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(1) Background. One of the causes of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is thrombus formation in situ followed by lysis, resulting in a morphologically normal angiogram but with an underlying prothrombotic state that is potentially predisposed to recurrence. Recent studies have shown that a subset of MINOCA patients may have thrombophilic conditions at screening. Objective: To compare the prothrombotic trend in MINOCA patients with that of subjects with MI and obstructive coronary arteries (MIOCA) by testing for known congenital thrombophilias and markers of coagulation activation. (2) Materials and methods. Screening included congenital thrombophilias (factor V Leiden; assessment of protein C, protein S, and antithrombin III) and eight genes. Of these, four genes represented the folate pathway enzymes: MTHFR 677 C>T (rs1801133), MTHFR 1298 A>C (rs1801131), MTR 2756 A>G (rs1805087), and MTRR 66 A>G (rs1801394). The other four genes represented the blood coagulation system: F13 (163 G>T) rs5985, F1 (−455 G>A) rs1800790, GP IIb–IIIa (1565 T>C) rs5918, and PAI-I (−675 5G>4G) rs1799889. Additionally, we examined the levels of homocysteine and lipoprotein (LP) (a). (3) Results. Our study included 269 patients: 114 MINOCA patients and 155 MIOCA patients with lesions of one coronary artery. The frequencies of polymorphisms in the genes of the blood coagulation system and the folate pathway did not differ between the groups. The following genes were associated with in-hospital mortality in the MINOCA group: MTHFR 1298 A>C rs1801131 (OR 8.5; 95% CI 1.67–43.1) and F1 (−455 G>A) rs1800790 (OR 5.8; 95% CI 1.1–27.8). In the MIOCA group, the following genes were associated with in-hospital mortality: MTHFR 1298 A>C rs1801131 (OR 9.1; 95% CI 2.8–28.9), F1 (−455 G>A) rs1800790 (OR 11.4; 95% CI 3.6–35.9), GP IIb–IIIa (1565 T>C) rs5918 (OR 10.5; 95% CI 3.5–30.8), and PAI-I (−675 5G>4G) rs1799889 (OR 12.9; 95% CI 4.2–39.7). We evaluated long-term outcomes (case fatality rate, recurrent MI, and stroke) over a period of 12 months in both groups. The variables associated with these outcomes were laboratory parameters, such as protein C deficiency, hyperhomocysteinemia, and a content of LP (a) > 30 mg/dL. However, we did not reveal the prognostic value of polymorphisms of the studied genes representing the blood coagulation system and the folate pathway. (4) Conclusion. We established no statistically significant differences between the MINOCA and MIOCA groups in the prevalence of congenital thrombophilias and the prevalence of folate pathway enzyme genes and blood coagulation system genes. The MTHFR 1298 A>C (rs1801131) and F1 (−455 G>A) rs1800790 genes were associated with in-hospital mortality in both groups. More significant prognostic factors in both groups during the one-year period were protein C deficiency, hyperhomocysteinemia, and LP (a) > 30 mg/dL.

Objective: In-stent restenosis (ISR) is the narrowing of a stented coronary artery lesion. A considerable number of patients undergoing percutaneous coronary intervention (PCI) are affected by ISR. The predominant mechanism in the development of ISR is an inflammatory response to vessel wall injury during PCI. Vitamin D is reported to have anti-inflammatory properties, so it may also be related with ISR. Therefore, in this study the relationship between vitamin D receptor (VDR), vitamin D binding protein (VDBP) gene variations and ISR were investigated.Methods: Fifty-eight ISR patients who have chest pain, underwent angiography and were found to have restenosis in the previously inserted stent were included in the patient group and thirty-five patients who have chest pain and were not found to have restenosis in their previous stent in coronary angiography were included in the control group. rs7041 and rs4588 variations in VDBP; rs1544410 and rs2228570 variations in VDR were investigated by real-time polymerase chain reaction (RT-PCR).Results were evaluated statistically. Results: The CC genotype of rs2228570 variation of VDR and the CA genotype of rs4588 variation of VDBP were found statistically high in patient group. rs7041 variation was found statistically high in patients who had myocardial infarction history before stent implantation. Additionally, it was demonstrated that vitamin D deficiency (vitamin D level

Objectives: Osteoporosis (OP) is a usual disease with a possible genetic predisposition. IL-23 plays a role in physiological bone remodeling and regulates the activity of cells of the bone either directly or indirectly on bone-resorbing osteoclasts as well as on bone-forming osteoblasts. Recent animal and human trials have revealed the main pro-osteoclastogenic activities for the IL-23 pathway. We examined nine single nucleotide polymorphisms (SNPs) in the interleukin-23 receptor (IL-23R) in 100 OP patients and gender- and age-matched 96 healthy volunteers. The most analyzed SNPs in the recent rheumatology literature were selected. Methods: In addition to gene polymorphisms several laboratory parameters (osteocalcin, parathormone, vitamine D) were investigated. Independent Samples t-test and Mann-Whitney-U test were used to compare several demographic and clinical parameters between the groups. P-value < 0.05 was accepted to be statistically significant. Results: Having the heterozygous GA genotype of IL-23R rs1004819 and the heterozygous CT genotype of Il-23R rs7530511 significantly increase the risk of developing OP (adjusted OR: 3.51, p = 0.031 and OR: 2.41, p = 0.027, respectively). The wild homozygous GG genotype of Il-23R rs11209032 had higher osteocalcin levels compared with the mutant homozygous AA genotype (18.75 ± 9.76, p = 0.009). Conclusions: Our findings suggest that several IL-23R gene polymorphisms are seen more often in osteoporosis patients than in healthy volunteers. In addition, some SNPs were related to higher serum osteocalcin levels.

Εισαγωγή: Οι περι-εγxειρητικές ανάγκες σε αναισθητικά ή/και αναλγητικά φάρμακα παρουσιάζουν αξιοσημείωτη διακύμανση και μέρος αυτής φαίνεται να είναι γενετικά καθοριζόμενο. Ο σκοπός της παρούσας μελέτης ήταν να διερευνήσει την επίδραση κοινών πολυμορφισμών των γονιδίων SLC6A4 και ABCB1, στις διεγχειρητικές απαιτήσεις σε ρεμιφεντανύλη καθώς και στις μετεγχειρητικές ανάγκες σε αναλγητικά, σε ασθενείς που υποβάλλονται σε εκλεκτικές επεμβάσεις ελάχιστα επεμβατικής θυρεοειδεκτομής. Υλικό και Μέθοδος: Πρόκειται για μία μελέτη παρατήρησης, τύπου κοόρτης, η οποία συμπεριέλαβε 90 ασθενείς που υποβλήθηκαν σε εκλεκτική θυρεοειδεκτομή, υπό γενική αναισθησία με σύστημα ελεγχόμενης έγχυσης στόχου (Target Controlled Infusion – TCI) ρεμιφεντανύλης. Μετεγχειρητικά τα αναλγητικά φάρμακα χορηγούνταν τόσο βάσει πρωτοκόλλου όσο και κατ΄επίκληση, αναλόγως του πόνου που αισθανόταν ο κάθε ασθενής. Ο καθορισμός του γονοτύπου έγινε με εφαρμογή καθιερωμένων μεθόδων PCR-RFLP. Για κάθε ασθενή έγινε καταγραφή του γονοτύπου, των διεγχειρητικών αιμοδυναμικών παραμέτρων, της συνολικής κατανάλωσης ρεμιφεντανύλης, των μετεγχειρητικών αναγκών σε αναλγητικά και της αντίληψης του πόνου (με την κλίμακα VAS). Αποτελέσματα: Οι διεγχειρητικές ανάγκες σε ρεμιφεντανύλη δεν συσχετίσθηκαν με κανέναν πολυμορφισμό. Οι ασθενείς με τον γονότυπο ABCB1 3435TT ένιωθαν στατιστικά σημαντικά λιγότερο μετεγχειρητικό πόνο μέχρι και μία ώρα μετά την επέμβαση, συγκριτικά με τους φορείς του C αλληλομόρφου [μέση κλίμακα VAS (SD) στην 1 ώρα = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], ένα εύρημα το οποίο περιοριστήκε μόνο στην ομάδα εκείνη των ασθενών που χρειάζονταν επιπρόσθετη αναλγητική αγωγή (επιπλέον της σταθερά χορηγούμενης βάσει πρωτοκόλλου). Οι πολυμορφισμοί του SLC6A4 δεν είχαν κάποια σημαντική επίδραση στην αντίληψη του πόνου ή στις ανάγκες σε αναλγητικά. Συμπεράσματα: Ο πολυμορφισμός ABCB1 C3435T φαίνεται να επηρεάζει την αντίληψη του μετεγχειρητικού χειρουργικού πόνου σε ασθενείς με χαμηλό ουδό πόνου, που υποβάλλονται σε ελάχιστα επεμβατική θυρεοειδεκτομή. Αντίθετα, οι πολυμορφισμοί του SLC6A4 δεν έδειξαν κάποια επίδραση. Μελλοντικές, μεγαλύτερες μελέτες, με περισσότερα γονίδια και περισσότερους πολυμορφισμούς ενδέχεται να αποκαλύψουν περαιτέρω και ισχυρότερες συσχετίσεις μεταξύ γενετικού υποβάθρου και περιεγχειρητικών αναγκών σε αναλγητικά φάρμακα., Introduction: Perioperative anesthetic and/or analgesic demands present considerable variation, and part of that variation appears to be genetic in origin. The aim of this study was to investigate the impact of common polymorphisms in SLC6A4 and ABCB1 genes, on the intra-operative consumption of remifentanil, as well as the postoperative analgesic needs, in patients subjected to minimal invasive thyroidectomy surgery. Materials and Methods: We conducted a prospective cohort study with 90 patients scheduled to undergo elective thyroidectomy, under total intravenous anesthesia achieved by target control infusion (TCI) of remifentanil. Postoperative analgesics were administered by protocol and as on-demand of the individual patient. Genotyping was established by PCR-RFLP methods. Genotyping data, intraoperative hemodynamics, and total consumption of remifentanil, as well as postoperative analgesic needs and pain perception, were recorded for each individual. Results: Intraoperative remifentanyl consumption was not associated with any polymorphism. Patients with the ABCB1 3435TT genotype appeared to experience significantly less pain, up to one hour post-operatively, compared to C carriers [mean VAS (SD) at 1 h = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], a finding limited to those seeking rescue analgesic treatment (additional to the standard analgesics per protocol). The SLC6A4 polymorphisms did not have a significant effect on pain or analgesic needs. Conclusions: The ABCB1 C3435T polymorphism appears to affect post-operative perception of surgical pain among patients with low pain threshold who undergo minimally invasive thyroid surgery. The SLC6A4 polymorphisms did not show any effect. Future, larger studies involving more genes and more polymorphisms may reveal further, stronger assocciations between genetic substrate and peri-operative analgesic needs.

