Evaluation of MMP1 and MMP3 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma

Purpose: To investigate possible genetic associations of matrix metalloproteinase-1 (MMP1) and MMP3 gene polymorphisms with exfoliation syndrome (XFS) with (XFS/+G) and without (XFS/-G) glaucoma in a cohort of Greek patients. Methods: A total of 182 unrelated Greek patients with XFS, including 92 patients with XFS/+G, and 214 unrelated age- and gender-matched controls were enrolled in the study. MMP1-1607 1G/2G (rs1799750) and MMP3-1171 5A/6A (rs3025058) polymorphisms were determined using standard PCR/restriction fragment length polymorphism methods. Differences in allele and genotype distributions were analyzed using logistic regression. Results: The distribution of genotypes and alleles in MMP1 and MMP3 polymorphisms was not significantly different between cases with exfoliation syndrome, with or without glaucoma, and controls. However, the allele contrast for the MMP1 variant showed a trend for a significant association with XFS/-G (Odds Ratio=1.47 [1.03-2.10]), since after correction for multiple comparisons, this association was no longer statistically significant. Conclusions: Our study provided some evidence of a possible role of the MMP1 variant in the development of exfoliation syndrome in Greek patients

Genetical association studies in sleep apnea

Obstructive sleep apnea syndrome (OSAS) is a pathological condition which disturbs the biological phenomenon of sleep and is the leading cause of breathing sleep disordered breathing. Obstructive sleep apnea syndrome is present in 5-6% of the general adult population of the Western world and the risk of developing the disease is 2-3 times greater in men compared to women and increases progressively with age. The most important predisposing factor for developing the syndrome is obesity, whereas smoking, alcohol consumption and congestion of the nasal cavity has been reported as further risk factors. OSAS is diagnosed by a polysomnographic study of nocturnal sleep and the resulting apnea hypopnea index indicates the severity of the syndrome. The most serious implications of OSAS are daytime sleepiness, the increased risk of cardiovascular disease, whilst the disorder is many times the hidden cause of sudden death, unexplainable hypertension or even inexplicable road accidents. Some cytokines, and in particular TNF-a, IL-1b and IL-6 have been observed to be increased in OSAS patient’s plasma. The aim of the present thesis was, for the first time in Greek OSAS patients, to study the association of genes and OSAS. Five hundred and thirty nine individuals participated in this study, of which 43.4% were OSAS patients. The investigation of the single nucleotide polymorphism (SNP) at position -308 of the TNF-a gene demonstrated significant differences between the OSAS patients and the healthy controls, with the most important being the presence of the AA genotype. In addition, a statistically significant association was observed between the SNP C/T at +3953 of IL-1b and OSAS. Finally, no association was observed for the G/C (position -174) polymorphism of the IL-6 gene and OSAS.Το σύνδρομο άπνοιας στον ύπνο (ΣΑΥ) είναι μία παθολογική κατάσταση που διαταράσσει το βιολογικό φαινόμενο του ύπνου και είναι ο κυριότερος εκ-πρόσωπος των διαταραχών της αναπνοής στον ύπνο. Το ΣΑΥ αφορά το 5-6% του ενήλικου πληθυσμού του δυτικού κόσμου και ο κίνδυνος ανάπτυξης της νόσου είναι 2-3 φορές μεγαλύτερος στους άνδρες σε σχέση με τις γυναίκες και αυξάνεται προοδευτικά με την ηλικία. Ο σημαντικότερος προδιαθεσικός παρά-γοντας για την ανάπτυξη του συνδρόμου είναι η παχυσαρκία, ενώ το κάπνισμα, το αλκοόλ και η ρινική συμφόρηση λειτουργούν επιβαρυντικά. Απαραίτητη για τη διάγνωση είναι η πλήρης πολυσωματοκαταγραφική μελέτη ύπνου και ο δείκτης απνοιών-υποπνοιών που λαμβάνεται δείχνει τη βαρύτητα της πάθησης. Οι σημα-ντικότερες επιπτώσεις του συνδρόμου είναι η ημερήσια υπνηλία, ο αυξημένος κίνδυνος για καρδιαγγειακά νοσήματα, ενώ πολλές φορές είναι η κρυφή αιτία αιφνίδιων θανάτων, ανερμήνευτης υπερτάσεως ή ακόμα και ανεξήγητων τροχαίων ατυχημάτων. Στον ορό των ασθενών με ΣΑΥ η συγκέντρωση κάποιων κυτταροκινών και συγκεκριμένα του TNF-α, της IL-1β και της IL-6 έχει βρεθεί αυξημένη. Σκοπός της παρούσας διδακτορικής διατριβής είναι να μελετηθεί για πρώτη φορά σε Έλληνες ασθενείς με ΣΑΥ η γενετική συσχέτιση πολυμορφισμών σε γονίδια προ-φλεγμονωδών κυτταροκινών και ασθενών με ΣΑΥ. Μελετήθηκαν συνολικά 539 άτομα και το 43,4% αυτών βρέθηκαν να πάσχουν από ΣΑΥ. Η μελέτη του πολυμορφισμού G/A στη θέση -308 του γονιδίου του TNF-α ανέδειξε σημαντικές διαφορές μεταξύ των πασχόντων από ΣΑΥ και των μη πασχόντων, με τις πιο σημαντικές να αφορούν την παρουσία του γονότυπου AA. Επίσης βρέθηκε στατιστικά σημαντική συσχέτιση του πολυμορφισμού C/T στη θέση +3953 του γονιδίου της IL-1β με το ΣΑΥ. Τέλος δεν βρέθηκε καμία συσχέτιση του πολυμορφισμού G/C στη θέση -174 του γονιδίου της IL-6 με το ΣΑΥ

