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PubMed2005

Interleukin-2 and interleukin-6 gene promoter polymorphisms, and early failure of dental implants.

Single nucleotide polymorphisms in the promoter region of the human interleukin (IL)-2 (T-330G) and IL-6 (G-174C) genes have modified the transcriptional activity of these cytokines and are associated with several diseases. The aim of this study was to investigate the possible relationship between these single nucleotide polymorphisms and early implant failure. A sample of 74 nonsmokers was divided into 2 groups: test group comprising 34 patients (mean age 49.3 years) with >or=1 implants that failed and control group consisting of 40 patients (mean age 43.8 years) with >or=1 healthy implants. Genomic deoxyribonucleic acid from oral mucosa was amplified by polymerase chain reaction and analyzed by restriction fragment length polymorphism. Monte Carlo simulations (P < 0.05) were used to assess differences in allele and genotypes frequencies of the single nucleotide polymorphisms between the 2 groups. No significant differences were observed in the allele and genotypes distribution of both polymorphisms when the 2 groups were compared. The results indicate that polymorphisms in the IL-2 (T-330G) and IL-6 (G-174C) genes are not associated with early implant failure, suggesting that the presence of those single nucleotide polymorphisms does not constitute a genetic risk factor for implant loss in the studied population.

Adult↗

PubMed2004

Polymorphisms in the myocilin promoter unrelated to the risk and severity of primary open-angle glaucoma.

PURPOSE: To investigate the proximal 2.5 kb promoter in the myocilin (MYOC) gene for mutations in Chinese patients with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: We screened for sequence alterations in the MYOC promoter in 88 unrelated Chinese patients with POAG and 94 unrelated individuals without glaucoma, aged 50 years or above, as control subjects. In addition, the specific MYOC.mt1 polymorphism was determined in a total of 212 POAG patients and 221 control subjects. The relationships between POAG phenotype and the identified polymorphisms were studied by univariate analysis, multivariable logistic regression analysis, and haplotype analysis. RESULTS: All polymorphisms identified in this study followed Hardy-Weinberg equilibrium (P > 0.12) both in POAG patients and controls. Both univariate and multivariable logistic regression analyses showed no polymorphism that was significantly associated with the risk of POAG, P > 0.08 and P > 0.044 respectively. Haplotype analysis further indicated no association of MYOC promoter polymorphisms with the susceptibility for POAG (P > 0.1). On the other hand, there was no difference of POAG phenotypes among different genotypes of MYOC.mt1 (P > 0.31). CONCLUSIONS: In this study on the Chinese population, polymorphisms in the MYOC promoter are not related to the risk of POAG. There is no association between the MYOC.mt1 promoter polymorphism with the severity of POAG.

Adolescent↗

PubMed2006

Association of apolipoprotein E polymorphisms with normal tension glaucoma in a Chinese population.

PURPOSE: To evaluate the role of apolipoprotein E (APOE) polymorphisms in primary open angle glaucoma (POAG). METHODS: A cohort of 400 unrelated Chinese POAG patients was examined, including 294 cases of high tension glaucoma (HTG) and 106 with normal tension glaucoma (NTG). Also studied were 300 unrelated Chinese control subjects. The genotypes of the APOE polymorphisms in exon 4 and in the promoter at positions -491, -427, and -219 were determined by polymerase chain reaction and restriction endonuclease analysis. Frequencies of the genotypes were compared between patients and controls by chi test or Fisher exact test. The association of APOE polymorphisms with POAG phenotypes including age at diagnosis, intraocular pressure (IOP) at diagnosis, highest IOP, cup-disc ratio, and visual field score was investigated by the Kruskal-Wallis test. RESULTS: No significant difference was detected in the frequencies of APOE promoter polymorphisms between POAG patients and control subjects (P>0.0125). For the exon 4 polymorphism, when compared with control subjects, the frequency of epsilon 4 carriers was significantly lower in patients with NTG (P=0.008; odds ratio=0.36, 95% confidence interval=0.17, 0.79) but not in HTG (P=0.07). Compared with -219TT, the -219G carriers had a significant higher age at diagnosis (P=0.0046). No significant association was found between other APOE polymorphisms and POAG phenotypes (P>0.07). CONCLUSIONS: Our findings suggest that the APOE epsilon 4 allele confers a protective effect against NTG, whereas the APOE promoter polymorphisms do not contribute to POAG risk. However, the APOE -219G carriers tended to have later-onset POAG.