Ο σακχαρώδης διαβήτης τύπου 2 (ΣΔ2) είναι μία χρόνια, πολυπαραγοντική νόσος με ισχυρό γενετικό υπόβαθρο. Καθοριστικό ρόλο στην εκδήλωσή του έχουν περιβαλλοντικοί παράγοντες, με την παχυσαρκία να αποτελεί τη συχνότερη αιτία εκδήλωσης της νόσου. Βασική επιπλοκή του διαβήτη αποτελεί η αγγειοπάθεια, η οποία σε συνδυασμό με την παχυσαρκία, αυξάνει τον καρδιαγγειακό κίνδυνο που αποτελεί την κυριότερη αιτία θανάτου σε ασθενείς με ΣΔ2. Η ρύθμιση των επιπέδων γλυκόζης (νηστείας και μεταγευματικών) οδηγεί σε καλύτερη γλυκαιμική ρύθμιση και μειώνει των κίνδυνο των επιπλοκών σε ασθενείς με ΣΔ2 και αποτελεί στόχο των κλασσικών φαρμακευτικών αγωγών. Παράλληλα όμως τα κλασσικά αντιδιαβητικά δισκία (σουλφονυλουρίες) οδηγούν σε εμφάνιση υπογλυκαιμικών επεισοδίων και σε αύξηση του σωματικού βάρους στους ασθενείς ενώ η δράση τους στον καρδιαγγειακό κίνδυνο δεν έχει διευκρινιστεί. Τα τελευταία 20 χρόνια χρησιμοποιούνται στη θεραπεία του ΣΔ2 νέοι φαρμακευτικοί παράγοντεςανάλογα ινκρετινών (κυρίως GLP-1 και τελευταία και GIP), δηλαδή πεπτιδίων που εκκρίνονται από τον εντερικό βλεννογόνο και επάγουν την έκκριση ινσουλίνης μετά τη λήψη τροφής, ρυθμίζοντας τα επίπεδα της μεταγευματικής γλυκόζης και τον έλεγχο του μεταβολισμού των λιπιδίων. Η χορήγηση φαρμάκων ανάλογων του GLP-1, έχει φανεί πως διεγείρει την έκκριση ινσουλίνης με γλυκοζοεξαρτώμενο τρόπο, βελτιώνοντας το γλυκαιμικό προφίλ των ασθενών, ενώ παράλληλα καταστέλλει την έκκριση γλυκαγόνης, μειώνει τη γαστρική κένωση και αυξάνει το αίσθημα κορεσμού συμβάλοντας στη ρύθμιση του σωματικού βάρους των ασθενών. Έχει παρατηρηθεί ωστόσο πως η απόκριση των ασθενών στη θεραπεία με ανάλογα του GLP-1 παρουσιάζει σημαντική ετερογένεια ακόμα και μεταξύ ατόμων με ανάλογη γλυκαιμική ρύθμιση ή ανάλογες απαιτήσεις αντιδιαβητικής αγωγής. Η ετερογένεια που παρατηρείται τόσο ως προς την απόκριση ή/και την ανθεκτικότητα προς τη θεραπεία, όσο και ως προς τις ανεπιθύμητες ενέργειες που παρατηρούνται από ασθενή σε ασθενή, είναι πολύ πιθανό να σχετίζεται με το διαφορετικό γενετικό υπόβαθρο των ασθενών που αφορά γονίδια που εμπλέκονται στο μονοπάτι των ινκρετινών. Πρόσφατες invitro μελέτες έχουν δείξει πως μονονουκλεοτιδικοί πολυμορφισμοί (SNPs) στα γονίδια του υποδοχέα του GLP-1, είτε μεταβάλλουν τη χημική συγγένεια του υποδοχέα με το πεπτίδιο GLP-1 επηρεάζοντας την ικανότητα δέσμευσής του στον υποδοχέα, είτε επηρεάζουν τη δραστικότητα του φυσικού προσδέτη. Επιπρόσθετα, μελέτες στο γονίδιο TCF7L2, έχουν δείξει πως ασθενείς με διαβήτη τύπου 2 που φέρουν το αλληλόμορφο TCF7L2rs7903146 παρουσιάζουν σημαντικά μειωμένη έκκριση ινσουλίνης, επαγόμενης από το GLP-1. Επίσης, πολυμορφισμοί στα γονίδια CTBR1/2 έχει βρεθεί πως επηρεάζουν την ευαισθησία των ασθενών στην εν λόγω ασθένεια. Στην παρούσα διατριβή, το κύριο ερευνητικό ερώτημα ήταν ο ρόλος των μονονουκλεοτιδικών πολυμορφισμών (SNPs) rs7903146 στο γονίδιο του μεταγραφικού παράγοντα TCF7L2, rs367543060 στο γονίδιο του υποδοχέα GLP-1R, και rs7202877 στο γονίδιο CTBR1/2, στην υπογλυκαιμική δράση των αναλόγων του GLP-1 ή/και στη δράση τους στη μείωση του βάρους ασθενών με ΣΔ2. Προκειμένου να διερευνηθεί αυτό το ερώτημα, εξετάσθηκε η σχέση μεταξύ των παραπάνω γενετικών πολυμορφισμών και της ετερογενούς θεραπευτικής ανταπόκρισης σε γλυκαιμία και σε μείωση του σωματικού βάρος σε 191 Καυκάσιους ασθενείς στην αγωγή των οποίων προστέθηκε ανάλογο GLP-1, χωρίς να πραγματοποιηθεί καμία θεραπευτική ή άλλη παρέμβαση στο ήδη υπάρχον θεραπευτικό σχήμα. Οι ασθενείς με ΣΔ2 που μελετήθηκαν, διαχωρίστηκαν σε αυτούς που δεν εμφανίζουν αντίσταση στη δράση των εν λόγω φαρμάκων (Ομάδα Α1 και Β1) και σε αυτούς που εμφανίζουν αντίσταση στη δράση των GLP-1 αναλόγων (Ομάδα Α2 και Β2). Οι συμμετέχοντες κατατάχθηκαν αρχικά σε αποκριθέντες και μη αποκριθέντες στη θεραπεία με ανάλογα του GLP-1, όσον αφορά τον γλυκαιμικό έλεγχο (Ομάδα Α1 και Α2 αντίστοιχα). Στη συνέχεια, οι ασθενείς χωρίστηκαν περαιτέρω σε δύο ομάδες, ανάλογα με την απόκρισή τους στη θεραπεία με ανάλογα του GLP-1 όσον αφορά την απώλεια βάρους, ανεξάρτητα από την απόκρισή τους ή μη στον γλυκαιμικό έλεγχο (Ομάδα Β1 και Β2 αντίστοιχα). Η γονοτύπηση των πολυμορφισμών rs7202877, rs7903146 και rs367543060 πραγματοποιήθηκε στο Εργαστήριο Γενικής Βιολογίας του τμήματος Ιατρικής, στο Πανεπιστήμιο Πατρών. Το γονιδιωματικό DNA ελήφθη από δείγμα φλεβικού αίματος κάθε ασθενούς, που εκχυλίστηκε και ποσοτικοποιήθηκε και στη συνέχεια διεξήχθη γονοτυπική ανάλυση στο DNA κάθε υποψηφίου μέσω της τεχνικής της αλυσιδωτής αντίδρασης πολυμεράσης σε πραγματικό χρόνο (Real-Time PCR). Επιπλέον, εξετάσθηκε μια σειρά κλινικών παραμέτρων, προκειμένου να εντοπιστούν πιθανοί προγνωστικοί παράγοντες απόκρισης στη θεραπεία με GLP-1 ανάλογα. Το σύνολο των αποτελεσμάτων της μελέτης μας, έδειξε ότι:α) οι πολυμορφισμοί στα γονίδια που εξετάσθηκαν, δε φαίνεται να σχετίζονται με την απόκριση των ασθενών στη θεραπεία με ανάλογα του GLP-1, β) μεγαλύτερο ποσοστό γυναικών είναι πιθανό να αποκριθεί στην αγωγή όσον αφορά τη γλυκαιμία συγκριτικά με τους άνδρες, γ) ασθενείς με χαμηλότερο σωματικό βάρος στην αρχή της θεραπείας είχαν περισσότερες πιθανότητες να αποκριθούν στην αγωγή με GLP-1 ανάλογα όσον αφορά τη ρύθμιση του βάρους, δ) χαμηλότερη τιμή της FPG κατά την έναρξη της αγωγής, αυξάνει τις πιθανότητες απόκρισης στη θεραπεία όσον αφορά τη ρύθμιση του βάρους, ε) χαμηλότερη τιμή γλυκοζυλιωμένης αιμοσφαιρίνης κατά την έναρξη της θεραπείας με GLP-1 ανάλογα, αυξάνει τις πιθανότητες να αποκριθούν οι ασθενείς στην αγωγή όσον αφορά τη ρύθμιση του βάρους, στ) ασθενείς που είχαν λάβει λιγότερα σκευάσματα πριν την έναρξη της θεραπείας τους με GLP-1 ανάλογα (πρώιμη ένταξη GLP-1 αναλόγου στην αγωγή), φαίνεται πως έχουν περισσότερες πιθανότητες να αποκριθούν στην εν λόγω αγωγή, όσον αφορά τη ρύθμιση του βάρους., Type 2 diabetes mellitus (T2DM) is a chronic, multifactorial disease with a strong genetic background. Environmental factors play a decisive role in its manifestation, with obesity being the most common cause of the disease. A basic complication of diabetes is vasculopathy, which, in combination with obesity, increases the cardiovascular risk which is the main cause of death in patients with T2DM. The regulation of glucose levels (fasting and postprandial) leads to better glycemic control and reduces the risk of complications in patients with T2DM and is the goal of classical pharmaceutical treatments.At the same time, however, classic antidiabetic tablets (sulfonylureas) lead to the appearance of hypoglycemic episodes and an increase in body weight in patients, while their effect on cardiovascular risk has not been clarified. In the last 20 years, new pharmaceutical agents have been used in the treatment of T2DM. These agents are called incretin analogues (mainly GLP-1 and recently GIP) and constitute substances that imitate peptides that are secreted by the intestinal mucosa and induce insulin secretion after eating, regulating postprandial glucose levels and control of lipid metabolism. The administration of analogues to GLP-1 has been shown to stimulate insulin secretion in a glucose-dependent manner, improving the glycemic profile of patients, while at the same time suppressing glucagon secretion, reducing gastric emptying and increasing the feeling of satiety, contributing to the regulation of the body weight of the patients. It has been observed, however, that the response of patients to treatment with GLP-1 analogues shows significant heterogeneity even between individuals with similar glycemic control or similar antidiabetic treatment requirements.The heterogeneity observed both in terms of response and/or resistance to treatment, and in side effects observed from patient to patient, is most likely related to the different genetic background of the patients regarding to genes involved in incretin pathway. Recent in vitro studies have shown that single nucleotide polymorphisms (SNPs) in the GLP-1 receptor genes either alter the chemical affinity of the receptor for the GLP-1 peptide affecting its ability to bind to the receptor, or affect the activity of the natural ligand.Additionally, studies on the TCF7L2 gene have shown that patients with type 2 diabetes who carry the TCF7L2rs7903146 allele show significantly reduced GLP-1-induced insulin secretion. Also, polymorphisms in the CTBR1/2 genes have been found to influence the susceptibility of patients to this disease. In the present PhD thesis, the main research question was the role of single nucleotide polymorphisms (SNPs) rs7903146 in the gene of transcription factor TCF7L2, rs367543060 in the GLP-1R receptor gene, and rs7202877 in the CTRB1/2 gene, on the hypoglycemic effect of GLP-1 analogs and/or their effect on weight reduction in T2DM patients. In order to investigate this question, the relationship between the above genetic polymorphisms and the heterogeneous therapeutic response in glycemia and body weight was examined in 191 Caucasian patients to whose treatment a GLP-1 analog was added, without performing any therapeutic or other intervention on the already existing treatment regimen. In addition, a number of clinical parameters were examined in order to identify potential predictors of response to treatment with GLP-1 analogues. Participants were initially categorized into responders and non-responders to GLP-1 analogue therapy with regard to glycemic control (Group A1 and A2, respectively). Patients were then further divided into two groups according to their response to GLP-1 analogue therapy in terms of weight loss, regardless of their response to glycemic control (Group B1 and B2, respectively). The genotyping of the rs7202877, rs7903146 and rs367543060 polymorphisms was performed at the General Biology Laboratory of the Department of Medicine, University of Patras. Genomic DNA was obtained from a venous blood sample of each patient, extracted and quantified, and DNA genotyping was then performed using the Real-Time PCR (Real-Time PCR) technique. The results of our study showed that: a) the polymorphisms in the genes examined do not seem to be related to the response of patients to treatment with GLP-1 analogues, b) a greater percentage of women are likely to respond to the treatment in terms of regarding glycemia compared to men, c) patients with a lower body weight at the beginning of treatment were more likely to respond to GLP-1 treatment proportionally in terms of weight regulation;d) a lower value of FPG at the start of treatment increases the chances of response to treatment in terms of weight regulation, e) a lower value of glycated hemoglobin at the start of treatment with GLP-1 analogues, increases the chances that patients will respond to weight management treatment, f) patients who had received fewer medical agents before starting their treatment with GLP-1 analogues (early inclusion of a GLP-1 analogue in the treatment), appear to be more likely to respond to this treatment, in terms of weight regulation.

