metabolic syndrome (MS). There was a higher prevalence of AA (86.9%), CG (51.1%) and AT (46.2%) genotypes for the PCSK9, INSIG2 and FTO polymorphisms, respectively. There was no association of these polymorphisms with the prevalence of MS (p > 0.05). On the other hand, individuals with at least one variant allele (G) for the INSIG2 gene had higher triglycerides levels, systolic and diastolic blood pressure (p < 0.05). Conclusions: the polymorphism rs7566605 of the INSIG2 gene is associated with higher triglycerides levels and blood pressure values, which are also considered as risk factors for the development of MS.
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DLK1, Notch Signaling and the Timing of Puberty.
Macedo, DB, Kaiser, UB
Seminars in reproductive medicine. 2019;(4):174-181
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Abstract
The factors that trigger human puberty are among the central mysteries of reproductive biology. Several approaches, including mutational analysis of candidate genes, large-scale genome-wide association studies, whole exome sequencing, and whole genome sequencing have been performed in attempts to identify novel genetic factors that modulate the human hypothalamic-pituitary-gonadal axis to result in premature sexual development. Genetic abnormalities involving excitatory and inhibitory pathways regulating gonadotropin-releasing hormone secretion, represented by the kisspeptin (KISS1 and KISS1R) and makorin ring finger 3 (MKRN3) systems, respectively, have been associated with sporadic and familial cases of central precocious puberty (CPP). More recently, paternally inherited genetic defects of DLK1 were identified in four families with nonsyndromic CPP and a metabolic phenotype. DLK1 encodes a transmembrane protein that is important for adipose tissue homeostasis and neurogenesis and is located in the imprinted chromosome 14q32 region associated with Temple syndrome. In this review, we highlight the clinical and genetic features of patients with CPP caused by DLK1 mutations and explore the involvement of Notch signaling and DLK1 in the control of pubertal onset.
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Effect of genetic polymorphisms in SREBF-SCAP pathway on therapeutic response to rosuvastatin in Saudi metabolic syndrome patients.
Rafeeq, MM, Habib, HS, Murad, HAS, Gari, MA, Gazzaz, ZJ
Pharmacogenomics. 2018;(3):185-196
Abstract
AIM: Genetic variants contribute to statins' therapeutic variability. SREBF-SCAP pathway is a key player in lipid homeostasis. Hence, effect of SREBF-SCAP polymorphisms on therapeutic response was studied. PATIENTS & METHODS Metabolic syndrome patients of either sex were prescribed rosuvastatin 10 mg for 24 weeks. Clinical, anthropometric and lipid measurements were done before and after treatment. Genotyping was done by pyrosequencing. RESULTS & CONCLUSION No associations of SCAP and SREBF-1a genotypes with baseline lipids but significant associations with lipid reductions were observed. Significant effect of SCAP (GG; B = -8.16, p = 0.001); SREBF-1a (GG; B = -7.47, p = 0.001) and SREBF-1a (-delG; B = -7.42, p = 0.001) was observed on total cholesterol reduction. Additive trend was found between SCAP genotypes and lipid reductions. A total of 88% responders have SCAP 'G' allele (p = 0.001). Patients carrying SCAP (GG) and SREBF-1a (GG and -delG) have 9.5-, 8.6- and 14.6-times more likelihood of being responders (p < 0.05). 'G' allele in SCAP and SREBF-1a is significant predictor of rosuvastatin response.
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Nonalcoholic Fatty Liver Disease and Metabolic Syndrome.
Kim, D, Touros, A, Kim, WR
Clinics in liver disease. 2018;(1):133-140
Abstract
Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) are highly prevalent, affecting approximately one-third of the US population. The relationship between NAFLD and MS is complex and may be bidirectionally associated. NAFLD is strongly associated with MS, the components of which include abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. NAFLD associated with certain genetic factors such as the PNPLA3 G allele variant is not accompanied by insulin resistance and MS. Lifestyle modification, including diet and physical activity targeting visceral adiposity, remains the standard of care for patients with NAFLD and MS.