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Increasing evidence points to host genetics as a factor in COVID-19 prevalence and outcome. CCR5 is a receptor for proinflammatory chemokines that are involved in host responses, especially to viruses. The CCR5-Δ32 minor allele is an interesting variant, given the role of CCR5 in some viral infections, particularly HIV-1. Recent studies of the impact of CCR5-Δ32 on COVID-19 risk and severity have yielded contradictory results. This ecologic study shows that the CCR5-Δ32 allelic frequency in a European population was significantly negatively correlated with the number of COVID-19 cases (p=0.035) and deaths (p=0.006) during the second pandemic wave. These results suggest that CCR5-Δ32 may be protective against SARS-CoV-2 infection, as it is against HIV infection, and could be predictive of COVID-19 risk and severity. Further studies based on samples from populations of different genetic backgrounds are needed to validate these statistically obtained findings.

IntroductionParkinson’s disease (PD) is neurodegenerative disease with a multifactorial etiopathogenesis with accumulating evidence identifying microbiota as a potential factor in the earliest, prodromal phases of the disease. Previous research has already shown a significant difference between gut microbiota composition in PD patients as opposed to healthy controls, with a growing number of studies correlating gut microbiota changes with the clinical presentation of the disease in later stages, through various motor and non-motor symptoms. Our aim in this systematic review is to compose and assess current knowledge in the field and determine if the findings could influence future clinical practice as well as therapy in PD.MethodsWe have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.Results20 studies were included in this systematic review according to the selected inclusion and exclusion criteria. The search yielded 18 case control studies, 1 case study, and 1 prospective case study with no controls. The total number of PD patients encompassed in the studies cited in this review is 1,511.ConclusionThe link between gut microbiota and neurodegeneration is a complex one and it depends on various factors. The relative abundance of various microbiota taxa in the gut has been consistently shown to have a correlation with motor and non-motor symptom severity. The answer could lie in the products of gut microbiota metabolism which have also been linked to PD. Further research is thus warranted in the field, with a focus on the metabolic function of gut microbiota in relation to motor and non-motor symptoms.

We investigated the effect of the functional insertion/ deletion (I/D) polymorphism in the angiotensin- converting enzyme (ACE) gene on the response to interferon-β (IFN-β) therapy in Croatian and Slovenian patients with multiple sclerosis (MS). A total of 275 IFN-β treated MS patients [162 responders (Rs) and 113 nonresponders (NRs)] were genotyped by PCR. The ACE I/D genotype distribution and allele frequencies did not differ between female Rs and NRs. However, male NRs tended to have a greater prevalence of the DD genotype (P=0.073 ; odds ratio: 2.64 ; 95% confidence interval: 0.91–7.60) and a significantly higher frequency of the D allele (P=0.022 ; odds ratio: 2.43 ; 95% confidence interval: 1.13–5.20) than male Rs. Multiple forward stepwise regression analysis indicated that the negative response to IFN-β therapy was associated with the ACE-DD genotype in men ( β=0.371 ; multiple R2 change: 0.132 ; P=0.009) and a higher pretreatment relapse rate in both men ( β=−0.438 ; multiple R2 change: 0.135 ; P=0.015) and women ( β=−0.208 ; multiple R2 change: 0.042 ; P=0.034). The ACE I/D polymorphism and pretreatment relapse rate accounted for ∼26.7% of the IFN-β response variability among the men in the sample. Further studies of a larger number of MS patients from different populations are necessary to evaluate these preliminary findings.