Plasminogen Activator Inhibitor Type-1 Tag Single-Nucleotide Polymorphisms in Patients with Diabetes Mellitus Type 2 and Diabetic Retinopathy

<p><i>Background</i>: There is accumulating evidence for genetic susceptibility to the development of diabetic retinopathy (DR). The role of plasminogen activator inhibitor-1 (PAI-1) in DR risk remains controversial.</p> <p><i>Objective</i>: The present study was designed to investigate possible influence of PAI-1 gene region polymorphisms on the risk of DR and on the risk of developing DR early vs late in the course of type 2 diabetes mellitus (T2DM).</p> <p><i>Methods</i>: A total of 138 patients with DR, 107 patients with T2DM without DR, and 315 healthy controls were recruited. To cover the majority of the genetic variability across the extended region of PAI-1 gene, five tag single-nucleotide polymorphisms (SNPs) from the HapMap using a pairwise approach and an <i>r</i>² ≥ 0.8 and a minor allele frequency (MAF) of >0.05 were identified. Using logistic regression analyses, tag SNPs and haplotypes were tested for associations with DR risk and risk of DR development early or late in the course of T2DM. The generalized odds ratio (OR_G) was calculated to estimate the mutational load effect on DR development among all participants. Corrections for multiple comparisons were carried out (<i>p</i>-value < 0.01).</p> <p><i>Results</i>: A significant effect of rs2070682 on the risk of early DR onset was found in the codominant model of inheritance [odds ratio, OR (95% confidence interval, CI): 5.04 (1.47–17.28), <i>p</i> = 0.018]. However, this association marginally did not survive multiple testing corrections. No other significant association between PAI-1 tag-SNPs and haplotypes was revealed. Furthermore, no significant mutational load effect of PAI-1 tag SNPs on the risk of DR development in T2DM course was found.</p> <p><i>Conclusions</i>: In conclusion, the present study does not provide any strong evidence that <i>PAI-1</i> gene variants are implicated in the risk of DR or the development of DR during T2DM course.</p