Objective: To investigate the association between obstructive sleep apnea syndrome (OSAS), glutathione peroxidase-1 (GPX1) Pro198Leu, and manganese superoxide dismutase (MnSOD) Ala16Val gene polymorphisms. Materials and Methods: The study included 81 patients with OSAS and 75 healthy controls from the Turkish population. Genotypes of the MnSOD rs4880 T/C (Ala16Val) and GPX1 rs1050450 T/C (Pro198Leu) variants were determined via single-nucleotide polymorphisms genotyping analysis, which is based on simple probe melting curve analysis. Results: The frequencies of the MnSOD rs4880 T/T, T/C, and C/C were 35.8%, 50.6%, and 13.5% in patients with OSAS and 34.6%, 49.3%, and 16% in the controls, respectively. No statistically significant difference was determined between patients and controls in terms of MnSOD rs4880 variant genotype and allele distribution (odds ratio: 1.07; 95% confidence interval: 0.68-1.69; p>0.05). The frequencies of the GPX1 rs1050450T/T, T/C, and C/C were 12.0%, 38.5%, and 49.4% in patients with OSAS and 13.1%, 42.1%, and 44.7% in the controls, respectively. No statistically significant difference was determined in the genotype and allele frequencies of the GPX1 rs1050450 variant between the patients and controls (p>0.05). Additionally, the haplotype was examined on the basis of combined genotypes for the two variants in patients with OSAS and controls, which revealed no statistically significant correlation. Conclusion: Our study indicates that two polymorphisms in these antioxidant enzymes were not associated with Turkish patients with OSAS. Further studies may reveal an association between these two polymorphisms with some clinical parameters in patients with OSAS.

Natchaya Vanwong,1,2 Sayanit Tipnoppanon,1 Chalitpon Na Nakorn,3 Pornpen Srisawasdi,4 Punyanuch Rodcharoen,4 Sadeep Medhasi,5 Pajaree Chariyavilaskul,2,6,7 Sarawut Siwamogsatham,2,8,9 Yongkasem Vorasettakarnkij,2,9 Chonlaphat Sukasem10– 12 1Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand; 2Cardiovascular Precision Medicine Research Group, Special Task Force of Activating Research (STAR), Chulalongkorn University, Bangkok, Thailand; 3Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Thailand; 4Division of Clinical Chemistry, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 5Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand; 6Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 7Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Chulalongkorn University, Bangkok, Thailand; 8Chula Clinical Research Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 9Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 10Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 11Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand; 12Pharmacogenomics and Precision Medicine, The Preventive Genomics & Family Check-up Services Center, Bumrungrad International Hospital, Bangkok, ThailandCorrespondence: Chonlaphat Sukasem, Division of Pharmacogenetics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand, Tel +66-2-200-4331, Fax +66-2-200-4332, Email chonlaphat.suk@mahidol.ac.thPurpose: Statins are increasingly widely used in the primary and secondary prevention of cardiovascular disease. However, there is an inter-individual variation in statin response among patients. The study aims to determine the association between genetic variations in drug-metabolizing enzyme and transporter (DMET) genes and lipid-lowering response to a statin in Thai patients with hyperlipidemia.Patients and Methods: Seventy-nine patients who received statin at steady-state concentrations were recruited. Serum lipid profile was measured at baseline and repeated after 4-month on a statin regimen. The genotype profile of 1936 DMET markers was obtained using Affymetrix DMET Plus genotyping microarrays.Results: In this DMET microarray platform, five variants; SLCO1B3 (rs4149117, rs7311358, and rs2053098), QPRT (rs13331798), and SLC10A2 (rs188096) showed a suggestive association with LDL-cholesterol-lowering response. HDL-cholesterol-lowering responses were found to be related to CYP7A1 gene variant (rs12542233). Seven variants, SLCO1B3 (rs4149117, rs7311358, and rs2053098); SULT1E1 (rs3736599 and rs3822172); and ABCB11 (rs4148768 and rs3770603), were associated with the total cholesterol-lowering response. One variant of the ABCB4 gene (rs2109505) was significantly associated with triglyceride-lowering response.Conclusion: This pharmacogenomic study identifies new genetic variants of DMET genes that are associated with the lipid-lowering response to statins. Genetic polymorphisms in DMET genes may impact the pharmacokinetics and lipid-lowering response to statin. The validation studies confirmations are needed in future pharmacogenomic studies.Keywords: drug-metabolizing enzymes, drug transporters, gene polymorphisms, statin

AIM: To assess the association of vascular endothelial growth factor(VEGF)gene polymorphisms(rs2010963 and rs3025039)with diabetic retinopathy(DR)in Li nationality type 2 diabetic(T2DM)patients in Hainan.METHODS: Prospective study. A total of 89 patients with T2DM in the Li nationality in Hainan were randomly categorized(between 09/2016 to 10/2019)into three groups, 30 patients in nonproliferative diabetic retinopathy(NPDR)group, 33 patients in proliferative diabetic retinopathy(PDR)group, and 26 patients in T2DM without retinopathy(DWR)group as control. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine the polymorphism in the VEGF gene. Differences in allele frequencies and genotype frequencies between cases and controls were compared. RESULTS: Compared with the DWR group, the CC genotype of rs2010963 polymorphic site was significantly increased(P0.05). Meanwhile, no significant differences were detected in the frequencies of genotype CC, CT, C, and T in rs3025039 among the three groups(all P>0.05). Plasma levels of serum urea and creatinine were significantly increased in PDR group compared to DWR and NPDR groups in Li nationality group in Hainan(all P

Aim The association of polymorphisms in the three genes of SOCS3, JAK2 and STAT3 with genetic susceptibility to type 2 diabetes mellitus (T2DM) was explored, and its interaction with environmental factors such as hypertension and triglycerides was analyzed. Methods The Hardy–Weinberg balance test was used to analyze the random balance of genes in the population. The analysis of the association of SNPs with T2DM was performed using Pearson’s chi-square test. Haplotype frequency distribution, SNPs-SNPs interaction and environmental factors were analyzed by chi-square test and logistic regression. Results The genotype distribution of SNPs rs2280148 of the SOCS3 gene was statistically significant. The allele frequency distribution of SNPs (rs4969168/rs2280148) was statistically different. After covariate correction, the SOCS3 gene locus (rs4969168) showed an association with T2DM in additive model, while the rs2280148 locus showed an association with T2DM in all three models. The locus (rs10974914/rs10815157) allele and genotype frequency distribution of JAK2 were statistically significant. After covariate correction, two SNPs in the gene showed association with T2DM in both additive and recessive models. The distribution of genotype frequencies of SNPs rs1053005 locus in gene STAT3 was statistically significant between the two groups. In recessive genetic models, rs1053005 locus polymorphisms was associated with T2DM. Haplotype S3 (G G)/S 4 (G T) of the SOCS3 gene as well as haplotype J2 (A G)/J 3 (G C) of the JAK2 gene were closely associated with T2DM. There was an interaction between SNPs rs4969168 and SNPs rs2280148 in the SOCS3 gene. There was an interaction between the SOCS3, JAK2 and STAT3 genes and hypertension/triglycerides. Conclusion The SOCS3 and JAK2 genes may be associated with T2DM in the Chinese population, in which SNPs carrying the A allele (rs4969168)/G allele (rs2280148)/C allele (rs10815157) have a reduced risk of T2DM. Haplotype S3 (G G)/S 4 (G T) of the SOCS3 gene and haplotype J2 (A G)/J 3 (G C) of the JAK2 gene may be influencing factor for T2DM. The interaction between SNPs rs4969168 and SNPs rs2280148 increases the risk of T2DM. Hypertension and triglycerides may interact with SNPs of T2DM susceptibility genes.

Relevance. Currently, the number of percutaneous coronary interventions continues to increase, which leads to an increase in the absolute number of restenosis cases, which is the main complication of the long-term postoperative period. The search for risk factors responsible for restenosis and artery re-narrowing mechanisms in order to prevent this complication is an important goal in interventional cardiology. Risk factors for the restenosis development include clinical, angiographic and genetic factors. An active search for biomolecular markers associated with the coronary artery restenosis is currently underway. Objective: to study the role of polymorphic variants C-174G of the IL6 gene and C-819T of the IL10 gene as a risk factor for the development of restenosis in patients after stent implantation. Materials and Methods : The study included 113 patients with stable coronary artery disease, who had previously undergone balloon angioplasty and implantation of drug-eluting stents, and 62 patients with intact arteries that were included to the control group. Statistical data processing was carried out using the R-language program and the SPSS Statistics 20 software package. Results: GG genotype for IL6 gene was associated with the development of coronary artery disease. In the subgroup of patients over 65 years of age and instent restenosis, the GG genotype was significantly less frequent. The homozygous CC genotype for IL10 gene was associated with rapid angiographic in-stent restenosis progression.