Objective: Schizophrenia patients are often smokers which make them an interesting group to study the etiology of nicotine dependence. We investigated the relationship between the rs10798059 (BanI) and rs4375 polymorphisms in phospholipase A2 (PLA2)G4A and PLA2G6 genes and the risk of nicotine dependence in Croatian schizophrenia patients. We also tested whether interactions between these polymorphic variants and smoking status might contribute to disease onset and scores for the Positive and Negative Syndrome Scale (PANSS). Patients and methods: Genotyping was performed for 263 patients by polymerase chain reaction. Results: There were no significant differences in the distribution of PLA2G4A genotypes and alleles in patients according to smoking status and no PLA2G4A genotype-smoking interaction on disease onset or PANSS. A significant overrepresentation of PLA2G6-CC homozygous and PLA2G6-CT heterozygous genotypes was detected in male nonsmokers compared to smokers (χ2=3.03, p=0.041) ; PLA2G6-CC homozygous and PLA2G6-CT heterozygous males had about a 2.5-fold lower smoking risk than PLA2G6-TT homozygous. We also revealed a significant PLA2G6 genotype-smoking interaction that predicted the time of schizophrenia onset among males (F=4.07, p

Objective: Blood-borne angiotensin II is generated from angiotensinogen via cleavage by renin and angiotensin-converting enzyme (ACE), an enzymatic cascade known as the renin–angiotensin system (RAS). Several lines of evidence indicate that ACE, beyond its classical role of mediating blood pressure regulation, might contribute to the etiology of substance addictions by influencing dopaminergic signaling. A functional insertion/deletion (I/D) polymorphism of the ACE gene was associated with risk for being a smoker among individuals with depression and with smoking severity in studies comprising patients with depression and healthy controls. Several reports have described significantly increased ACE activity in cerebrospinal fluid and serum among MS patients. Furthermore, in our previous work with MS patients from Croatian and Slovenian populations, we demonstrated that the ACE-I/D polymorphism contributes to an elevated MS risk among male patients. Here we investigated whether the ACE-I/D polymorphism might influence smoking behavior among patients with MS. Patients and methods: Genotyping was performed in 521 patients (males/females: 139/382) using polymerase chain reaction. Results: We revealed no significant differences in ACE genotype and allele frequencies between smokers and nonsmokers and no significant association between the ACE-I/D polymorphism and either pack-year smoking history or number of cigarettes smoked daily (P > 0.05, respectively). Conclusion: The ACE-I/D polymorphism does not contribute either to risk for nicotine dependence or to smoking severity among MS patients. In the context of reports on the ACE-I/D polymorphism and nicotine dependence among healthy controls and patients with depression, we may speculate that the mechanism by which this polymorphism influences nicotine dependence risk differs in MS compared to depression, although not compared to a healthy population. In addition to angiotensin II, other potential ACE substrates, such as substance P and neurotensin, which also influence dopaminergic neurotransmission (and are proposed to be associated with MS), may deserve study in future.