Adolescent↗

PubMed2005

A polymorphism of the osteopontin gene is related to urinary calcium stones.

PURPOSE: We investigated polymorphisms of the osteopontin (OPN) gene to explore whether they could be used as a gene marker for determining the risk of urinary calcium stones. MATERIALS AND METHODS: A total of 76 patients with urinary calcium stones and 124 controls were studied. Two single nucleotide polymorphisms with nonsynonymous amino acid located at positions 9,402 (Arg/His) and 9,171 (Asn/Ser) in the OPN gene were genotyped using the TaqMan 5' nuclease assay in a PRISM 7700 sequence detection system. Results were analyzed with Fisher's exact test. RESULTS: Results revealed a significant different polymorphism at OPN gene position 9,402 between patients with urinary calcium stones and control subjects. The frequency of the A/G genotype at position 9,402 in patients with urinary calcium stones was significantly higher than that in control subjects (p <0.01). The frequency of the A allele at position 9,402 was significantly higher in the patient than in the control group (4.6% vs 0.4%, p <0.01). There was no statistical difference in this polymorphism at OPN gene position 9,402 between genotype distribution and clinical characteristics associated with urinary calcium stones. There was no difference in the polymorphism at OPN gene position 9,171 between the patient and control groups. CONCLUSIONS: Polymorphism at position 9,402 of the OPN gene is highly associated with urinary calcium stones and it is a candidate genetic marker for evaluating the genetic risk of urinary calcium stone disease, whereas polymorphism at position 9,171 of the OPN gene is not associated with urinary calcium stone disease.

Adult↗

PubMed2006

Cytokine tumor necrosis factor-alpha A promoter gene polymorphism at position -308 G-->A and pediatric inflammatory bowel disease: implications in ulcerative colitis and Crohn's disease.

OBJECTIVES: Our pilot study aimed to determine the effect of tumor necrosis factor-alpha (TNF-alpha) 308 G-->A promoter single-nucleotide polymorphism in pediatric inflammatory bowel disease (IBD), its influence on inflammatory activity and the clinical manifestations. METHODS: We obtained genomic DNA from 164 subjects, 82 with long-standing IBD aged 8 to 18 years: 46 with Crohn disease (CD) and 36 with ulcerative colitis (UC). Eighty-two healthy children served as the control population. Genotyping was determined by using a restriction enzyme-based assay. TNF-alpha 308 G-->A polymorphism was assessed in terms of inflammatory (C-reactive protein [CRP]) and disease activity. The latter was assessed by the Pediatric Crohn's Disease Activity Index (PCDAI) and the Truelove index for CD and UC, respectively. RESULTS: Significant differences in TNF-alpha 308 A polymorphism were found between the IBD group and controls (P < 0.05) and the UC group and controls (P < 0.001). No differences were noted between TNF-alpha 308 A polymorphism and clinical characteristics in UC. The frequency of the -308 A allele of TNF was not different in CD compared with that in the control group. The frequency of TNF-alpha 308 A genotype was significantly higher in CD patients with predominantly stenosing/penetrating disease compared with patients without complications (P < 0.001) and healthy controls (P < 0.01). In CD patients, those carrying TNF -308 A had a significant increase in CRP (P < 0.05) and the PCDAI (P < 0.05). In CD, CRP levels strongly correlated with the PCDAI (r = 0.6150, P < 0.001). In UC, significant differences among the mean levels of CRP (P < 0.05) and disease activity (P < 0.001) related to TNF-alpha 308 A polymorphism were found. Allele distribution (odds ratio, 12.9; CI, 1.18-140.81, P < 0.001) and CRP serum levels (odds ratio, 1.020; CI, 1.00-1.04, P < 0.001) were independently associated with CD complications. CONCLUSIONS: Although not necessarily dictating IBD initiation, the TNF-alpha 308 A polymorphism may play a role in modifying the CD phenotype. The polymorphism may influence disease activity as well as more intense inflammatory activity in both forms of IBD and may modify the progression of chronic digestive tract inflammation.

Adolescent↗

PubMed2006

No evidence of association between NOD2/CARD15 gene polymorphism and atherosclerotic events after renal transplantation.