Objectives The aim of the study is to analyze the association of different bitter and sweet gene receptor polymorphisms and bitter and sweet food consumption on formation of dental caries in Turkish adult population. Methods This study included 205 adults whose detailed intraoral health examination was completed and decayed, missing, filled teeth (DMFT) index values were recorded. A mini questionnaire was applied to assess the consumption of bitter and sweet food. A venous blood sample from each participant was collected in Ethylenediamine tetraacetic acid (EDTA) tubes. Further, DNA samples were isolated from the blood samples by utilizing a DNA isolation kit, which were stored at +4 °C prior to the analysis. Taste receptor type 2 member 38 (TAS2R38; rs10246939, rs713598, rs1726866), Taste receptor type 1 member 2 (TAS1R2; rs35874116, rs9701796), and Taste receptor type 1 member 3 (TAS1R3; rs307355) gene polymorphisms were detected using real-time polymerase chain reaction (PCR). Results There was no statistically significant association between the TAS2R38, TAS1R2, and TAS1R3 gene polymorphism and the DMFT index (p>0.05). No significant difference was found between the consumption of bitter and sweet food and the DMFT index (p>0.05). Conclusions TAS2R38 (rs10246939, rs713598, rs1726866), TAS1R2 (rs35874116, rs9701796), and TAS1R3 (rs307355) gene polymorphism may not be associated with the formation of dental caries in the Turkish adult population.

Antipsychotic-induced parkinsonism (AIP) is the most common type of extrapyramidal side effect (EPS), caused by the blockage of dopamine receptors. Since dopamine availability might influence the AIP risk, the dopamine transporter (DAT) and serotonin receptors (5-HTRs), which modulate the dopamine release, may be also involved in the AIP development. As some of the individual differences in the susceptibility to AIP might be due to the genetic background, this study aimed to examine the associations of SLC6A3, HTR2C and HTR6 gene polymorphisms with AIP in haloperidol-treated schizophrenia patients. The Extrapyramidal Symptom Rating Scale (ESRS) was used to evaluate AIP as a separate entity. Genotyping was performed using a PCR, following the extraction of blood DNA. The results revealed significant associations between HTR6 rs1805054 polymorphism and haloperidol-induced tremor and rigidity. Additionally, the findings indicated a combined effect of HTR6 T and SLC6A3 9R alleles on AIP, with their combination associated with significantly lower scores of ESRS subscale II for parkinsonism, ESRS-based tremor or hyperkinesia and ESRS subscales VI and VIII. These genetic predictors of AIP could be helpful in better understanding its pathophysiology, recognizing the individuals at risk of developing AIP and offering personalized therapeutic strategies for the patients suffering from this EPS.

In advanced cancer, pain is a poor prognostic factor, significantly impacting patients’ quality of life. It has been shown that up to 30% of cancer patients in Southeast Asian countries may receive inadequate analgesia from opioid therapy. This significant under-management of cancer pain is largely due to the inter-individual variability in opioid dosage and relative efficacy of available opioids, leading to unpredictable clinical responses to opioid treatment. Single nucleotide polymorphisms (SNPs) cause the variability in opioid treatment outcomes, yet their association in Asian populations remains unclear. Therefore, this review aimed to evaluate the association of SNPs with variability in opioid treatment responses in Asian populations. A literature search was conducted in Medline and Embase databases and included primary studies investigating the association of SNPs in opioid treatment outcomes, namely pharmacokinetics, opioid dose requirements, and pain control among Asian cancer patients. The results show that CYP2D6*10 has the most clinical relevance in tramadol treatment. Other SNPs such as rs7439366 (UGT2B7), rs1641025 (ABAT) and rs1718125 (P2RX7) though significant have limited pharmacogenetic implications due to insufficient evidence. OPRM1 rs1799971, COMT rs4680 and ABCB1 (rs1045642, rs1128503, and rs2032582) need to be further explored in future for relevance in Asian populations. Refereed/Peer-reviewed

The association of glutathione S-transferase (GST) enzymes with vitiligo is inconclusive. To evaluate tissue expressions of GST isoenzymes in vitiligo patients and to compare these expressions with healthy controls, we used 26 active depigmented patches on the trunk of vitiligo patients and 20 healthy sex and age matched controls. Punch biopsies were taken from the lesioned or normal skin. Tissue expression of GST isoenzymes were analyzed immunohistochemically. Tissue expression of GSTT1, GSTA1 and GSTP1 was significantly higher in the patient group than controls. Tissue expression of GSTM1 was not significantly different between the two groups. The increased tissue expression of GSTT1, GSTA1 and GSTP1 may represent a response to excess free radical formation in vitiligo and may support the role of oxidative stress in the pathogenesis of vitiligo. WOS:000698255600001 2-s2.0-85115232607 PubMed: 34547977

The occurrence and severity of chemotherapy-induced nausea and vomiting (CINV) are influenced by many factors; this includes therapeutic factors, such as the dose, administration mode, and chemotherapeutic agent emetogenicity, as well as patient-related risk factors, such as the gender, age, alcohol consumption history, and anxiety level. However, these factors cannot fully explain the individual CINV differences. In recent years, the correlation between gene polymorphism and CINV has been a hot research topic; the present paper reviews current research on CINV-related gene polymorphisms, and the results indicate that the use of gene polymorphism for the optimization of CINV efficacy is of important clinical significance.

Yilan Jin,&ast; Xiaorong Li,&ast; Caihong Jiang,&ast; Jun Zhao, Guang Liu, Hui Li, Gaowa Jin, Quanfu Li Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Quanfu Li; Gaowa JinDepartment of Medical Oncology, Ordos Central Hospital, 23th Yinjihuoluo Western Road, Ordos, 017000, People’s Republic of ChinaTel +86 0477-8363279Fax +86 0477-8363158Email li_qfedu@163.com; jingw145@126.comAbstract: The occurrence and severity of chemotherapy-induced nausea and vomiting (CINV) are influenced by many factors; this includes therapeutic factors, such as the dose, administration mode, and chemotherapeutic agent emetogenicity, as well as patient-related risk factors, such as the gender, age, alcohol consumption history, and anxiety level. However, these factors cannot fully explain the individual CINV differences. In recent years, the correlation between gene polymorphism and CINV has been a hot research topic; the present paper reviews current research on CINV-related gene polymorphisms, and the results indicate that the use of gene polymorphism for the optimization of CINV efficacy is of important clinical significance.Keywords: chemotherapy-induced nausea and vomiting, gene polymorphisms, prevention and treatment, antiemetic

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the zoonotic pathogen that causes the "Coronavirus Disease of 2019 (COVID-19)", and COVID-19 itself is yet to be thoroughly understood. Both the disease as well as the mechanisms by which the host interacts with the SARS-CoV-2 have not been fully enlightened. The epidemiological factors -e.g. age, sex, race-, the polymorphisms of the host proteins, the blood types and individual differences have all been in discussions about affecting the progression and the course of COVID-19 both individually and collectively, as their effects are mostly interwoven. We focused mainly on the effect of polymorphic variants of the host proteins that have been shown to take part in and/or affect the pathogenesis of COVID-19. Additionally, how the procedures of diagnosing and treating COVID-19 are affected by these variants and what possible changes can be implemented are the other questions, which are sought to be answered.

Previous studies have reported that the single nucleotide polymorphisms (SNPs) of SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease (NAFLD). However, no studies have examined the effect of interactions between these three genotypes to affect liver disease severity. We assessed the effect of these three SNPs on nonalcoholic steatohepatitis (NASH) and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.

Introduction: Cervical cancer is the fourth most common form of cancer among women. Smoking tobacco seems to be a risk factor for the development of cervical intra-epithelial neoplasia (CIN) and cervical cancer, but the exact role of smoking in the process of cervical carcinogenesis is not known. The aim of this study is to investigate the relationship between smoking and the development of CIN and cervical cancer. Areas covered: We searched Embase, Medline, Cochrane Central, Web of Science, and Google Scholar for studies on smoking and CIN and cervical cancer, published between 2009 and 2018. The following were the outcomes: CIN3 alone, CIN2 and CIN3 combined, CIN2+, CIN3+, and cervical cancer alone. We included 49 studies in our review and 45 in our meta-analyses. Expert opinion: Based on the available evidence it can be – cautiously – concluded that smoking increases the risk of cervical abnormalities. However, the high risk of bias indicates that for future studies, it will be important to adjust for relevant predictors, to separate CIN from cervical cancer as outcome measures, and to report research methods in detail.

Introduction: Cervical cancer is the fourth most common form of cancer among women. Smoking tobacco seems to be a risk factor for the development of cervical intra-epithelial neoplasia (CIN) and cervical cancer, but the exact role of smoking in the process of cervical carcinogenesis is not known. The aim of this study is to investigate the relationship between smoking and the development of CIN and cervical cancer. Areas covered: We searched Embase, Medline, Cochrane Central, Web of Science, and Google Scholar for studies on smoking and CIN and cervical cancer, published between 2009 and 2018. The following were the outcomes: CIN3 alone, CIN2 and CIN3 combined, CIN2+, CIN3+, and cervical cancer alone. We included 49 studies in our review and 45 in our meta-analyses. Expert opinion: Based on the available evidence it can be - cautiously - concluded that smoking increases the risk of cervical abnormalities. However, the high risk of bias indicates that for future studies, it will be important to adjust for relevant predictors, to separate CIN from cervical cancer as outcome measures, and to report research methods in detail.

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response ( VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene–gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test P value = 1.5 × 10−5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

Periodontitis is a chronic multifactorial inflammatory disease originating from microbial, environmental and genetic factors. The present study aimed to find an association of genetic polymorphisms at IL-1A−889 and IL-1B+3953 loci in Polish patients with stage III grade B periodontitis and periodontally healthy subjects. Fifty patients with stage III grade B periodontitis (tests) and thirty-five periodontally healthy controls were included in the study. To determine IL-1A and IL-1B gene polymorphisms, buccal swab-derived DNA obtained by means of the GenoType PST test was used. There were no statistically significant differences regarding the prevalence of IL-1A−889 or IL-1B+3953 alleles between groups. The frequencies of different IL-1A−889 genotypes did not differ significantly between groups. The IL-1B+3953 C/T genotype was significantly more predominant in periodontitis patients than in controls, whereas C/C genotype prevalence was significantly lower in the test group. Complex genotypes consisting of at least one IL-1A−889 and IL-1B+3953 T allele occurred significantly more frequently in subjects with periodontitis. Stage III grade B periodontitis may be associated with the IL-1B+3953 T allele and composite IL-1 polymorphism. Reduced susceptibility to periodontal disease was present in IL-1A−889 and IL-1B+3953 C/C homozygotic patients.

