Association between Adora2A rs2298383 polymorphism and Parkinson’s disease in a Greek population

Σκοπός της συγκεκριμένης μελέτης ήταν η αναζήτηση συσχέτισης μεταξύ του rs2298383 πολυμορφισμού του γονιδίου Adora2A με την νόσο του Parkinson, καθώς και με την εμφάνιση δυσκινησίας που προκαλείται από την φαρμακευτική αγωγή με L-dopa σε Έλληνες ασθενείς με νόσο του Parkinson. Στην έρευνα πήραν μέρος συνολικά 127 Έλληνες ασθενείς με την νόσο του Parkinson, που αποτέλεσαν την ομάδα μελέτης και 102 υγιείς, που αποτέλεσαν την ομάδα ελέγχου και οι οποίοι ελέγχθηκαν ως προς την ύπαρξη του πολυμορφισμού. Από τους 127 ασθενείς με Parkinson που μελετήθηκαν οι 94 ασθενείς έλαβαν ως φαρμακευτική αγωγή L-dopa και από αυτούς οι 24 εμφάνισαν δυσκινησία ως παρενέργεια της φαρμακευτικής αγωγής με L-dopa. Τα αποτελέσματά μας δεν φανερώνουν σημαντική συσχέτιση του rs2298383 πολυμορφισμού του γονιδίου Adora2A με την νόσο του Parkinson, αλλά ούτε και με την εμφάνιση δυσκινησίας που προκαλείται από την φαρμακευτική αγωγή με λεβοντόπα σε Έλληνες ασθενείς με νόσο του Parkinson. Αξίζει να σημειωθεί ότι είναι αναγκαίο να διεξαχθούν ανάλογες έρευνες στον ελληνικό πληθυσμό, όπου οι ομάδες μελέτης θα περιλαμβάνουν μεγαλύτερο αριθμό ασθενών. Επιπλέον μελέτες και σε άλλους πολυμορφισμούς του γονιδίου Adora2A θα συμβάλλουν σημαντικά τόσο στην κατανόηση της παθογένεσης της νόσου του Parkinson αλλά και των φαρμακοεπαγώμενων δυσκινησιών.Parkinson’s Disease (PD) is a serious neurodegenerative syndrome that affects mostly the movement control in PD patients. L-dopa is the main drug that is given as a treatment in PD patients, but its chronic use is linked with the occurrence of additional motor problems, such as motor fluctuations and dyskinesia. Recent data support that Adora2A rs2298393 polymorphism may be a potential risk factor not only for PD, but for Levodopa-Induced Dyskinesia (LID), as well. In this study, we examined 127 Greek patients with PD and 102 healthy controls with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method, in order to evaluate the association between Adora2A rs2298383 polymorphism and PD in a Greek population. In addition, we explored the association between this particular polymorphism and LID. Our results do not seem to find significant correlation between rs2298393 polymorphism of Adora2A gene with PD or LID

Polymerase chain reaction (PCR) and sequence specific oligonucleotide probes (SSOP) genotyping assay for detection of genes associated with rheumatoid arthritis and multiple sclerosis

Abstract-In this paper an assay for the detection of genes associated with rheumatoid arthritis (RA) and multiple sclerosis, using polymerase chain reaction (PCR) and sequence specific oligonucleotide probes (SSOP) is presented, in order to be further applied in a portable Lab-On-Chip (LOC) device. A substantial part of these reagents were based on the literature (11 th International Histocompatibility Workshop, IHW), bearing the advantage of proven successful implementation in genotyping, while others were designed for this study. More precisely, our methodology discriminates HLA-DRB1 as DRB1*01, *04 and *10, which include shared epitope (SE) alleles associated with RA and additionally DRB1*15 allele, including DRB1*1501 associated with MS (broad genotyping method). To further present the basic elements of the assay for high resolution genotyping of SE DRB1 alleles, we provide as an example the case of HLA-DRB1*10 alleles (HLA-DRB1*100101, *100102, *100103, *1002 and *1003). Regarding the methodology for developing a detection assay, for SNPs associated with RA or MS the basic steps are presented. DNA sequence data are obtained from IMGT/HLA and SNP database. Online software tools are used to define hybridization specificity of primers and probes towards human DNA, leading to hybridization patterns that uniquely designate a target allele and evaluate parameters influencing PCR efficiency. Respecting current technological limitations of autonomous molecular-based LOC systems the approach of broad genotyping of HLA-DRB1*01/*04/*10/*15 genes, is intended to be initially used, leaving, high resolution genotyping of SE alleles for future implementations. This method is easy to be updated and extended to detect additional associated loci with RA or MS