Stable renal transplant recipients (RTR) display high rates of atherosclerotic events (AE). Innate immunity and especially vascular inflammation play a role in the pathogenesis of atherosclerosis. It is illustrated both by an increased occurrence of postrenal transplant cardiovascular events in patients with elevated levels of C-reactive protein and by a correlation between posttransplant AE and Toll-like receptor-4 Asp299Gly polymorphism. Here, we analyze the influence NOD2/CARD15 gene polymorphism since NOD2 can modulate macrophage pro-inflammatory activity and macrophage is present in early atherosclerotic lesions. The incidence of single nucleotide polymorphism (SNP) in the three major polymorphic region of NOD2 gene (SNP8, SNP12 and SNP13) was assessed in 182 RTR and the correlation between such polymorphism and the development of AE was analyzed. No correlation was observed between NOD2 gene polymorphism and the occurrence of AE after renal transplantation. NOD2 gene polymorphism thus does not appear to influence cardiovascular complications in RTR.

Adult↗

PubMed1999

Assessment of polymorphism in zebrafish mapping strains.

To assess the level of heterozygosity within two commonly used inbred mapping zebrafish strains, C32 and SJD, we genotyped polymorphic CA-repeat markers randomly dispersed throughout the zebrafish genome. (For clarity purposes we will primarily use the term polymorphic to define polymorphism between strains, and the term heterozygous to address heterogeneity within a strain.) Eight male individuals each from C32 and SJD stocks were typed for 235 and 183 markers, respectively. Over 90% of the markers typed were polymorphic between these two strains. We found a limited number of heterozygous markers persisting in clusters within each inbred line. In the SJD strain, these were mainly limited to a few telomeric regions or regions otherwise distant from centromeres. As expected, centromeric regions were homozygous in the SJD strain, consistent with its derivation from a single half-tetrad individual. In contrast, heterozygous clusters were distributed randomly throughout the genome in the C32 strain, and these clusters could be detected with linked polymorphic markers. Nevertheless, most regions of the C32 strain are homozygous for CA-repeat markers in current stocks. This identification of the heterozygous regions within C32 and SJD lines should permit rapid fixation of these remaining regions in future generations of inbreeding. In addition, we established levels of polymorphism between the inbred, C32 and SJD, strains and three other commonly used strains, the *AB, WIK, and Florida wild type (hereafter referred as EKK), with CA-repeat markers as well as SSCP polymorphisms. These data will maximize the use of these strains in mapping experiments.

Animals↗

PubMed2004

Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation.

AIMS: Polymorphisms of the NOSIII gene and of the CYBA gene have been associated with a number of pathological conditions such as arterial hypertension, coronary artery disease, and myocardial infarction. Because endothelium-dependent vasodilation is impaired in these disorders, we hypothesized that polymorphisms of NOSIII or CYBA might modulate endothelial function of venous capacitance vessels already before cardiovascular disease becomes overt. METHODS: Endothelium-dependent and -independent venodilation was assessed by measuring local vascular responses to bradykinin and sodium nitroprusside in the dorsal hand vein after preconstriction with phenylephrine in 72 healthy male Caucasians after careful exclusion of cardiovascular risk factors. Genotyping was performed for polymorphisms of the NOSIII gene (T-786C, G894T, (CA)(n)) and the CYBA gene (C242T). RESULTS: Genotype distribution for each polymorphism followed the Hardy-Weinberg equilibrium. In all studied single nucleotide polymorphisms no significant difference between the respective genotypes and the venodilator response to either sodium nitroprusside or bradykinin was observed, and the number of CA repeat copies was not related to the venodilator response to bradykinin. Mean venodilation induced by bradykinin 50 ng min(-1) (+/-SEM) for homozygote carriers of the single nucleotide polymorphisms was 48.9 +/- 8.5% venodilation (G894T; wild type: 49.8 +/- 6.9), 50.3 +/- 11.0% venodilation (T-786C; wild type: 42.6 +/- 5.2), and 30.4 +/- 9.1% venodilation (C242T; wild type: 49.2 +/- 6.0), respectively. CONCLUSIONS: This study suggests that the studied polymorphisms of NOSIII and CYBA do not significantly modulate endothelium-dependent venodilation in individuals without vascular risk factors.