Objective: Vitiligo is a common pigmentary disorder caused by the destruction of functional melanocytes. Its immunopathogenesis is not completely understood, but inflammatory alterations in the skin microenvironment, and particularly increased expression of the cytokines, are thought to be essential regulators of melanocyte dysfunction and death. Treatment of vitiligo using IFN-γ inhibition has given positive responses. Interleukin-18 (IL-18) is a cytokine that plays an important role in the Th1 response, by its ability to induce IFN-γ production in T cells and natural killer cells. The IL18 promoter is highly polymorphic containing several polymorphisms which have been described in the promoter region of IL18. Most of them were not reported to be associated with IL-18 production, only the -137 G/C (rs187238) and -607 C/A (rs1946518) SNPs in the promoter affect its promoter activity and IL-18 production was demonstrated. In addition, these SNPs have been reported to be associated with several autoimmune and inflammatory disorders. To our knowledge, no study has investigated the association between vitiligo and IL18 gene polymorphisms. We investigated the frequencies of the two above-mentioned IL18 promoter alterations in vitiligo patients and control subjects to determine whether these variants might represent susceptibility factors for vitiligo.Method: IL18 promoter polymorphisms of 89 patients with vitiligo and 87 healthy participants were analyzed by PCR-RFLP method.Results: There were no significant differences in the genotype and allele frequency of IL18 rs187238, and rs1946518 SNPs when compared to vitiligo patients with healthy subjects. The frequency of the CC genotype of IL18 rs187238 tended to decrease in vitiligo patients compared to healthy subjects but was not statistically significant (p=0.213). In haplotype analysis of two SNPs in the IL18 gene also did not reach statistical significance (p=0.715).Conclusion: In conclusion, our results suggest that IL18 gene polymorphisms were not played a key role in the pathogenesis of vitiligo. In addition, because of the relatively small number of subjects, our findings are preliminary and need to be validated in further studies with larger sample sizes., Amaç: Vitiligo, fonksiyonel melanositlerin kaybı ile karakterize yaygın bir pigment bozukluğudur. İmmünopatogenezi tam olarak aydınlatılamasa da cilt mikroçevresindeki inflamatuar değişikliklerin ve özellikle sitokin ekspresyonunun artmasının, melanosit disfonksiyonu ve ölümünün temel nedeni olduğu düşünülmektedir. Vitiligonun IFN-γ inhibisyonu kullanılarak tedavisi ile pozitif sonuçlar elde edilmiştir. İnterlökin 18 (IL-18), T hücrelerinde IFN-γ üretimini indükleyen ve Th1 yanıtında rolü olan önemli bir sitokindir. IL18 promotörü, çok sayıda polimorfizm içeren oldukça polimorfik bir bölgedir. Ancak bu polimorfizmlerden birçoğunun IL-18 üretimi ile ilişkili olmadığı bildirilmiştir, sadece promotördeki -137 G/C (rs187238) ve -607 C/A (rs1946518) polimorfizmlerinin promotörün aktivitesini etkilediği ve buna bağlı olarak da IL-18 üretimini etkilediği gösterilmiştir. Ayrıca bu polimorfizmlerin çeşitli otoimmün ve inflamatuar bozukluklarla ilişkili olduğu bildirilmiştir. Bildiğimiz kadarıyla, vitiligo ve IL18 gen polimorfizmleri arasındaki ilişkiyi araştıran hiçbir çalışma yoktur. Bu çalışmada, bu varyantların vitiligoya yatkınlıkla ilişkili olup olmadığının belirlenmesi için vitiligo hastalarında ve kontrol grubunda yukarıda bahsedilen rs187238 ve rs1946518 promotör polimorfizmlerinin sıklığı araştırıldı.Yöntem: Vitiligo tanılı 89 hasta ve 87 sağlıklı katılımcının, IL18 promotor polimorfizmleri PCR-RFLP yöntemi ile incelendi.Bulgular: Vitiligo hastaları, kontrol grubu ile karşılaştırıldığında IL18 rs187238 ve rs1946518 polimorfizmleri genotip ve alel frekanslarında anlamlı bir farklılık bulunamadı. IL18 rs187238'in CC genotipi frekansının, vitiligo hastalarında kontrol grubuna göre daha az olduğu görülmekle birlikte bu fark istatistiksel olarak anlamlı değildi (p=0.213). IL18 genindeki iki SNP'nin haplotip analizinde de gruplar arasında istatistiksel anlamlılığa ulaşılamadı (p=0.715).Sonuç: Sonuç olarak, elde ettiğimiz bulgular IL18 gen polimorfizmlerinin (-137 G/C (rs187238) ve -607 C/A (rs1946518)) vitiligo riski ve aktivitesi ile herhangi bir ilişkisinin olmadığını göstermektedir. Ancak, örneklem sayımızın nispeten küçük olmasından dolayı bulgularımızın ileri çalışmalarda etnik açıdan çeşitlilik içeren büyük örneklem gruplarıyla tekrarlanarak doğrulanması daha anlamlı olacaktır.

Xiaohua Liang,1 Shengqiang Dang2 1Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, 710038, People’s Republic of China; 2Department of Oncology, Chang’an Hospital of Xi’an, Xi’an, Shaanxi, 710016, People’s Republic of ChinaCorrespondence: Shengqiang DangDepartment of Oncology, Chang’an Hospital of Xi’an, 17 Wenjing Road, Xi’an, Shaanxi, 710016, People’s Republic of ChinaEmail sqdangcah@163.comPurpose: This study aimed to evaluate the associations between mitochondrial dynamics related genes -MFN1, MFN2 and DRP1 polymorphisms and risk of lung cancer.Methods: Six polymorphisms of MFN1, MFN2 and DRP1 were genotyped in 600 cases and 600 controls using a MassARRAY platform.Results: The MFN1 rs13098637-C and DRP1 rs879255689-A alleles were associated with an increased risk of lung cancer (prs13098637=0.004, prs879255689=0.005), while MFN2 rs4240897-A and rs2236058-G were related to a decreased risk of disease (p< 0.001). The rs13098637-TC/CC and rs879255689-GA/AA were determined as risk genotypes for lung cancer (prs13098637=0.014, prs879255689=0.013), whereas the rs4240897-GA/AA and rs2236058-GG were identified as protective genotypes against lung cancer risk (p< 0.001). Genetic model analysis showed that rs13098637 was correlated with an elevated risk of lung cancer in dominant and log-additive models (pdominant=0.007, plog-additive=0.004). Moreover, rs879255689 was associated with an increased risk of disease in all three models (pdominant=0.014, precessive=0.028, plog-additive=0.005). In contrast, rs4240897 and rs2236058 were related to reduced risk of disease in all three models (rs4240897: pall< 0.001; rs2236058: pdominant=0.008, precessive< 0.001, plog-additive< 0.001). In addition, these associations were related to the smoking status and pathological type of lung cancer patients.Conclusion: These results shed new light on the association between mitochondrial dynamics related genes and risk of lung cancer.Keywords: lung cancer, gene polymorphisms, mitochondrial dynamics, MFN1, MFN2

Qing Shu,1,* Qingqing Fan,1,* Bingzhu Hua,2 Hang Liu,1 Shiying Wang,2 Yunxing Liu,1 Yao Yao,1 Han Xie,1 Weihong Ge1 1Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China; 2Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihong GeDepartment of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of ChinaEmail 6221230@sina.comIntroduction: Mycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.Methods: This study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 − 118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 − 106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.Results: SLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 − 106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).Conclusion: For Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 − 106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.Keywords: mycophenolic acid, gene polymorphisms, adverse drug reactions, infections, anemia, autoimmune diseases

There is evidence that the concomitance of psoriasis and obesity may originate from the interplay between multiple genetic pathways and involve gene–gene interactions. The aim of this study was to compare the genetic background related to obesity among psoriatic patients versus healthy controls by means of a Genome-Wide Association Study (GWAS). A total of 972 psoriatic patients and a total of 5878 healthy donors were enrolled in this study. DNA samples were genotyped for over 500,000 single nucleotide polymorphisms (SNPs) using Infinium CoreExome BeadChips (Illumina, San Diego, CA, USA). Statistical analysis identified eleven signals (p < 1 × 10−5) associated with BMI across the study groups and revealed a varying effect size in each sub-cohort. Seven of the alternative alleles (rs1558902 in the FTO gene, rs696574 in the CALCRL gene, as well as rs10968110, rs4551082, rs4609724, rs9320269, and rs2338833,) are associated with increased BMI among all psoriatic patients and four (rs1556519 in the ITLN2 gene, rs12972098 in the AC003006.7 gene, rs12676670 in the PAG1 gene, and rs1321529) are associated with lower BMI. The results of our study may lead to further insights into the understanding of the pathogenesis of obesity among psoriatic patients.

Fetal alcohol spectrum disorders (FASD) in a course of high prenatal alcohol exposure (hPAE) are among the most common causes of developmental disorders. The main reason for pharmacological treatment of FASD children is attention deficit hyperactivity disorder (ADHD), and methylphenidate (MPH) is the drug of choice. The aim of the study was to assess whether children born of hPAE with ADHD, with or without morphological FASD, differ in terms of catechol-O-methyltransferase (COMT) and dopamine receptor D2 (DRD2) gene polymorphisms, and if genetic predisposition affects response and safety of MPH treatment. The polymorphisms of COMT (rs4680) and DRD2 (rs1076560, rs1800497) were analyzed in DNA samples. A borderline significance was found for the correlation between MPH side effects and the G allele of COMT (rs4680) (p = 0.04994) in all ADHD children. No effect of COMT (rs4680) and DRD2 (rs1076560, rs1800497) polymorphisms and the treatment efficacy was observed. The analyzed DRD2 and COMT gene polymorphisms seem to play no role in MPH efficacy in ADHD children with hPAE, while low-activity COMT (Met158) variant carriers may be more intolerant to MPH. The MPH treatment is effective in ADHD independent of FASD, although the ADHD-FASD variant requires higher doses to be successful. These results may help in optimization and individualization in child psychiatry.

Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme of alcohol metabolism and it is involved in the cellular mechanism of alcohol liver disease. ALDH2 gene mutations exist in about 8% of the world’s population, with the incidence reaching 45% in East Asia. The mutations will result in impairment of enzyme activity and accumulation of acetaldehyde, facilitating the progression of other liver diseases, including non-alcoholic fatty liver diseases, viral hepatitis and hepatocellular carcinoma, through adduct formation and inflammatory responses. In this review, we seek to summarize recent research progress on the correlation between ALDH2 gene polymorphism and multiple liver diseases, with an attempt to provide clues for better understanding of the disease mechanism and for strategy making.

Background: The relationship between bone metabolism-related gene polymorphisms and low bone mineral density (BMD) risk factors in female athletes is unclear. This study aimed at investigating whether the sensitivity of low BMD risk factors to BMD depends on estrogen receptor α (ERα) gene polymorphisms in Japanese female athletes. Materials and Methods: This study included 280 collegiate female athletes from 12 competitive sports (age, 19.2 ± 1.3 years). Data on sports participation, age at menarche, menstrual cycles, prior stress fractures, and prior eating disorders were obtained through a questionnaire-type survey. Sports types were classified into endurance, esthetic, aquatic, ball, and high load in consideration of exercise load characteristics. ERα gene PvuII (rs2234693) and XbaI (rs9340799) polymorphisms were analyzed by TaqMan® assay. The total body BMD was measured by dual-energy X-ray absorptiometry. Results: On multiple regression analysis, sports types, body mass index (BMI), menarche, and XbaI polymorphism remained robust independent predictors of BMD. However, prior stress fractures and menstrual cycles were excluded. In athletes carrying the XX+Xx genotype of XbaI polymorphism, sports types and BMI were associated with BMD. However, in athletes carrying the xx genotype of XbaI polymorphism, sports types, BMI, and menarche were associated with BMD. These results indicated that athletes carrying the xx genotype with delayed menarche had low BMD. Conclusions: In collegiate female athletes, participation in endurance, esthetic, and aquatic sports types and a low BMI are associated with low BMD. In addition, delayed menarche may negatively affect BMD in athletes carrying the xx type of ERα gene XbaI polymorphism.

