Igor Medica

Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis

AbstractA great number of association studies have been performed to identify the genes involved in the etiology and prognosis of sarcoidosis. We performed a systematic review of case-control studies through the PubMed database and evaluated them for a possible inclusion into a meta-analysis in order to assess whether the reported genetic polymorphisms are the risk factors of sarcoidosis. Case-control studies with clear diagnostic criteria and interventions were included. Only investigations of a single polymorphism/gene involvement in sarcoidosis reported more than five times were selected. Aggregating data from 12 studies on ID/ACE polymorphisms, the odds ratio (OR) for sarcoidosis, if the polymorphism was considered under the dominant genetic model, was not significantly increased: 1.19 (95% CI 0.98-1.43); OR under the recessive model was 1.20 (95% CI 0.98-1.46). In seven case-control studies on −308/TNF-α polymorphism, the OR for sarcoidosis if the polymorphism considered under the dominant genetic model was significantly increased at 1.47 (95% CI 1.03-2.08); the OR under the recessive model was 1.39 (95% CI 0.67-2.90). In conclusion, the results showed that the TNF-α genotype could be a significant risk factor for sarcoidosis, whereas the risk of sarcoidosis due to the ACE genotype was not substantially elevated.

Association between genetic polymorphisms in cytokine genes and recurrent miscarriage – a meta-analysis

A meta-analysis of association studies was performed to assess whether the reported genetic polymorphisms in cytokine genes are risk factors for recurrent miscarriage (RM). The electronic PubMed database was searched for case-control studies on immunity-related genes in RM. Investigations of a single polymorphism/gene involvement in RM reported more than five times were selected. Aggregating data from seven case-control studies on -308/tumour necrosis factor-alpha polymorphism, the odds ratio (OR) for RM was 1.1 (0.87-1.39) if the polymorphism was considered under a dominant genetic model. In six studies on -1082/interleukin-10 (IL-10) polymorphism, the OR under a dominant model was 0.76 (0.58-0.99), and under a recessive model the OR was 0.90 (0.71-1.15). In five case-control studies on -174/IL-6 polymorphism, the OR for RM under a recessive model was 1.29 (0.69-2.40). The results show a statistically significant association with RM for the -1082/IL-10 genotype.

Polymorphisms in the interleukin-12/18 genes and recurrent spontaneous abortion.

Interleukin (IL) IL‐12/IL‐18 are involved in uterine NK cells control of uterine vascular development. Polymorphisms in the IL‐12/IL‐18 genes could modify the cytokine balance, which might result in an increased susceptibility to recurrent spontaneous abortion (RSA).

Patients with primary cataract as a genetic pool of DMPK protomutation

AbstractMyotonic dystrophy 1 (DM1) is known to diminish reproductive fitness in its severe form. Since no de novo mutations are known for this disease, it has the tendency to become extinct from a population. To explain the preservation of DM1 in a population, a hypothesis that a pool of subjects for the mutated gene exists in the apparently healthy (non-DM1) population was tested. In order to determine the (CTG) repeat number, PCR was performed in 274 patients found to have primary cataract of adult onset who showed no DM1 symptoms, and were not related to DM1 patients. In four cataract patients (1.46% 95% CI 0.5–3.7), a protomutation in the myotonin protein kinase gene was found which might lead to a complete mutation after transmission through the next generations. The number of (CTG) repeats in the remaining 270 cataract patients did not differ significantly from the control subjects in terms of the distribution of larger [(CTG)n ≥ 19] versus smaller [(CTG)n < 19] alleles. We consider the primary cataract patients to be the pool of DMPK protomutation from which DM1 mutation is maintained in the population.

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome — meta-analysis

Folate metabolism deficiency has been related to increased occurrence of maternal non-disjunction resulting in trisomy 21. Several polymorphisms in genes coding for folate metabolism enzymes have been investigated for association with the maternal risk of Down syndrome (DS) yielding variable results. We performed a meta-analysis of case-control studies obtained through the PubMed database. The studies on polymorphisms in the MTHFR, MTRR, MTR, RFC1 and CBS genes were included. The summary OR demonstrated a statistically significant increased risk of giving birth to a child with DS in mothers carrying the mutant allele of the MTHFR/C677T gene polymorphism (both genetic models) and in mothers homozygous for the mutant allele of the MTRR/A66G polymorphism (recessive genetic model). Analyses of other polymorphisms, MTHFR/A1298C, MTR/A2756G, RFC1/A80G, and CBS/844ins68, resulted in borderline or no statistical significance. In conclusion, our meta-analysis showed the significance of genetic alterations in the folate metabolism genes in maternal susceptibility to DS offspring. Our results suggest that the importance of folate supplementation to women in reproductive age in prevention of non-disjunction be revised. Further genetic studies on a combined effect of multiple folate metabolism genes is recommended. Additionally, more thorough studies on the haplotype analyses of genes is recommended as well, especially in populations that have not yet been investigated thus far.