Uzrok polovice do dvije trećine smrtnih ishoda pacijenata sa shizofrenijom pripisuje se kardiovaskularnim bolestima. Smatra se da visoka učestalost metaboličkog sindroma najviše povećava rizik za nastanak kardiovaskularnih oboljenja u shizofreniji. Iako je metabolički sindrom jedan od vodećih uzroka morbiditeta i mortaliteta u pacijenata sa shizofrenijom, do prije petnaestak godina istraživanje etiologije metaboličkog sindroma u shizofreniji nije predstavljalo veći znanstveni interes. Novije spoznaje ukazuju na mogućnost da bi pojačano stanje upalnog odgovora u organizmu moglo predstavljati zajedničku etiopatogenetsku podlogu u nastanku metaboličkog sindroma i shizofrenije. Primjerice, značajno povišena koncentracija proupalnih citokina te C reaktivnog proteina uočena je u pacijenata sa shizofrenijom koji nisu uzimali antipsihotične lijekove ili su ih uzimali u vrlo malim dozama, a zamijećeno je i da uzimanje inhibitora ciklooksigeneze-2, uz antipsihotičnu terapiju, može ublažiti težinu kliničkih simptoma i kognitivnih deficita u oboljelih. U ovom preglednom radu iznesene su najnovije spoznaje o ulozi okolišnih i genetičkih čimbenika u etiopatogenezi metaboličkog sindroma u shizofreniji. Mnogi mehanizmi kojima bi okolišni čimbenici, poput nezdrave prehrane i pušenja, mogli pridonijeti nastanku metaboličkog sindroma u shizofreniji ne razlikuju se značajno u odnosu na opću populaciju. Ipak, uzimanje antipsihotičnih lijekova, posebice tzv. atipičnih antipsihotika, te njihova interakcija s okolišnim čimbenicima, kao i genetičkim čimbenicima podložnosti, dodatno pridonose heterogenosti etiopatogeneze metaboličkog sindroma u shizofreniji, ali i otežavaju adekvatan terapijski pristup. Budući da su dosadašnja istraživanja uglavnom bila usredotočena na moguću poveznicu antipsihotičnih lijekova i metaboličkih abnormalnosti u oboljelih, detaljnije su razmotrene značajke nezdrave prehrane i ovisnosti o pušenju te njihova moguća povezanost s metaboličkim sindromom., The etiology of one half to two-thirds of deaths among patients with schizophrenia could be attributed to cardiovascular diseases. It is believed that high prevalence of metabolic syndrome mostly contributes to the risk of cardiovascular diseases in schizophrenia. Although the metabolic syndrome is among the leading causes of morbidity and mortality among patients with schizophrenia, fifteen years ago studies investigating the etiology of the metabolic syndrome among patients with schizophrenia were not a part of scientific interest. Recent findings indicate the possibility that increased state of inflammatory response in the organism may underlie the etiopathogenesis of both schizophrenia and metabolic syndrome. For instance, significantly increased levels of proinflammatory cytokines and C reactive protein have been observed in schizophrenia patients with minimal or no exposure to antipsychotics and it has also been revealed that cyclooxygenase-2 inhibitor drugs add-on treatment to the antipsychotic therapy may lead to decrease in clinical symptom severity and alleviate cognitive deficits in the patient group. In this review we aim to provide an update on genetics and environmental factors in the etiopathogenesis of metabolic syndrome in schizophrenia. Numerous mechanisms by which the environmental factors such as unhealthy diet pattern and smoking could contribute to the etiology of the metabolic syndrome in schizophrenia do not differ significantly compared to a healthy population. However, treatment with antipsychotic medications, particularly with atypical antipsychotics, as well as interaction between antipsychotic drugs and environmental and genetic risk factors may additionally lead to heterogeneity of the etiopathogenesis of metabolic syndrome in schizophrenia as well as to complicate treatment approach. Since previous studies have been mostly focused on plausible associations between antipsychotic medications and metabolic abnormalities, we provided a more detailed characteristic of unhealthy diet among schizophrenia patients and its plausible relation to metabolic syndrome. Furthermore, more deeply have been discussed the possible associations between nicotine dependence and metabolic syndrome.

OBJECTIVES: The research objective of this study is to enlarge and deepen the Y chromosome research on the Croatian population and enable additional insights into the population diversity and historic events that shaped the current genetic landscape of Croatia and Southeastern Europe (SEE). MATERIALS AND METHODS: A high-resolution phylogenetic and phylogeographic analysis of 66 biallelic (SNPs) and 17 microsatellite (STRs) markers of the Y chromosome was performed using 720 Croatian samples. The obtained results were placed in a wider European context by comparison with ∼4450 samples from a number of other European populations. RESULTS: A high diversity of haplogroups was observed in the overall Croatian sample, and all typical European Y chromosome haplogroups with corresponding clinal patterns were observed. Three distinct genetic signals were identifiable in the Croatian paternal gene pool - I2a1b-M423, R1a1a1b1a*-M558, and E1b1b1a1b1a-V13 haplogroups. DISCUSSION: The analyses of the dominant and autochthonous I2a1b-M423 lineage (>30%) suggest that SEE had a significant role in the Upper Paleolithic, the R1a1a1b1a*-M558 lineage (19%) represents a signal from present day Slavic populations of Central Europe in the Croatian population, and the phylogeography of the E1b1b1a1b1a-V13 clade (around 9%) implies cultural diffusion of agriculture into Europe via the Balkan Peninsula.