Both excessive production of reactive oxygen species (ROS) and impaired antioxidant function are found in patients with chronic kidney disease (CKD). Therefore, individual susceptibility towards CKD can be induced by functional variations of genes encoding antioxidant regulatory (nuclear factor erythroid 2 - related factor 2 (Nrf2)) and catalytic (superoxide dismutase (SOD2) and glutathione peroxidase (GPX1)) proteins. Several types of single nucleotide polymorphisms (SNPs) have been found within the genes encoding these proteins, with Nrf2 (-617C/A), SOD2 (Ala16Val) and GPX1 (Pro198Leu) conferring impaired catalytic activity. The most unexplored gene polymorphism in CKD susceptibility, progression and survival, with only two original studies published, is the Nrf2 (-617C/A) polymorphism. The results of these studies showed that there was no individual impact of this polymorphism on the susceptibility towards end stage renal disease (ESRD) development, oxidative phenotype and mortality. However, Nrf2 had a significant role in ESRD risk and survival, when combined with other antioxidant genes. The results regarding the impact of SOD2 (Ala16Val) and GPX1 (Pro198Leu) polymorphisms on either CKD or ESRD are still inconclusive. Namely, some studies showed that patients having variant SOD2 (Val) or GPX1 (Leu) allele were at increased risk of CKD development and progression, while other studies reported only weak or no association between these polymorphisms and CKD. Surprisingly, the only study that reported an association of GPX1 polymorphism with overall/cardiovascular survival in ESRD patients showed a significant impact of low activity GPX1 (Leu/Leu) genotype on better survival. In this review, we comprehensively and critically appraise the literature on these polymorphisms related to oxidative stress in CKD patients, in order to identify gaps and provide recommendations for further clinical research and translation. New developments in the field of antioxidant polymorphisms in CKD patients could lead to better stratification of CKD patients, based on a prognostic antioxidant gene panel, and provide a more personalised medicine approach for the need of antioxidant therapy in these patients.

Nonsyndromic cleft lip with/without cleft palate is a common congenital birth defect of the maxillofacial region. The pathogenic mechanism is related to the interaction of genes and environmental factors. At present, there are many studies on genes, and genome-wide association analysis has found that the new susceptibility gene v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is associated with the development of nonsyndromic cleft lip with/without cleft palate. This paper reviews the research progress on the correlation between single nucletide polymorphism(SNPs) in MAFB and nonsyndromic cleft lip with/without cleft palate. The results of this review reveal how the MAFB gene is expressed and differentiated in various cell types and plays an important role in maintaining the development of various organs, such as the brain, pancreas, and parathyroid glands. The MAFB gene is significantly associated with the occurrence of nonsyndromic cleft lip with/without cleft palate in the Asian population. rs13041247, rs11696257, rs17820943 and other teratopoietic single nucleotide loci are the most commonly studied teratopoietic single nucleotide loci, and the research conclusions on the correlation between SNPs in MAFB genes are obviously different in different populations. The interaction between the MAFB gene and other susceptibility genes leads to the occurrence of nonsyndromic cleft lip with/without cleft palate; nevertheless, more in-depth research is needed on specific mechanisms and approaches based on the relationship between these two factors

This study aimed to explore the roles of ERCC1/XPF gene polymorphisms in the occurrence of breast cancer in the Uygur and Han ethnic groups in Xinjiang, China. Single nucleotide polymorphisms (SNPs) were detected by TaqMan real‐time PCR. The rs11615 G>A and rs2276466 C>G variant frequencies were higher in Uygur patients with breast cancer than in Han patients, while the frequency of rs2298881 C>A was higher in Han patients. We found that rs2298881 C>A (CA vs. CC: OR = 0.35, 95% CI = 0.20‐0.60; AA vs. CC: OR = 0.13, 95% CI = 0.04‐0.34; CA + AA vs. CC: OR = 0.33, 95% CI = 0.18‐0.51; AA vs. CA + CC: OR = 0.24, 95% CI = 0.08‐0.62; CA vs. AA + CC: OR = 0.49, 95% CI = 0.29‐0.82) was associated with a reduced breast cancer risk and rs3212986 C>A (AA vs. CC: OR = 4.80, 95% CI = 1.79‐15.29,; CA+AA vs. CC: OR = 1.71, 95% CI = 1.06‐2.77; AA vs. CA+CC: OR = 4.12, 95% CI =1.58‐12.89) and rs11615 G > A (AA vs. GG: OR = 3.49, 95% CI =1.54‐8.55; GA + AA vs. GG: OR = 1.98, 95% CI = 1.21‐3.27; AA vs. GA+GG: OR = 2.87, 95% CI = 1.30‐6.85) were associated with an elevated breast cancer risk among Uygur individuals. In addition, Uygur patients with breast cancer with 2‐3 combined risk genotypes of ERCC1 had a higher risk than patients with 0‐1 risk genotypes (OR = 2.91; 95% CI = 1.54‐5.71, p = 0.001). However, we failed to detect a statistically significant association between ERCC1/XPF polymorphisms and breast cancer risk in five genetic models among Han individuals. Our results showed that ERCC1/XPF gene polymorphisms predispose Uygur individuals to breast cancer; this finding should be verified by further large‐scale analyses., Distribution of ERCC1/XPF gene polymorphisms in Han and Uygur women with breast cancer was different. ERCC1/XPF gene polymorphisms predispose Uygur individuals to breast cancer.

Background: Whether polymorphisms in VDR gene affect the risk of postmenopausal osteoporosis or not remain unclear. Thus, the authors performed a meta-analysis to more robustly assess associations between polymorphisms in VDR gene and the risk of postmenopausal osteoporosis by integrating the results of previous literature. Methods: Medline, Embase, Wanfang, VIP and CNKI were searched comprehensively for eligible literature, and 67 genetic association studies were finally selected to be included in this meta-analysis. Results: We found that ApaI rs7975232 (dominant comparison: OR = 0.77, P = 0.007; allele comparison: OR = 0.81, P = 0.04), BsmI rs1544410 (dominant comparison: OR = 0.69, P = 0.002; allele comparison: OR = 0.78, P = 0.008) and TaqI rs731236 (recessive comparison: OR = 1.32 , P = 0.01) polymorphisms were significantly associated with the risk of postmenopausal osteoporosis in Caucasians, whereas FokI rs10735810 polymorphism was significantly associated with the risk of postmenopausal osteoporosis in Asians (dominant comparison: OR = 0.61, P = 0.0001; recessive comparison: OR = 2.02, P = 0.001; allele comparison: OR = 0.68, P = 0.002). Conclusions: This meta-analysis shows that ApaI rs7975232, BsmI rs1544410 and TaqI rs731236 polymorphisms may affect the risk of postmenopausal osteoporosis in Caucasians, while BsmI rs1544410 polymorphism may affect the risk of postmenopausal osteoporosis in Asians.

Background: Non-neutropenic pulmonary aspergillosis is one of the most common and serious fungal infections. Previous studies have shown that single nucleotide polymorphisms (SNPs) of pattern recognition receptors genes are associated with susceptibility to aspergillosis. NOD-like receptors (NLRs) play an important role in the immunological response against fungal infection. In this study, we investigated the relationship between polymorphisms of three NLRs and susceptibility to pulmonary aspergillosis disease in non-neutropenic patients. Methods: We included 73 patients with proven pulmonary aspergillosis and 103 healthy controls. A total of sixteen SNPs in the NLRP3, NLRC4, and NLRC5 genes were detected by PCR-direct sequencing. Then, we evaluated the association between these polymorphisms and susceptibility to aspergillosis. Results: Fifteen SNPs were consistent with Hardy–Weinberg equilibrium except for NLRP3 rs7525979. A total of eight SNPs (NLRP3 rs3806265, NLRC4 rs212704 and NLRC5 rs1684579, rs12598522, rs3995817, rs3995818, rs34531240, rs28438857) were observed an association with susceptibility of pulmonary aspergillosis. The CC homozygote of NLRP3 rs3806265, TT homozygote of NLRC5 rs1684579 and T allele of NLRC5 rs12598522 were associated with a higher risk of aspergillosis while TT homozygote of NLRC4 rs212704 was associated with a lower risk of aspergillosis. Especially in the invasive pulmonary aspergillosis subgroup, the TT homozygote of NLRC5 rs1684579 and rs3995817, the CC homozygote of NLRC5 rs34531240 and rs28438857, GG homozygote of NLRC5 rs3995818, the C allele and CC homozygote of NLRP3 rs3806265 were associated with higher susceptibility. Conclusions: This study showed an association between polymorphisms of NLRP3, NLRC4, and NLRC5 and susceptibility to pulmonary aspergillosis for the first time. Further investigations in larger populations are needed, and functional studies are also required to investigate the function of these NLRs in aspergillosis, as well as other fungal infection diseases.

Background: In recent years, the interest in genetic predisposition studies for coronary artery disease and restenosis has increased. Studies show that polymorphisms of genes encoding folate cycle and homocysteine metabolism enzymes significantly contribute to atherogenesis and endothelial dysfunction. The purpose of this study was to examine some SNPs of genes coding for folate cycle enzymes and DNA methyltransferases as risk factors for in-stent restenosis. Methods: The study included 113 patients after stent implantation and 62 patients without signs of coronary artery disease at coronary angiography as the control group. Real-time PCR and RFLP-PCR were applied to genotype all participants for MTHFR rs1801133, MTHFR rs1801131, MTR rs1805087, MTRR rs1801394, DNMT1 rs8101626, DNMT3B rs1569686, and DNMT3B rs2424913 gene polymorphisms. Statistical data processing was carried out using the R language and the SPSS Statistics 20 software. Results: Statistically significant differences in the DNMT3B gene polymorphisms were found between patients with and without in-stent restenosis. An association of TT rs1569686 and TT rs2424913 genotypes with the development of restenosis was revealed. The TT rs1569686 genotype was more frequent in the patients under the age of 65 years and in the subgroup of patients with post-12-month restenosis, as was the minor GG genotype for MTR rs1805087. The homozygous TT genotype for MTHFR rs1801133 was significantly more frequent in the subgroup over 65 years old. The frequencies of the heterozygous genotype for the MTRR gene and the minor GG homozygotes for the DNMT1 gene were significantly higher in the subgroup with in-stent restenosis under 65 years old. Conclusions: The results of this study could be used for a comprehensive risk assessment of ISR development, determining the optimal tactics and an individual approach in the treatment of patients with coronary artery disease before or after percutaneous coronary interventions, including homocysteine-lowering treatment in patients with hyperhomocysteinemia and a high risk of in-stent restenosis.