Bradykinin↗

PubMed2006

Cytokine gene polymorphisms in bullous pemphigoid in a Chinese population.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune bullous disease mostly associated with autoantibodies to the hemidesmosomal BP autoantigens BP180 and BP230. High levels of interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma have been detected in skin lesions or sera of patients with BP. Cytokine gene polymorphisms may affect cytokine production and contribute to susceptibility to autoimmune diseases. Until now, no cytokine gene polymorphism study has been conducted on patients with BP. OBJECTIVES: We aimed to determine whether the genetic polymorphisms of the cytokine genes might influence the development of BP. METHODS: DNA samples were obtained from 96 BP patients and 174 control subjects. Using direct sequencing and microsatellite genotyping, we examined 23 polymorphisms in 11 cytokine genes including the IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-4, IL-6, IL-8, IL-10, IL-13, IL-4 receptor, TNF-alpha and IFN-gamma genes. RESULTS: Although the BP patients were more likely to carry the -511T and -31C alleles of the IL-1beta gene (P = 0.04), the significance disappeared after correction for multiple testing (Pc). There was complete linkage disequilibrium between the -511T and -31C alleles of the IL-1beta gene. In female patients with BP, the associations with IL-1beta (-511T) and (-31C) alleles were much stronger (68% vs. 40.6%, odds ratio = 3.11, Pc = 0.006). No significantly different allelic and genotypic distributions of other cytokine gene polymorphisms could be found between the patients with BP and controls. Moreover, no association with the extent of disease involvement (localized or generalized) was observed. CONCLUSIONS: The IL-1beta (-511) and (-31) polymorphisms were significantly associated with BP in women. The other genetic polymorphisms of cytokine genes that we analysed do not appear to be associated with BP susceptibility in our Chinese population.

Adult↗

PubMed2006

TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behçet's disease.

BACKGROUND: Genetic factors that predispose individuals to Behçet's disease (BD) are considered to play an important role in development of the disease. The tumour necrosis factor (TNF)-alpha gene, which is closely linked to the HLA-B51 gene, is involved in susceptibility for BD. Recently, a polymorphism at position -1031 within the TNF-alpha promoter region was demonstrated to be responsible for susceptibility to BD in a British population. However, the functional effects of this polymorphism have not yet been determined. OBJECTIVES: To investigate the possible relation of the TNF-alpha-1031 T/C polymorphism with susceptibility to BD in a Turkish population and to determine the functional importance of this polymorphism. METHODS: Ninety-nine unrelated patients (47 women, 52 men; mean +/- SD age, 34.10 +/- 10.53 years) with BD and 103 ethnically matched healthy controls (52 males, 51 females; mean +/- SD age, 40.25 +/- 14.15) were enrolled in the study. For genotyping, polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) analysis was employed. The functional importance of TNF-alpha-1031 T/C polymorphism was determined with an enzyme-linked immunospot (ELISPOT) assay. For this purpose, mononuclear cells obtained from BD patients and controls were analysed for TNF-alpha and interferon (IFN)-gamma production. RESULTS: A significant difference was observed between BD patients and controls with respect to the allele frequency of TNF-alpha-1031C [P = 0.018, OR = 1.83, 95% confidence interval (CI) = 1.07-3.13]. When the allele frequencies were analysed according to the clinical features, the T allele in patients with positive skin pathergy test (SPT) was significantly increased when compared with those of patients without these findings (P = 0.004, OR = 2.75, 95% CI = 1.3-5.86). To demonstrate the frequency of TNF-alpha and IFN-gamma producing cells, mononuclear cells from four representative individuals of each genotype were used and the spontaneous and stimulated TNF-alpha and IFN-gamma values (spot numbers) were analysed. Compared with the control groups, a significant increase was observed in the number of cells producing TNF-alpha obtained from BD patients (P < 0.001). Moreover, the stimulation index for TNF-alpha [bacterial lipopolysaccharide (LPS) stimulated/unstimulated] was higher for the CC genotype (9 +/- 9.5) with respect to the other genotypes (TT; 1.3 +/- 0.3 and TC; 1.2 +/- 0.2). While the difference in the spontaneous IFN-gamma values between groups were not statistically significant, the stimulated IFN-gamma values were found to be significantly increased in the BD group when compared with the healthy control group (P = 0.004). CONCLUSIONS: Our results showed that, in the Turkish population the TNF-alpha-1031C allele is associated with susceptibility to BD. On the other hand, carrying the T allele may render patients more prone to developing a positive skin pathergy test. In addition, ELISPOT assays revealed that BD patients exhibited a significantly higher number of mononuclear cells producing TNF-alpha, and cells obtained from patients with a CC genotype had a stronger response to LPS stimulation. The strong IFN-gamma response upon LPS stimulation in BD patients supports the previous findings that BD is a Th1 driven disease. These findings suggest that the TNF-alpha-1031 polymorphism may have a functional effect and could explain the reason for high levels of TNF-alpha production observed in BD patients.