U ovom kratkom preglednom članku prikazani su trenutni prijepori i napredci vezani uz definiciju i uzroke ponavljajućih spontanih pobačaja, s posebnim osvrtom na genetičke čimbenike. Prikazane spoznaje temeljene su na najnovijim rezultatima opažajnih i pokusnih istraživanja te sustavnih pregleda i metaanaliza., The aim of this mini-review is to give an overview of the current controversies and advances regarding the definition and causes of recurrent spontaneous abortion, with particular emphasis on genetic factors. The presented knowledge is based on the most recent findings of observational and experimental studies, as well as systematic reviews and meta-analyses.

Cilj: Utvrditi učestalost alela i genotipova HLA-DQA1 i HLA-DQB1 gena u oboljelih od celijakije, kao i njihov utjecaj na kliničku ekspresiju bolesti. Ispitanici i metode: U ispitivanje je uključeno 110 pacijenata (60 žena i 50 muškaraca) s dijagnosticiranom celijakijom prema revidiranim ESPGHAN kriterijima (The European Society for Pediatric Gastroenterology Hepatology and Nutrition) koji su klinički obrađeni na Klinici za internu medicinu i Klinici za pedijatriju KBC-a Rijeka. Genotipizacija HLA alela klase II u pacijenata izvršena je metodom lančane reakcije polimerazom (PCR, engl. Polymerase Chain Reaction) s alel specifičnim početnicama (engl. Sequence Specific Primer – SSP), pri čemu su korišteni komercijalni kitovi niske i srednje rezolucije GenoVision SSP. Rezultati: Svi pacijenti imali su barem jedan rizični HLA-DQA1 ili HLA–DQB1 alel. Homozigota za rizične HLA-DQB1 alele bilo je 36,3 %, a za HLA-DQA1 34,5 %. Genotipovi za HLA-DQ2 i/ili DQ8 heterodimere prisutni su u 92,7 % pacijenata. HLA-DQ2 prisutan je u 79,1 % pacijenata, a HLA-DQ8 u 20,9 %. Nije utvrđena značajna razlika (P < 0,05) u učestalosti nosioca HLA-DQ2 i/ili DQ8 ovisno o tipu celijakije. Opažen je trend ranijeg postavljanja dijagnoze kao i veća pojavnost drugih autoimunosnih bolesti u homozigota u odnosu na ostale genotipove. Zaključci: Dobiveni rezultati ukazuju da je prisutnost HLA-DQ2/DQ8 heterodimera u hrvatskih pacijenata s celijakijom sukladna postojećem gradijentu sjever-jug u europskim populacijama. HLA genotipizacija pacijenata ima nesumnjiv značaj u kliničkoj praksi pri postavljanju dijagnoze., Objective: To determine the frequency of alleles and genotypes of HLA-DQA1 and HLA-DQB1 genes in patients with celiac disease and their impact on the clinical expression of the disease. Subjects and Methods: The study involved 110 patients (60 women and 50 men) with celiac disease diagnosed according to the revised ESPGHAN (The European Society for Pediatric Gastroenterology Hepatology and Nutrition) criteria at the Clinic of Internal Medicine and Pediatric Clinic, University Hospital Centre Rijeka. The genotyping of HLA class II alleles was performed by polymerase chain reaction method (PCR) with allele-specific primers (Sequence Specific Primer-SSA) using commercial kits of low and medium resolution GenoVision SSP. Results: All patients had at least one risk HLA-DQA1 or HLA-DQB1 allele. Homozygotes for the HLA-DQB1 alleles were 36.3 %, and for HLA-DQA1 34.5 %. Genotypes for the HLA-DQ2 and/or HLA-DQ8 heterodimers were present in 92.7 % of patients. HLA-DQ2 was present in 79.1 % of patients while HLA-DQ8 in 20.9 %. There are no significant difference (P > 0.05) in the frequency of the HLA-DQ2 and/or HLA-DQ8 carriers depending on the type of celiac disease. An earlier diagnosis and greater incidence of other autoimmune diseases in homozygotes, compared to other genotypes, was observed. Conclusions: The results have shown that the presence of HLA-DQ2/DQ8 heterodimers in Croatian celiac patients is in range with the existing north-south gradient in European populations. HLA genotyping in celiac patients has explicit effects in clinical practice when setting up the diagnosis.