Arterial hypertension (AH) is a major independent risk factor for cardiovascular (CV) and cerebral mortality and morbidity and is one of the major risk factors for chronic kidney disease. Prehypertension (PHT) i.e. high normal arterial pressure (AP) is also associated with CV risk and risk of progression in AH. Previous studies of the genetic background of PHT have been insufficiently conducted, and the results indicate a possible association of certain genes involved in the etiopathogenesis of AH and PHT. The lack and sometimes inconsistency of information and results on the role of gene polymorphisms in the etiopathogenesis of PHT were the impetus to this research. Our hypothesis was that polymorphisms rs2004776 AGT, rs1799752 ACE, rs5196 AGTR1, rs1801253 ADRB1, rs13333226 UMOD and rs266729 and rs17300539 ADIPOQ, which are associated with AH and metabolic syndrome, are more common in individuals with high normal AP i.e. prehypertension than in individuals with optimal and normal AP. We chose these polymorphisms because these genes are involved in various mechanisms that lead to an increase in AP and metabolic complications. In this cross-sectional, observational study, 601 subjects were included ; 319 with high normal AP (PHT, 120/80–139/89 mmHg), both sexes, aged 20–45 years, and 282 subjects with normal and optimal AP as a control group (NT). The results showed that the investigated gene polymorphisms are not found more frequently in the PHT group than in the NT. However, a significantly lower frequency of the heterozygous genotype rs266729 ADIPOQ was found in PHT (35.1%), compared to the frequency in NT (44.7%), P = 0.03. The incidence of PHT is 0.66-fold lower in heterozygous (C/G) carriers of rs266729 ADIPOQ. We demonstrated a significant association of the minor allele G rs13333228 UMOD with lower values of systolic and diastolic AP and the minor allele A rs17300539 ADIPOQ with lower values of systolic AP. Additionally, our study resulted in the identification of two haplotypes that were significantly positively associated with PHT formation. The first is hIAGC with a 41% higher probability of developing PHT (rs1799752 ACE + rs13333226 UMOD + rs17300539 ADIPOQ + rs266729 ADIPOQ). The frequency of this haplotype is 8% higher in PHT than in NT. The second haplotype is hIAGCA and is 47% more likely to develop PHT (rs1799752 ACE + rs13333226 UMOD + rs17300539 ADIPOQ + rs266729 ADIPOQ + rs5186 AGTR1). The frequency of hIAGCA in NT is 18%, while in PHT it is 23%. Furthermore, the finding of a model of multivariate prediction of PHT (gene-gene-other determined parameters interaction) which includes a pro-prehypertensive significant effect of male sex, body weight, heart rate, fasting glucose concentration and total cholesterol is significant, while the protective effect within this model have body height and heterozygous (G/A) genotype rs17300539 ADIPOQ. We pointed to the possible importance of genes encoding proteins involved in essential biological pathways responsible for AP control, which include, among others, the renin-angiotensin-aldosterone system, the kidney, the central nervous system, blood vessels, and adipose tissue. In conclusion, the performed analyzes confirmed and showed the presence of significant gene - gene and gene - other determined parameters interactions (anthropometric, biochemical, environmental factors), but also gene - gene - other determined parameters in the etiology of PHT.

Background: Interleukin (IL)-17 family is a group of six cytokines that plays a central role in inflammatory processes and participates in cancer progression. Interleukin-17A has been shown to have mainly a protumorigenic role, but the other members of the IL-17 family, including IL-17F, have received less attention. Methods: We applied systematic review guidelines to study the role of IL-17F, protein and mRNA expression, polymorphisms, and functions, in cancer. We carried out a systematic search in PubMed, Ovid Medline, Scopus, and Cochrane libraries, yielding 79 articles that met the inclusion criteria. Results: The findings indicated that IL-17F has both anti- and protumorigenic roles, which depend on cancer type and the molecular form and location of IL-17F. As an example, the presence of IL-17F protein in tumor tissue and patient serum has a protective role in oral and pancreatic cancers, whereas it is protumorigenic in prostate and bladder cancers. These effects are proposed to be based on multiple mechanisms, such as inhibition of angiogenesis, vasculogenic mimicry and cancer cell proliferation, migration and invasion, and aggravating the inflammatory process. No solid evidence emerged for the correlation between IL-17F polymorphisms and cancer incidence or patients’ prognosis. Conclusions: IL-17F is a multifaceted cytokine. There is a clear demand for more well-designed studies of IL-17F to elucidate its molecular mechanisms in different types of cancer. The studies presented in this article examined a variety of different designs, study populations and primary/secondary outcomes, which unfortunately reduces the value of direct interstudy comparisons.

Objective: P-selectin is an adhesion molecule with a pivotal role in the initial phases of adhesion of leukocytes on activated platelets and endothelial cells during physiological or pathological inflammation and hemostasis. To date, multiple polymorphisms in P-selectin gene (SELP) have been described, but the distribution of poly morphism frequencies vary greatly between different ethnic groups. The aim of this study was to estimate ge notype, allele and haplotype frequencies of four common SELP variants (S290N, N562D, V599L, T715P) in the Croatian healthy population and to compare them with the frequencies reported for other ethnic groups. Methods: SELP S290N, N562D, V599L and T715P genotypes were determined in 250 unrelated Croatian healthy subjects using the polymerase chain reaction with sequence-specific primers. SELP S290N/N562D/V599L/T715P haplotypes were calculated using the web tool for single nucleotide polymorphism (SNP) analysis, SNPStats. For the purpose of this review, allele and haplotype frequencies of healthy controls were selected from to date published ethnic case- control studies. Results: For all investigated single SELP polymorphisms no difference of genotype frequencies was found between children and adults and neither according to gender, except for the S290N polymorphism. The wild-type SS290 genotype was significantly more common in males than in females (P = 0.024). Obtained SELP major allele frequencies were: S290 (0.786), N562 (0.506), V599 (0.890) and T715 (0.924). A total of ten SELP S290N/N562D/V599L/T715P haplotypes were identified and among them four most frequent haplotypes were: SDVT (0.374), SNVT (0.252), NDVT (0.097) and NNVT (0.095). Obtained data are similar to the frequencies reported in most European populations. Conclusions: Data obtained in this study are essential and can be used in future investigatations of the genetic background of cardiovascular and thrombotic diseases in the Croatian population.

Background Childhood obesity represents a serious global health crisis. Apelin and its receptor system are widely distributed throughout the central nervous system and have been demonstrated to serve a role modulating feeding behaviour and energy homeostasis. The purposes of this study were to examine apelin concentrations and anthropometric-cardiometabolic parameters in obese and non-obese children and to identify associations of APLN T-1860C and APLNR G212A polymorphisms with apelin levels and obesity among Thai children. Methods This case-control study included an analysis of 325 Thai children: 198 children with obesity and 127 healthy non-obese children. Anthropometric-cardiometabolic variables and apelin concentration were measured. Genotyping of APLN T-1860C and APLNR G212A was performed using the polymerase chain reaction-restriction fragment length polymorphism technique. Results The obese group had significantly lower apelin and HDL-C levels but significantly higher triglycerides and glucose (TyG) index values, TG/HDL-C ratio and TC/HDL-C ratio than the non-obese group (p p APLN T-1860C polymorphism (OR = 4.39, 95% CI = 1.25–15.28) and apelin concentration (OR = 0.45, 95% CI = 0.23–0.92) were significantly associated with obesity among female children (p APLNR G212A polymorphism showed no significant relationship with apelin concentration or obesity. Conclusion These findings in Thai children suggest that apelin concentrations are related to obesity and cardiometabolic parameters. Furthermore, the APLN T-1860C polymorphism may influence susceptibility to obesity among female children.

Aims Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously heart-healthy women. A common pathomechanism in PPCM involves the angiostatic 16 kDa-prolactin (16 kDa-PRL) fragment, which via NF-κB-mediated up-regulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyse whether the plasminogen activator inhibitor-1 (PAI-1) is involved in the pathophysiology of PPCM. Methods and results In healthy age-matched postpartum women (PP-Ctrl, n = 53, left ventricular ejection fraction, LVEF > 55%), PAI-1 plasma levels were within the normal range (21 ± 10 ng/mL), but significantly elevated (64 ± 38 ng/mL, P Conclusion In PPCM patients, circulating and cardiac PAI-1 expression are up-regulated. While circulating PAI-1 may add 16 kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised.

Mario Cazzola,1 Paola Rogliani,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: There is a large interindividual variability in response to ICSs in asthma. About 70% of the variance in ICS response is likely due at least partially to genetically determined characteristics of target genes. In this article, we examine the effects on the ICS response of gene variations in the corticosteroid pathway, and in the pharmacokinetics of corticosteroids, and also those outside the corticosteroid pathway, which have the potential to influence corticosteroid activity. Although the available evidence indicates that responses to ICSs in asthma are influenced by different genetic variants, there are still deep uncertainties as to whether a real association between these genetic variants and corticosteroid response could also possibly exist because there are difficulties in reproducing pharmacogenetic findings. This explains at least partly the insufficient use of pharmacogenomic data when treating asthmatic patients, which creates a real limitation to the proper use of ICSs in an era of precision medicine that links the right patient to the right treatment. Knowing and dealing with the genetic factors that influence the therapeutic ICS response is a fundamental condition for prescribing the right dose of ICS to the right patient at the right time.Keywords: asthma, inhaled corticosteroids, gene polymorphisms, genome-wide association studies, precision medicine

Background The relationships between polymorphisms in interleukin-10 (IL-10) gene and the risk of viral hepatitis remain inconclusive. Therefore, the authors conducted so far the very first meta-analysis to robustly assess the relationships between polymorphisms in IL-10 gene and the risk of viral hepatitis by integrating the results of previous works. Methods Medline, Embase, Wanfang, VIP and CNKI were searched throughly for eligible studies, and 76 genetic association studies were finally included in this meta-analysis. Results We noticed that rs1800871 (− 819 C/T), rs1800872 (− 592 C/A) and rs1800896 (− 1082 G/A) polymorphisms were all significantly associated with the risk of viral hepatitis in Asians, whereas only rs1800896 (− 1082 G/A) polymorphism was significantly associated with the risk of viral hepatitis in Caucasians. In further analyses by disease subtypes, we noticed that the three investigated polymorphisms were all significantly associated with the risk of both HBV and HCV. Conclusions This meta-analysis demonstrates that rs1800871 (− 819 C/T), rs1800872 (− 592 C/A) and rs1800896 (− 1082 G/A) polymorphisms may influence the risk of viral hepatitis in Asians, while only rs1800896 (− 1082 G/A) polymorphism may influence the risk of viral hepatitis in Caucasians. In further analyses by disease subtypes, we noticed that the three investigated polymorphisms may influence the risk of both HBV and HCV.