Adult↗

PubMed2007

Association between cutaneous melanoma, Breslow thickness and vitamin D receptor BsmI polymorphism.

BACKGROUND: Literature data report an association between some vitamin D receptor (VDR) polymorphisms and different kinds of tumours, including malignant melanoma (MM). Only three VDR polymorphisms (FokI, TaqI and A-1012G) have been investigated in association with the presence of cutaneous MM or the development of metastases. OBJECTIVES: The present paper analyses for the first time the association between BsmI polymorphism and MM prevalence together with Breslow thickness. In addition, the FokI single nucleotide polymorphism was also determined. METHODS: One hundred and one patients with MM and 101 healthy donors matched for age and sex were enrolled. Molecular VDR typing was performed by means of restriction fragment length polymorphism analysis. RESULTS: All cases and controls were in Hardy-Weinberg equilibrium for BsmI, FokI and A-1012G. Significant associations were found between the BsmI bb genotype frequency and MM (P = 0.02) along with Breslow thickness (P = 0.001). This same behaviour was not observed for the FokI or A-1012G polymorphisms. Multivariate logistic regression analysis confirmed these significant results after correction for age, gender, skin type and MM localization. CONCLUSIONS: Although the biological meaning of the effects exerted by BsmI polymorphism is still under debate, the statistical association found in the present study suggests that further work should be done to verify this variant as a possible risk marker for MM and its aggressiveness, also considering that the real association may be due to other unknown genes linked to the BsmI b allele.

Adult↗

PubMed1994

Multiplex analysis of two intragenic microsatellite repeat polymorphisms in the genetic diagnosis of haemophilia A.

Use of molecular genetic studies for carrier detection and prenatal diagnosis of haemophilia A will be informative in approximately 75% of kindreds with a prior history of the disorder if previously reported bi-allelic intragenic polymorphisms are used. In this study we report the use of two multi-allelic, microsatellite repeat polymorphisms within the factor VIII gene in genetic testing for this disease. These two, dinucleotide repeat, polymorphisms have been analysed using a multiplex polymerase chain reaction (PCR) protocol, and results can be available within 3 d of receipt of samples. At the intron 13 polymorphic locus we have confirmed the original observation of eight alleles, whilst at the intron 22 locus, in contrast to a preliminary report of this polymorphism, we have seen five alleles. We have analysed 32 families (174 subjects) with the two microsatellite repeat markers and have found that using these two polymorphisms alone, 81% of families are informative for linkage analysis. The intron 13 repeat was informative in 22/31 families tested (71%) and the intron 22 polymorphism was informative in 12/17 families (71%). We have also found that in 11/32 families tested (34%) the microsatellite repeats were the only informative intragenic markers. In view of these observations, we believe that the most effective strategy for initiating haemophilia A genetic testing is to combine the multiplex PCR analysis of the intron 13 and 22 dinucleotide repeats with the PCR analysis of the intron 18 BclI marker. In our population this protocol provided informative results in approximately 88% of families and results can be available within 3 d of receiving the samples for testing.

Alleles↗

PubMed2006

ABO blood group but not haemostasis genetic polymorphisms significantly influence thrombotic risk: a study of 180 homozygotes for the Factor V Leiden mutation.