Case report R831X mutation of the androgen receptor gene in an adolescent with Complete Androgen Insensitivity Syndrome and bilateral testicular hamartomata

ABSTRACT An 18-year old, phenotypically female individual was examined for primary amenorrhea. Three months before her referral, the patient underwent surgery and a pelvic mass was removed. The physical examination revealed normal female external genitalia, normal breast development, sparse pubic hair and absence of axillary hair. The gynecological examination revealed a short blind vagina pouch and absence of cervix and uterus. Serum testosterone and dihydrotestosterone levels were very high. Karyotype was that of a normal male (46,XY). The transabdominal ultrasound, computed tomography (CT) and Magnetic resonance imaging (MRI) showed absence of uterus and fallopian tubes and revealed testis-like gonads located at the internal opening of the inguinal canal bilaterally. Bilateral gonadectomy was subsequently performed. The pathology report was that of hamartomatous testes and associated paratesticular leiomyoma. The clinical, laboratory, imaging, genetic and histological findings confirmed the diagnosis of complete androgen insensitivity syndrome. DNA analysis revealed a R831X mutation in exon 7 of the androgen receptor gene. A Sertoli-cell dynamic test showed elevated basal serum inhibin-B and anti-Müllerian hormone levels without further rise following FSH stimulation. The patient was started on hormone replacement therapy with conjugated estrogens. Complete androgen insensitivity syndrome must be considered in any case of primary amenorrhea. Gonadectomy must be planned to eliminate the risk of gonadal malignancy

Klotho gene polymorphism -395 G<A in patients with chronic obstructive pulmonary disease (COPD)

SUMMARY. Background: The function of the Klotho gene, originally identified by insertional mutagenesis in mice, is to suppress multiple aging phenotypes. It has been shown that a mutant Klotho gene is associated with pulmonary emphysema in mice. The aims of this study were to detect Klotho gene polymorphisms (-395G>A SNP) and to identify their possible relationships with clinical findings in patients with chronic obstructive pulmonary disease (COPD). Methods: In 167 patients with COPD -395G>A SNP of the Klotho gene was genotyped by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) coupled with sequencing. The possible relationship was explored of -395G>A SNP with clinical findings such as lung function parameters, staging according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), and body mass index (BMI). Results: Of the 167patients with COPD, 99 (59.3%) presented the wild type -395G allele, 62 (37.1%) were heterozygotes (–395GA allele), and 6 (3.6%) presented the non-wild type–395A allele. In these COPD patients there was an association between Klotho genotypes and BMI (p=0.025). No association was found between Klotho gene polymorphism and disease severity, assessed by spirometry, arterial blood gases and GOLD stage. Conclusion: Klotho -395G>A polymorphisms are detected in patients with COPD and are associated with BMI, but not with various parameters of disease severity. This may suggest a possible metabolic pathway in the implication of Klotho deficient gene in the pathophysiology of emphysema in COPD patients. Pneumon 2010, 23(4):348-354

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P &lt; 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology

Association of Rare CYP39A1 Variants with Exfoliation Syndrome Involving the Anterior Chamber of the Eye

IMPORTANCE: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10(−6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10(−7)). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings

Genetic Association Study Of Exfoliation Syndrome Identifies A Protective Rare Variant At Loxl1 And Five New Susceptibility Loci

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.Wo