Incidence of the 35delG/GJB2 mutation in low-risk newborns.

Objective. To investigate, in a prospective study, the incidence of homozygotes and heterozygotes of the 35delG/GJB2 mutation for connexin 26 in the low-risk population of newborns undergoing two-stage universal neonatal hearing screening (UNHS). Patients and methods. The study population consisted of 1048 neonates born at the Department of Obstetrics and Gynecology, Rijeka University Hospital, Croatia, in the period between March 1, 2005 and June 30, 2005. The neonates underwent a two-stage UNHS program that included evoked otoacoustic emission (E-OAE) in all infants and automated auditory brainstem response (A-ABR) in those who did not pass the E-OAE. The 35delG/GJB2 mutation was determined in the umbilical cord blood of all examinees. Results. Fifteen out of 1048 infants (14.3 per 1000) did not pass the E-OAE, of whom three (2.86 per 1000) did not pass the A-ABR (two unilateral, one bilateral). The 35delG/GJB2 mutation was found in 13 out of 1033 infants who did pass the E-OAE and in one who did not pass the E-OAE. Thirteen out of 14 infants were heterozygotes (12.4 per 1000) and one infant was homozygote (0.95 per 1000) for the 35delG/GJB2 mutation. The homozygous infant had a bilateral pathological result on E-OAE and A-ABR, while 13 infants who were homozygotes passed the E-OAE. Conclusion. In all neonates, regardless of hearing impairment, genetic testing for the 35delG/GJB2 mutation is desirable in southern Croatia. The incidence of affected homozygous and healthy heterozygous transmitters of the 35delG/GJB2 mutation was in concordance with findings in southern European countries.

Distribution of HFE gene mutations in Slovenian patients with hereditary hemochromatosis

Dear Editor, Hereditary hemochromatosis (HH; HFE-related or type 1 genetic hemochromatosis) is a common autosomal recessive disorder of iron metabolism, its prevalence being two to five per 1,000 in Caucasians, characterized by increased iron absorption and progressive iron storage, resulting in organ damage, especially liver cirrhosis. Because the clinical consequences can be prevented by repeated phlebotomies, early accurate diagnosis is crucial. This can be achieved by genetic testing. By this approach, HH becomes a preventable genetic disorder on secondary level. In the hemochromatosis gene (HFE), two missense mutations were initially identified: C282Y (c.845G>A/p. C282Y) and H63D (c.187C>G/ p.H63D), followed by a third mutation: S65C (c.193A>T/p.S65C) [3, 10]. In European populations, the estimated contribution of C282Y homozygosity to the HH phenotype is up to 96%. The prevalence decreases from northern to southern Europe. The H63D mutation has a frequency of approximately 16% in the European populations, the proportion of the compound C282Y/H63D heterozygotes among HH patients being the highest in southern Europe. The S65C mutation accounts for approximately 8% of HH chromosomes, which are neither C282Y nor H63D [4, 6, 7, 10]. Reports on the prevalence of HFE mutations in HH patients in Slavic populations are scarce. The present study was performed in order to establish the frequencies of the three HFE mutations in Slovenian HH patients. Forty-nine unrelated HH patients of Slovenian origin were ascertained through the Registry at the Gastroenterology Department, University Medical Center Ljubljana, Slovenia (mean age 48 years, age range 22–69 years): there were 39 men and ten women. In all patients included in the study, the clinical diagnosis of HH was established based on the following criteria: increased transferrin saturation (TS): >50% for females and >60% for males; increased serum ferritin: >200 μg/l for females and >400 μg/l for males. Iron serum markers were measured by standard methods. In 47 of the 49 patients, HH diagnosis and staging was confirmed by liver biopsy and iron staining. Hepatic iron index was not calculated. In two patients who refused liver biopsy, liver iron overload was established by magnetic resonance imaging. Exclusion criteria were: alcohol abuse, secondary iron overload and antihepatitis C and B virus positivity. The study was approved by the National Medical Ethics Committee. Informed consent was obtained from all patients. The analysis of the HFE gene mutations was performed using polymerase chain reaction [3, 10]. The mutation analysis of 49 HH patients revealed that 35 (71.4%) were homozygous for C282Y mutation, and two patients (4.1%) were C282Y–H63D compound heterozygotes. Thus, the C282Y mutation was present in 37 of the 49 patients (75.5%). Among the 12 patients without the C282Y mutation, one (2%) was H63D–S65C compound heterozygote, five (10.2%) Ann Hematol (2008) 87:667–669 DOI 10.1007/s00277-008-0463-2