Limited data exist on the impact of additional genetic risk factors on the clinical manifestations of factor (F) V Leiden homozygotes. A retrospective multi-centre cohort study was performed to assess the role of the FII G20210A gene mutation, the protein C (PC) promoter CG haplotype, the combination of two PC polymorphisms (A-1641G, C-1654T), the FXIII Val34Leu polymorphism, two thrombin-activatable fibrinolysis inhibitor polymorphisms (Thr325Ile, Ala147Thr), two plasminogen activator inhibitor-1 polymorphisms (-675 4G/5G, A-844G), the methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism and the ABO blood group on the thrombotic phenotype in FV Leiden homozygotes. 127 subjects with venous thrombosis and 53 asymptomatic subjects were analysed. The T allele of MTHFR C677T was more frequent in symptomatic subjects than in asymptomatic ones (68% vs. 45%, P = 0.02; odds ratio (OR) 2.8, 95% CI 1.3-5.8, after adjustment for potential confounders). For the other polymorphisms, no difference was observed between symptomatic and asymptomatic subjects. The non-O blood group was more frequent among symptomatic carriers (84% vs. 57%, P = 0.0002; OR 4.1, 95% CI 1.7-9.7). In conclusion, except for the ABO blood group, none of the polymorphisms studied contribute strongly to the thrombotic risk in FV Leiden homozygotes.

ABO Blood-Group System↗

PubMed2004

Polymorphism of the immune-braking gene CTLA-4 (+49) involved in gender discrepancy of serum total IgE levels and allergic diseases.

BACKGROUND: A variety of genes are related to allergic disorders in different ethnic populations. The genetic basis for the gender discrepancy of allergic diseases remains to be determined. OBJECTIVE: This study was conducted to investigate whether IL-4 promoter (-590 C/T) and cytotoxic T lymphocyte antigen 4 (CTLA-4) (+49 A/G) polymorphisms were correlated with a gender discrepancy of total IgE levels and allergic diseases in a Chinese population. METHODS: A total of 1333 participants aged 19-49 years were enrolled in this study. Allergic diseases were recognized by the presence of asthma, rhinitis or atopic dermatitis in conjunction with detectable specific IgE in the blood. Polymorphisms of IL-4 promoter (-590) and CTLA-4 (+49) were determined by restriction fragment length polymorphism. RESULTS: Males or females with allergic diseases had higher total IgE levels than those without (P=0.000). Females with the A/A genotype in the CTLA-4 (+49) position had significantly higher total IgE levels than those with A/G, and those with the G/G genotype had the lowest IgE levels (154.9 vs. 107.1 vs. 79.8 KU/L; mean log values: 1.79 vs. 1.65 vs. 1.54, P< 0.001). However, males with different genotypes in the CTLA-4 (+49) position exhibited no difference in the total IgE levels. Females with allergic rhinitis had a significantly higher frequency of the A/A genotype in the CTLA-4 (+49) polymorphism than those without atopic diseases (P=0.016). In contrast, males with and without allergic disorders exhibited no significant difference in the CTLA-4 (+49) polymorphisms (P>0.05). The IL-4 promoter (-590) polymorphisms, however, had no correlation with the total IgE levels or allergic diseases in either females or males. CONCLUSION: In females only, the CTLA-4 (+49), but not the IL-4 promoter (-590), polymorphism was significantly associated with elevation of total IgE levels and allergic rhinitis. Here, we have, for the first time, demonstrated a gender-linked genetic relationship with allergic disease.

Adult↗

PubMed2005

CARD15 polymorphisms are associated with anti-Saccharomyces cerevisiae antibodies in caucasian Crohn's disease patients.

Carriage of CARD15 gene polymorphisms and the serological marker anti-Saccharomyces cerevisiae antibodies (ASCA) are two markers for Crohn's disease (CD). Similar phenotypes have been associated with both markers. In the present study we analysed whether both markers were associated with each other and, if so, whether this association could be explained by a direct link or by an indirect association with those phenotypes. Therefore, we included 156 consecutive Caucasian CD patients and assessed the prevalence of the three common single nucleotide polymorphisms in the CARD15 gene. Serum samples were analysed for IgA and IgG ASCA by ELISA. CD patients with CARD15 polymorphisms were more frequently ASCA positive (OR 2.7 (1.4-5.2); P = 0.002) and had higher titres for ASCA IgA (P = 0.005) and ASCA IgG (P < 0.001) compared to patients carrying the wild type polymorphisms. Multivariate analysis demonstrated that this association was independent from ileal disease, penetrating disease and stricturing disease, the need for resective bowel surgery, familial cases, smoking habits and early age at onset. Homozygotes or compound heterozygotes for CARD15 polymorphisms had significantly more frequent ASCA positivity compared to single heterozygotes (OR 9.1 (1.1-74.2), P(c) (corrected P-value) = 0.030). These data indicate that there is a significant association between the carriage of CARD15 polymorphisms and ASCA, independent of the described phenotypes. Moreover, ASCA positivity is more frequent in CD patients carrying 2 CARD15 polymorphisms compared to single heterozygotes.

