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.

Search for sarcoidosis candidate genes by integration of data from genomic, transcriptomic and proteomic studies.

BACKGROUND: The search for gene candidates in multifactorial diseases such as sarcoidosis can be based on the integration of linkage association data, gene expression data, and protein profile data from genomic, transcriptomic and proteomic studies, respectively. MATERIAL/METHODS: In this study we performed a literature-based search for studies reporting such data, followed by integration of collected information. Different databases were examined--Medline, HugGE Navigator, ArrayExpress and Gene Expression Omnibus (GEO). Candidate genes were defined as genes which were reported in at least 2 different types of omics studies. Genes previously investigated in sarcoidosis were excluded from further analyses. RESULTS: We identified 177 genes associated with sarcoidosis as potential new candidate genes. Subsequently, 9 gene candidates identified to overlap in 2 different types of studies (genomic, transcriptomic and/or proteomic) were consistently reported in at least 3 studies: SERPINB1, FABP4, S100A8, HBEGF, IL7R, LRIG1, PTPN23, DPM2 and NUP214. These genes are involved in regulation of immune response, cellular proliferation, apoptosis, inhibition of protease activity, lipid metabolism. Exact biological functions of HBEGF, LRIG1, PTPN23, DPM2 and NUP214 remain to be completely elucidated. CONCLUSIONS: We propose 9 candidate genes: SERPINB1, FABP4, S100A8, HBEGF, IL7R, LRIG1, PTPN23, DPM2 and NUP214, as genes with high potential for association with sarcoidosis.

Polymorphisms in genes coding for mediators in the interleukin cascade and their effect on susceptibility to sarcoidosis in the Slovenian population.

Sarcoidosis is a chronic inflammatory disease characterised by granulomatous inflammation in various organs. As genetic factors have been implicated in its aetiology, in our study we investigated whether the promotor polymorphisms in three genes coding for inflammatory mediators interleukin-6 (IL-6), interleukin-12 (IL-12), and interleukin-18 (IL-18) could be associated with susceptibility to sarcoidosis. The study sample consisted of 104 patients with sarcoidosis and 100 healthy control subjects. Following DNA isolation from peripheral blood the IL-6/-174G>C single nucleotide polymorphism (SNP), the IL-12B/4 bp insertion polymorphism, and the IL-18/-137G>C SNP were characterised by polymerase chain reaction. Our results showed an increased frequency of IL-6/-174C allele (p<0.01, OR=2.05, 95% CI=1.32-3.16), and also an increased genotype frequency of IL-6/-174 CC and CG carriers (p<0.01, OR=2.78, 95% CI=1.49-5.19) among sarcoidosis patients in comparison with healthy controls. Allele and genotype frequencies did not differ significantly between cases and controls for either the IL-12B/4 bp insertion polymorphism or for the IL-18/-137G>C polymorphism. In conclusion, we demonstrated that the -174G>C promotor polymorphism in the IL-6 gene may be a risk factor for sarcoidosis.

Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis.

There are controversies in reports on the association of polymorphisms in endothelial nitric oxide synthase, angiotensinogen, angiotensin receptor type 1 and angiotensin-converting enzyme genes with an increased risk of developing preeclampsia. We performed a systematic search of published case-control studies through the PubMed database up to January 2006, and report the results of a meta-analysis of polymorphisms investigated in more than five studies: Glu298Asp in eNOS gene (9 analyses involving 1055 patients and 1788 controls), Met235Thr in AGT gene (13 analyses involving 1128 patients and 2278 controls), and intron 16 insertion-deletion polymorphism in ACE gene (10 analyses involving 1121 patients and 1361 controls). Statistically significant associations with preeclampsia were identified for the Met235Thr/AGT polymorphism: OR 1.65 (95% CI 1.19, 2.29) if the polymorphism is considered under the dominant genetic model, and OR 1.54 (95% CI 1.12, 2.11) under the recessive model. For insertion-deletion/ACE polymorphism, statistical significance was demonstrated when the polymorphism was considered under the recessive model: OR 1.51 (95% CI 1.17, 1.94). No single polymorphism was identified as having a major effect.

C.35delG/ GJB2 and del(GJB6-D13S1830) mutations in Croatians with prelingual non-syndromic hearing impairment.

BACKGROUND: C.35delG/GJB2 mutation is the most frequent genetic cause of deafness in Caucasians. Another frequent mutation in some Caucasian populations is del(GJB6-D13S1830). Both GJB2 and GJB6 genes belong to the same DFNB1 locus and when the two mutations are found in combination in a hearing-impaired person, a digenic pattern of inheritance is suggested. METHODS: We examined 63 Croatian subjects (25 familial and 38 sporadic cases) with prelingual non-syndromic hearing impairment by polymerase chain reaction for the presence of the c.35delG/GJB2 and the del(GJB6-D13S1830) mutations. RESULTS: Of the 63 unrelated hearing-impaired subjects, the mutation c.35delG/GJB2 was found in 21 subjects (33.3%). In 5 of them the mutation was found in the heterozygous state, all of them being compound heterozygotes, as sequencing revealed a second mutation within the coding region of the gene in 3 subjects, and a splice site mutation in 2 subjects. The del(GJB6-D13S1830) mutation was not found in the investigated hearing-impaired Croatian subjects. CONCLUSION: Our results contribute to the knowledge of geographic distribution and population genetics of the GJB2 and GJB6 mutations in the Europeans.