Summary Vogt–Koyanagi–Harada (VKH) disease is an autoimmune disease leading to visual impairment. Its pathogenic mechanisms remain poorly understood. Our purpose was to investigate the distinctive protein and metabolic profiles of sweat in patients with VKH disease. In the present study, proteomics and metabolomics analysis was performed on 60 sweat samples (30 VKH patients and 30 normal controls) using liquid chromatography tandem mass spectrometry. Parallel reaction monitoring (PRM) analysis was used to validate the results of our omics analysis. In total, we were able to detect 716 proteins and 175 metabolites. Among them, 116 proteins (99 decreased and 17 increased) were observed to be significantly different in VKH patients when compared to controls. Twenty-one differentially expressed metabolites were identified in VKH patients, of which 18 included choline, L-tryptophan, betaine and L-serine were reduced, while the rest were increased. Our multi-omics strategy reveals an important role for the amino acid metabolic pathway in the pathogenesis of VKH disease. Significant differences in proteins and metabolites were identified in the sweat of VKH patients and, to some extent, an aberrant amino acid metabolism pathway may be a pathogenic factor in the pathogenesis of VKH disease.

Jing Gao,1,* Tanja Törölä,1,* Chuan-Xing Li,2 Steffen Ohlmeier,3 Tuula Toljamo,4 Pentti Nieminen,5 Noboru Hattori,6 Ville Pulkkinen,1 Hiroshi Iwamoto,6 Witold Mazur1 1Heart and Lung Centre, Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 2Pulmonomics Group, Respiratory Medicine Unit, Department of Medicine & Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; 3Proteomics Core Facility, Biocentre Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; 4Department of Pulmonary Medicine, Lapland Central Hospital, Rovaniemi, Finland; 5Medical Informatics and Statistics Group, University of Oulu, Oulu, Finland; 6Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan*These authors contributed equally to this workCorrespondence: Jing GaoHeart and Lung Centre, Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, FinlandTel +358417071559Email jing.gao@helsinki.fi, HelsinkiIntroduction: The vitamin D binding protein (VDBP, also known as GC-globulin) and vitamin D deficiency have been associated with chronic obstructive pulmonary disease (COPD). rs7041 and rs4588 are two single nucleotide polymorphisms of the VDBP gene, including three common allelic variants (GC1S, GC1F and GC2). Previous studies primarily assessed the serum levels of vitamin D and VDBP in COPD. However, less is known regarding the impact of the local release of VDBP on COPD lung function. Thus, we examined the association of sputum and plasma VDBP with lung function at baseline and at four years, and examined potential genetic polymorphism interactions.Methods: The baseline levels of sputum VDBP, plasma VDBP and plasma 25-OH vitamin D, as well as the GC rs4588 and rs7041 genotypes, were assessed in a 4-year Finnish follow-up cohort (n = 233) of non-smokers, and smokers with and without COPD. The associations between the VDBP levels and the longitudinal decline of lung function were further analysed.Results: High frequencies of the haplotypes in rs7041/rs4588 were homozygous GC1S/1S (42.5%). Higher sputum VDBP levels in stage I and stage II COPD were observed only in carriers with GC1S/1S genotype when compared with non-smokers (p = 0.034 and p = 0.002, respectively). Genotype multivariate regression analysis indicated that the baseline sputum VDBP and FEV1/FVC ratio at baseline independently predicted FEV1% at follow-up.Discussion and Conclusion: The baseline sputum VDBP expression was elevated in smokers with COPD among individuals with the GC1S/1S genotype, and predicted follow-up airway obstruction. Our results suggest that the GC polymorphism should be considered when exploring the potential of VDBP as a biomarker for COPD.Keywords: vitamin D binding protein, VDBP, genotype, COPD, prospective study, sputum

Objective To investigate the correlation of three CLDN23 SNPs with the hereditary susceptibility and prognosis of gastric carcinoma in Han nationality in Fujian. Methods Three SNP loci genotypes (rs12153, rs1060106 and rs11249884) of CLDN23 gene were detected using PCR-LDR method. Results There was no significant difference in genotypes and allele frequencies of CLDN23 SNP rs12153, rs1060106 and rs11249884 between the gastric carcinoma group and the control group(P > 0.05). The frequency of genotype distribution in these three loci of the gastric cancer group was significantly correlated with tumor differentiation and pT staging(P < 0.05). The genotype distribution frequencies of rs12153 and rs1060106 were significantly correlated with post-operative survival time of the patients(P < 0.05). Among rs12153, rs1060106 and rs11249884, linkage disequilibrium of CLDN23 gene was absent. There was significant difference of C-T-G haplotype distribution between the gastric carcinoma group and the control group(P < 0.01). Conclusion The polymorphisms of CLDN23 SNP rs12153, rs1060106 and rs11249884 are associated with tumor differentiation and pT staging, suggesting their possible role in the progression of gastric carcinoma in Han nationality in Fujian. The polymorphisms of rs12153 and rs1060106 are correlated with the prognosis of gastric cancer patients.

This study aimed to explore whether the polymorphisms of CYP4F2 and CYP3A5 are correlated with the risk of lung cancer development. A case–control study was conducted among 510 patients with pathologically confirmed lung cancer as the case group and 504 healthy individuals as the control group. Four single-nucleotide polymorphisms of the CYP4F2 and CYP3A5 genes were genotyped, and their correlations with the risk of lung cancer were examined using Chi-square test and logistic regression analysis. Stratified analysis found that the rs3093105 and rs3093106 loci of CYP4F2 gene were significantly associated with lower risk of lung cancer (P = 0.012, OR 0.64, 95% CI 0.45–0.91). The correlation was related to patients’ age and sex and pathological type of lung cancer. Similarly, the rs10242455 loci of CYP3A5 gene showed a statistical significance between the case group and the control group (P = 0.018, OR 0.71, 95% CI 0.53–0.94), which also was associated with reduced risk of squamous cell lung cancer in the dominant and additive models (dominant: OR 0.66, 95% CI 0.46–0.94, P = 0.021; additive: OR 0.71, 95% CI 0.53–0.95, P = 0.023). CYP4F2 and CYP3A5 gene polymorphisms are associated with the reduced risk of non-small cell lung cancer, and its correlation is related to patients’ age and sex and pathological type of lung cancer.

Background. Identification of predictive molecular markers of triple-negative breast cancer (TNBC) will enable the evaluation of the efficacy of neoadjuvant chemotherapy (NACT) and define optimum approaches for the prognosis of the disease course in TNBC patients. The aim of the study was to examine the correlation between the expression of the epidermal growth factor receptor (EGFR), its gene’s polymorphic variants and the neoadjuvant chemotherapy (NACT) efficacy in triple-negative breast cancer (TNBC) patients. Materials and methods. The study included 70 patients with triple-negative breast cancer, who had received 2-4 cycles of FAC and CAX regimens. The efficacy of the neoadjuvant chemotherapy was assessed according to the RECIST scale. The EGFR expression level in tumors before and after the NACT was evaluated with the help of immunohistochemistry. Genotypes for EGFR (rs2227983 and rs1468727) were detected by a real-time PCR. Results. It was found that NCT significantly decreases the EGFR expression level in the tumor ( p = 0.000). The research associates the objective clinical response as well as the pathological complete response with the low EGFR expression level ( p = 0.007 and p = 0.000 respectively). Patients carrying the EGFR CC mutant genotype of rs1468727 did not achieve a pathological complete response ( p = 0.042). In addition, patients with EGFRCC mutant genotype are more likely to have tumors with a high EGFR expression compared to EGFRTT wild-type genotype patients ( p = 0.047). Conclusion . The EGFR expression level in tumor tissue and the polymorphic variants of its gene in the rs1468727 locus can be considered as potential molecular markers with predictive significance in relation to the NACT efficacy in triple-negative breast cancer patients.

Background Sphingosine-1-phosphate (S1P) is a signaling phospholipid involved in pathophysiologic progression of acute respiratory distress syndrome (ARDS) through its roles in endothelial barrier function and immune modulation. We hypothesized that decreased serum S1P level is associated with the clinical outcomes of ARDS and polymorphisms in the S1P gene are associated with serum S1P levels. Methods This multicenter prospective study includes ARDS patients and healthy blood donors as controls. Serum S1P levels were quantified using enzyme-linked immunosorbent assays. Eight tag single nucleotide polymorphisms (SNPs) in the S1P gene were detected, and their associations with S1P levels were evaluated. Results A total of 121 ARDS patients and 100 healthy individuals were enrolled. Serum S1P levels were lower in ARDS patients than in controls (P

Ci Yan,1 Li Duan,1 Chunfeng Fu,1 Chunsheng Tian,1 Bihui Zhang,1 Xiaojun Shao,1 Gang Zhu1,2 1Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Department of Central Laboratory, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaCorrespondence: Gang ZhuDepartment of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaTel/Fax +86 248 328 2184Email gzhu@cmu.edu.cnBackground: Glutathione S-transferase (GST) is an important antioxidant enzyme in the body. The weakening of the antioxidant system causes damage to the cells and tissues that make up the organism, adversely affects the function of the nervous system, and ultimately leads to schizophrenia (SCZ). Previous studies have yielded inconsistent results across different ethnic populations.Purpose: This case–control study was carried out to investigate whether genetic polymorphisms in GST could be associated with SCZ in the Chinese Han population.Patients and Methods: A total of 794 participants, including 379 SCZ patients (case group) and 415 healthy individuals (control group), were genotyped by polymerase chain reaction-restriction fragment length for polymorphisms in GST genes.Results: The study found that the frequency of the GSTM1 null genotype was higher in case group than control group (p=0.003). The frequency of the GSTM1 and GSTT1 double null genotype was also higher in case group than control group (p=0.008).Conclusion: We conclude that the GSTM1 null genotype and the GSTM1 and GSTT1 double null genotype may be related to the onset of SCZ in Chinese Han population.Keywords: glutathione transferase, gene polymorphisms, schizophrenia

Ci Yan,1 Li Duan,1 Chunfeng Fu,1 Chunsheng Tian,1 Bihui Zhang,1 Xiaojun Shao,1 Gang Zhu1,2 1Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Department of Central Laboratory, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaCorrespondence: Gang ZhuDepartment of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaTel/Fax +86 248 328 2184Email gzhu@cmu.edu.cnBackground: Glutathione S-transferase (GST) is an important antioxidant enzyme in the body. The weakening of the antioxidant system causes damage to the cells and tissues that make up the organism, adversely affects the function of the nervous system, and ultimately leads to schizophrenia (SCZ). Previous studies have yielded inconsistent results across different ethnic populations.Purpose: This case–control study was carried out to investigate whether genetic polymorphisms in GST could be associated with SCZ in the Chinese Han population.Patients and Methods: A total of 794 participants, including 379 SCZ patients (case group) and 415 healthy individuals (control group), were genotyped by polymerase chain reaction-restriction fragment length for polymorphisms in GST genes.Results: The study found that the frequency of the GSTM1 null genotype was higher in case group than control group (p=0.003). The frequency of the GSTM1 and GSTT1 double null genotype was also higher in case group than control group (p=0.008).Conclusion: We conclude that the GSTM1 null genotype and the GSTM1 and GSTT1 double null genotype may be related to the onset of SCZ in Chinese Han population.Keywords: glutathione transferase, gene polymorphisms, schizophrenia