Adolescent↗

PubMed2006

The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis.

Osteomyelitis is a bone infection caused mostly by Staphylococcus aureus but also by Gram-negative bacteria. Toll-like receptors (TLRs), after recognizing microbial products, induce a signal in neutrophils, leading to NF-kappaB activation and transcription of pro-inflammatory genes. Polymorphisms in TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) genes are associated with bacterial infections, we therefore studied these polymorphisms in osteomyelitis patients. Homozygotes for the TLR4 (Asp299Gly) polymorphism were significantly more frequent among the 80 osteomyelitis patients than in the 155 healthy controls (3/80, 3.8%versus 0/155, 0%; P = 0.038). Carriers of one or two G alleles of this tlr4 polymorphism were more likely to have Gram-negative, haematogenous and/or chronic osteomyelitis than those without this mutation (P < 0.031). Patients with the TLR4 (Thr399Ile) mutant, which cosegregates with the TLR4 (Asp299Gly), were also carriers of this second polymorphism. No differences for the TLR2 (Arg753Gln) genotypes were found between patients and controls. Neutrophils of patients homozygous for the TLR4 (Asp299Gly) polymorphism showed lower LPS-induced apoptosis reduction, phosphorylation of the inhibitor of NF-kappaB, and lower IL-6 and TNF-alpha levels (P < 0.05). We report here for the first time an association between this TLR4 polymorphism and susceptibility to Gram-negative bacteria and haematogenous osteomyelitis.

Adolescent↗

PubMed1987

Genomic HLA-DQ beta polymorphism associated with insulin-dependent diabetes mellitus. Analysis of possible functional significance.

Twelve insulin-dependent diabetes mellitus (IDDM) patients and healthy controls, who all carried the serologically defined DR3 and DR4 antigens, were compared with respect to other HLA polymorphisms. No significant differences between patients and controls were found by typing for HLA-Dw determinants by homozygous cell typing, nor by studies of their genomic DR beta polymorphism using different restriction enzymes. In contrast, certain DR beta polymorphism using different restriction enzymes. In contrast, certain DR4-associated genomic DQ beta fragments had a significantly different distribution among the IDDM patients than among the controls. Furthermore, when the distribution of all DQ beta-specific fragments which demonstrated polymorphism in our material was taken into account, nine of the 12 DR3, 4 IDDM patients demonstrated a similar DQ beta polymorphism compared with only two out of the 12 DR3, 4 controls (P = 0.006; corrected P = 0.037). Cells from patients and controls who demonstrated this IDDM-associated DQ beta polymorphism stimulated each other significantly less in reciprocal MLC tests, compared with the responses seen when their cells were confronted with cells from the DR3, 4 individuals with other genomic DQ beta polymorphisms.

Adult↗

PubMed2004

MCP-1 gene regulatory region polymorphism in Chinese children with mild, moderate and near-fatal asthma.

BACKGROUND: A polymorphism in the monocyte chemoattractant protein 1 (MCP-1) gene regulatory region has been associated with asthma in Caucasians. This polymorphism is possibly endemic to the Asian region, but its impact on Asian populations is unclear. In addition, the relationship of this marker with life-threatening asthma has not been clarified. The aim of this study was to test the genetic association between the MCP-1 -2518A/G polymorphism and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 mild-to-moderate asthmatics, 69 allergic-disorder cases without asthma, and 107 nonasthmatic, nonatopic control children were genotyped by a polymerase chain reaction-based assay. RESULTS: Comparison of the four groups of children (n = 358) revealed no detectable differences in genotype or allele frequencies of the MCP-1 -2518A/G polymorphism. There was no evidence of association between the polymorphism and any of the outcomes of interest including clinical severity, blood eosinophil count, atopy, total serum IgE levels, and degree of bronchial hyper-responsiveness. CONCLUSION: These results suggest that the MCP-1 -2518A/G polymorphism is not a risk factor for near-fatal asthma. Furthermore, this polymorphism seems to play no role in the development of asthma or atopy in Chinese subjects, possibly as a result of the genetic heterogeneity between Asian and Caucasian populations with respect to regulation of MCP-1 expression. Our results underscore the necessity of accounting for ethnic background in the investigation of asthma-predisposition genes.

Asthma↗