Introduction: Increased local iron concentration in brain parenchyma of multiple sclerosis (MS) patients is documented by magnetic resonance imaging, but role of iron in MS etiopathogenesis is still debated. Brain iron homeostasis is regulated by different factors, among which the transferrin and hemochromatosis proteins seem to play a key role. The aim of study was to investigate weather HFE (C282Y, H63D), TF (P570S) and transferrin receptor (TFRC-S142G) gene variants contribute to MS development. Materials and Methods: We genotyped 455 patients diagnosed with MS according to the revised McDonald criteria and 400 healthy controls from Croatia and Slovenia by PCR-RFLP or Real-time PCR method. Results: A significantly higher frequency of the C282Y carrier mutation was observed in MS patients (6.3%) than in controls (3.1%) (P=0.033). Allele and genotypes frequencies for other polymorphisms did not differ significantly (P>0.05). A three year earlier onset was found in carriers of the C282Y mutation (P=0.106), and significantly earlier onset in TF-C2 homozygotes (P=0, 016). Disease began eight year later in H63D homozygotes but statistical difference show borderline significance (P=0.056). Progression index of MS was higher in carrier of TFRC- S142G A allele also with borderline significance (P=0.051). Conclusions: Our results indicate that HFE- C282Y mutation may be risk factor to MS susceptibility. Variants C282Y and TF-C2 are possible predictors for early onset of MS, while HFE-H63D prolong disease onset. Polymorphism TFRC-S142G might have influence on disease progression. Polymorphisms in HFE, TFRC and TF genes coding for iron binding and transporting proteins might contribute to pathogenesis of MS.

Multiple sclerosis (MS) is a chronic autoimmune neurological disorder with complex genetic architecture. Despite efforts, even large genome-wide association studies (GWAS) failed to completely explain heritability of MS based on common genetic variation. To characterize the possible role of rare, highly penetrant genetic variants in MS, we performed whole exome sequencing in 48 patients with familial MS, 40 patients with sporadic MS and 92 population-matched controls. We have focused the analysis to rare (

Introduction: MS is chronic inflammatory disease of the central nervous system with important genetic contribution. Although familial contribution to MS etiology is well established, much of genetic contribution still remains poorly defined. Several case reports reported comorbidity between different types of genetic peripheral neuropathies and MS. Therefore we hypothesized that there is an increased mutation burden in genes related to peripheral neuropathies among MS patients. Materials and Methods: Whole exome sequencing using Nextera Coding Exome enrichment was performed in 48 patients with familial MS, 40 patients with sporadic MS and 92 population- matched controls. Genotypes were called using GATK toolkit in multisample mode and only sites with variant quality over 100.0 and genotyping rate of over 60% across all samples were kept in downstream analyses. The selection of variants among bioinformatically focused panel of 52 peripheral neuropathy related genes was narrowed in accordance of functional impact predicted by snpEff - all truncating variants and missense variants predicted as pathogenic by a majority of in-silico predictors, were considered in further burden analyses. Results: We identified 8 candidate genetic variants (7 genes) that affect function in familial MS, and 11 candidate genetic variants (12 genes) in sporadic MS patients. Overall we detected a statistically significant 1.9-times enrichment of mutations (p=0.004) in the familial MS cases compared to the ExAC control samples. Conclusions: Exome sequencing of peripheral neuropathy causing genes revealed an excess burden of deleterious coding variants in familial MS patients which supports previous evidence of comorbidity among peripheral neuropathies and MS.