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.

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

A 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-alpha 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-alpha genotype could be a significant risk factor for sarcoidosis, whereas the risk of sarcoidosis due to the ACE genotype was not substantially elevated.

Patients with primary cataract as a genetic pool of DMPK protomutation.

Myotonic 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 > or = 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.

Association of angiotensin-converting enzyme/DD genotype with sarcoidosis susceptibility in Slovenian patients.

BACKGROUND: Sarcoidosis is a multisystemic chronic inflammatory disorder of unknown etiology with multifactorial genetic predisposition. An elevated ACE serum level is considered to be the activity marker of the disease. The involvement of the ACE I/D polymorphism in sarcoidosis susceptibility has been investigated in different populations, but results have been inconclusive. The purpose of this study was to evaluate the possible association of angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism with sarcoidosis in the Slovene population. MATERIAL/METHODS: In 105 sarcoidosis patients (69 female, 36 male, mean age: 41+/-1 years) and in 80 sex- and age-matched control subjects, genotyping for the ACE gene I/D polymorphism was performed by PCR and restriction enzyme digestion. RESULTS: An increased frequency of DD homozygotes vs. II homozygotes + ID heterozygotes was found in the group of sarcoidosis patients compared with the control group (OR: 2.19, 95%CI: 1.12-4.26, p=0.02). No differences in genotype frequencies were found in the group of sarcoidosis patients when considering the clinical course or presentation of the disease. CONCLUSIONS: These results indicate that the ACE gene I/D polymorphism might be a risk factor for sarcoidosis susceptibility in the Slovene population and imply the possible role of population origin in the modulation of the influence of ACE gene variability in the pathophysiology of sarcoidosis.

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

PROBLEM: 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). METHOD OF STUDY: A case-control study was conducted to determine the association between the IL12 (I/D) and IL18 (-607C>A, -137G>C) gene polymorphisms and the risk of RSA in 125 women with RSA and in 136 controls. RESULTS: The frequencies of DD, ID, II for IL-12 were, 25.6%, 52.8% and 21.6% respectively, in patients versus 21.3%, 51.5% and 27.2% respectively in controls; the frequencies of CC, CA, AA genotypes for IL-18 (-607) were, 34.4%, 54.4% and 11.2% respectively in patients versus 30.1%, 58.1% and 11.8% respectively in controls; the frequencies of GG, GC, CC genotypes for IL-18(-137) were 47.2%, 43.2% and 9.6% respectively in patients and 45.6%, 46.3% and 8.1% respectively in controls. CONCLUSION: IL-12B and IL-18 promoter gene polymorphisms were not associated with RSA in our women.

Incidence of the del35G/GJB2 mutation in Croatian newborns with hearing impairment.

BACKGROUND: The de135G mutation in the GJB2 gene is the most common cause of prelingual deafness. The mutation frequency has so far been estimated either by testing symptomatic children or adults, or by carrier testing of the general population. The purpose of our study was to establish the incidence of the del35G/GJB2 mutation in newborns with hearing impairment--in congenital deafness. MATERIAL/METHODS: Patients were identified through a neonatal screening program (performed on a regular basis in Croatia since 2002). Otoacoustic emission testing was performed on 3275 newborns, and allele-specific PCR was performed on newborns diagnosed with hearing impairment. RESULTS: Hearing impairment was found in 9 newborns, the frequency of congenital hearing impairment being 1/363; the del35G mutation was found in 3 of these 9 newborns. The established incidence of the mutation in the studied population of Croatian newborns with hearing impairment is 1/1091 (95CI: 1/372-1/3205). CONCLUSIONS: This particular approach to patient identification, based on exact clinical examination supplemented with molecular testing, allowed for complete diagnosis and precise estimation of the incidence of the mutation in cases of congenital deafness, which proved to be higher than previously reported in prelingual deafness. This finding has important implications in clinical evaluation and genetic counseling of patients and their families.

Molecular analysis in diagnostic procedure of hearing impairment in newborns.

AIM: To determine the proportion of newborns diagnosed with hearing impairment through the hearing impairment screening program in newborns, and the frequency of 35delG/GJB2 mutation as a cause of hearing impairment. The results of the study imply the integration of the mutation analysis in the neonatal screening program. METHODS: Evoked otoacustic emission (E-OAE) screening program was performed among 6019 newborns at the Department of Obstetrics and Gynaecology, Rijeka University Hospital Center, between October 2002 and December 2004. Newborns diagnosed with hearing impairment were re-examined after three weeks and if abnormal responses persisted, the diagnosis was evaluated by auditory brainstem evoked response (ABER) testing. Children with confirmed diagnosis were examined by allele-specific polymerase chain reaction to identify the presence of 35delG/GJB2 mutation. RESULTS: After the first and second stage of screening, 86 newborns were suspect of having hearing impairment. ABER confirmed the diagnosis of hearing impairment in 14 children. Molecular analysis revealed 35delG/GJB2 mutation in 2 of 8 children analyzed. The mutation was homozygous in one, and heterozygous in the other child. CONCLUSION: Neonatal hearing impairment screening is useful for early diagnosis of hearing impairment. It should be complemented with the 35delG/GJB2 mutation analysis, because the identification of the mutation and the etiologic diagnosis might improve the medical treatment and genetic counselling of patients and families with hearing impairment.