Objectives: The research objective of this study is to enlarge and deepen the Y chromosome research on the Croatian population and enable additional insights into the population diversity and historic events that shaped the current genetic landscape of Croatia and Southeastern Europe (SEE). Materials and Methods: A high-resolution phylogenetic and phylogeographic analysis of 66 biallelic (SNPs) and 17/19 microsatellite (STRs) markers of the Y chromosome was performed using 720 Croatian samples. The obtained results were placed in a wider European context by comparison with ~4450 samples from a number of other European populations. Results: A high diversity of haplogroups was observed in the overall Croatian sample, and all typical European Y chromosome haplogroups with corresponding clinal patterns were observed. Three distinct genetic signals were identifiable in the Croatian paternal gene pool - I2a1b-M423, R1a1a1b1a*-M558 and E1b1b1a1b1a- V13 haplogroups. Discussion: The analyses of the dominant and autochthonous I2a1b-M423 lineage (>30%) suggest that SEE had a significant role in the Upper Paleolithic, the R1a1a1b1a*-M558 lineage (19%) represents a signal from present day Slavic populations of Central Europe in the Croatian population, and the phylogeography of the E1b1b1a1b1a-V13 clade (around 9%) implies cultural diffusion of agriculture into Europe via the Balkan Peninsula.

Cilj: U okviru fosfolipidne membranske hipoteze ispitana je uloga polimorfizama gena PLA2G6 i PLA2G4C (rs4375 i rs1549637 varijante) za kalcij-neovisnu fosfolipazu A2 (iPLA2) i citosolnu fosfolipazu A2 (cPLA2) u podložnosti za nastanak shizofrenije i shizoafektivnog poremećaja, kliničkoj ekspresiji bolesti te etiologiji oslabljene niacinske reakcije kože. Metode: Identifikacija genskih polimorfizama provedena je PCR-RFLP metodom na 203 bolesnika i 191 kontroli. Klinička ekspresija bolesti evaluirana je kroz težinu simptoma ocjenske ljestvice PANSS-a (engl. Positive and Negative Symptom Scale) i prosječnu dob prve hospitalizacije. Na manjem uzorku od 75 bolesnika, na kojem je prethodno potvrđena oslabljena niacinska reakcija, testirana je povezanost volumetrijskog niacinskog odgovora (VNR) i genskih polimorfizama. Rezultati: Distribucija PLA2G6 i PLA2G4C genotipova i alela nije se značajno razlikovala između bolesnika i kontroli (χ2-test). Iako nije utvrđena interakcija PLA2G6 i PLA2G4C alela u podložnosti za bolest, ispitivanje interakcije genotipova pokazalo je značajno veću učestalost kombinacije PLA2G6-CT i PLA2G4C-AT genotipova u bolesnika (OR=2, 2, CI=1, 1 - 4, 3, z=2, 3, P=0, 02). Polimorfne varijante pokazale su značajan učinak na PANSS simptomatologiju isključivo u muškaraca ; prisutnost T-alela u PLA2G4C genotipu pridonijela je višim vrijednostima negativnih simptoma, dok je prisutnost C- i T-alela u kombiniranom PLA2G6/PLA2G4C genotipu pridonijela višim vrijednostima ukupne PANSS simptomatologije (jednosmjerni ANOVA test: P

Interferon beta (IFN-β) is widely used as the first-line disease-modifying treatment for multiple sclerosis (MS). However, response to IFN-β is largely heterogeneous, and a significant number of MS patients (20-50%) continue to experience clinical and MRI disease activity despite treatment. Identification of biomarkers that predict responsiveness to IFN-β is important to define therapy strategies. The aim of this study was to analyze the association of CCR5Δ32 mutation with presence or absence of clinical response to IFN-β treatment in Croatian and Slovenian MS patients. We genotyped 161 IFN-β-treated patients with relapsing-remitting or secondary-progres¬sive MS. Based on clinical criteria for efficiency of MS treatment, patients were classified as responders, Rs (N=93) and nonresponders, NRs (N=68). 32 bp deletion in the CCR5 gene was detected using one-step PCR. No significant differences between Rs and NRs in CCR5 allele (p=0, 826) and genotype (p=0, 823) frequencies were observed. Also, in stratifying MS patients by gender or disease course, no significant differences in allele and genotype distributions between Rs and NRs were found. Our results indicate that the carriage of CCR5Δ32 mutation was not associated with IFN-β treatment response in Croatian and Slovenian MS patients.

U ovom istraživanju nije utvrđena povezanost idiopatskih ponavljajućih spontanih pobačaja i insercijsko-delecijskih polimorfizama u ACE, NOS3 i VEGFA genima u žena.

Celijakija je bolest poremećenog imunosnog odgovora potaknutog glutenom koja se javlja u genetički predisponiranih osoba. Svrha ovog rada je prikazati dosadašnje spoznaje iz genetike celijakije. Genska podloga celijakije vezana za lokus humanih leukocitnih antigena kao dominantnog genetičkog elementa detaljno je razjašnjena. No postoji i velik broj gena izvan ove regije koji pridonose etiopatogenezi bolesti, a samo su dijelom zajednički pojedinim bolesnicima, što upućuje na genetičku heterogenost bolesti. Uz to je opaženo da su mnogi od tih rizičnih lokusa u celijakiji zajednički s lokusima za druge autoimunosne bolesti. Značajan doprinos novim spoznajama daju recentne cjelogenomske asocijacijske studije, ali tek treba istražiti velik dio još i sad nepoznate heritabilnosti u celijakiji., Celiac disease is a chronic infl ammatory disease of the small intestine triggered by gluten intake, which occurs in genetically susceptible individuals. The purpose of this paper is to present recent fi ndings in the genetics of celiac disease. Genetic background of celiac disease related to human leukocyte antigen locus (HLA) as a dominant genetic element has been well described. However, the existence of a large number of non-HLA celiac disease genes, only partly shared by each individual patient, suggests genetic heterogeneity of the disease. In addition, it has been observed that many of these risk loci in celiac disease are common with the loci for other autoimmune diseases. A signifi cant contribution to our knowledge has been provided by recent genome-wide association studies, but great part of the still unknown heritability in celiac disease is yet to be explored in the future.

Iako su HLA geni klase II nedvojbeno uključeni u razvoj celijakije procjenjuje se da je njihov doprinos genetičkoj podložnosti svega 40%, što upućuje na postojanje drugih gena unutar ili izvan HLA regije koji imaju ulogu u etiopatogenezi bolesti. Stoga su u ovoj studiji analizirani međusobni utjecaji specifičnih polimorfizama u CTLA4 i TNF-α genima, kao i interakcija s genima HLA-DQA1 i -DQB1, na predispoziciju i kliničku ekspresiju celijakije. Rezultati su pokazali da međudjelovanje CTLA4+49G, CT60G i TNF-α -308A polimorfizama, pored rizičnih HLA-DQA1 i -DQB1 gena, utječe na predispoziciju za celijakiju u naših bolesnika, ali ne i na promatrane parametre kliničke ekspresije bolesti, osim određenih trendova koji nisu dosegli razinu statističke značajnosti.

Introduction: Only 40% of the genetic susceptibility to celiac disease can be attributed to the HLA class II genes. The aim of our study was to determine the possible impact of specific polymorphisms of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and tumor necrosis factor-α (TNF-α) genes on the predisposition of celiac disease. Methods: The study included 202 patients with celiac disease and 400 healthy controls. Polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) method was used for the identification of TNF-α -238, TNF-α -308, and CTLA4 +49 and CTLA4 CT60 gene polymorphisms. Results: The presence of the CTLA4 +49 and CT60 polymorphisms had no individual impact on the genetic susceptibility to celiac disease. However, the interaction of risk alleles for both CTLA4 polymorphisms showed significant impact on the occurrence of the disease, which was confirmed by the analysis of the haplotype (OR=4.66, p=0.0003). The presence of the TNF-α -308 gene polymorphism strongly correlated with the presence of the disease at the significance level of p0.05). Examining the interaction of the TNF-α gene -308 and -238 polymorphisms has shown that TNF- -308/-238 AG haplotype represents a risk factor for the development of the disease (OR = 2.53, p