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PubMed2002

Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease.

BACKGROUND & AIMS: The clinical manifestations of Crohn's disease (CD) are diverse, ranging from fibrostenosing small-bowel disease to colon-predominant inflammation. These distinctions may represent genetic, immunologic, and microbial heterogeneity. NOD2 gene mutations in CD have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CD. METHODS: Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between 1999 and 2001) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers. RESULTS: Univariate analysis showed that CD-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively). When both cohorts were analyzed together, the association between NOD2 variants and fibrostenosing disease was more significant (P = 0.001). These relationships were observed in both Jews and non-Jews. Forty-six percent of patients with fibrostenosing disease carried at least 1 of these alleles, compared with only 23.5% of patients without fibrostenosing disease (odds ratio, 2.8; 95% confidence interval, 1.6-5.2). Multivariate and conditioning analyses showed a primary association between NOD2 allelic variants and fibrostenosing disease, but not with small-bowel disease. CONCLUSIONS: In this description of a genotype/phenotype correlation in CD patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CD of the small bowel.

Adolescent↗
PubMed2001

Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair.

Melanocortin-1 receptor (MC1R) gene variants are associated with fair skin and red hair and, independently of these, with cutaneous malignant melanoma. The association of MC1R gene variants with nonmelanoma skin cancer is largely unknown. A total of 838 subjects were included in the present study: 453 patients with nonmelanoma skin cancer and 385 subjects with no skin cancer. The coding sequence of the human MC1R gene was tested using single-stranded conformation polymorphism analysis followed by sequencing of unknown variants. Risk of skin cancer dependent on the various MC1R gene variants was estimated using the exposure odds ratio. We investigated whether subjects with MC1R variant alleles were at increased risk of developing nonmelanoma skin cancer and, if so, whether this increased risk was mediated by fair skin and red hair. A total of 27 MC1R gene variants were found. The number of carriers of one, two, or three MC1R gene variants was 379 (45.2%), 208 (24.8%), and 7 (0.9%), respectively. A strong association between MC1R gene variants and fair skin and red hair was established, especially the variants Arg151Cys and Arg160Trp (P < .0001). Carriers of two variant alleles were at increased risk for developing cutaneous squamous cell carcinoma (odds ratio 3.77; 95% confidence interval [CI] 2.11-6.78), nodular basal cell carcinoma (odds ratio 2.26; 95% CI 1.45-3.52), and superficial multifocal basal cell carcinoma (odds ratio 3.43; 95% CI 1.92-6.15), compared with carriers of two wild-type alleles. Carriers of one variant allele had half the risk. The highest relative risks of nonmelanoma skin cancer were found in carriers of the Asp84Glu, His260Pro, and Asp294His variant alleles, and the risk was only slightly lower for carriers of the Val60Leu, Val92Met, Arg142His, Arg151Cys, and Arg160Trp variant alleles. When subjects were stratified by skin type and hair color, analysis showed that these factors did not materially change the relative risks. These findings indicate that MC1R gene variants are important independent risk factors for nonmelanoma skin cancer.

Adult↗
PubMed2005

eNOS G894T polymorphism as a mild predisposing factor for abdominal aortic aneurysm.

OBJECTIVE: Abdominal aortic aneurysm (AAA) represents a chronic degenerative condition associated with atherosclerosis. Actually, data from experimental and clinical studies suggest that nitric oxide (NO) is a modulator in maintaining endothelial function and antithrombotic intravascular environment. Reduced vascular NO generation in subjects carrying the rare variants of the eNOS gene might predispose to AAA. No information is available about the influence of the eNOS gene T-786C, G894T, and 4a/4b polymorphisms in the susceptibility to the disease. METHODS: In this study, we evaluated the role of these polymorphisms in the predisposition to AAA and their influence in hypertensive and normotensive patients. We studied 250 consecutive patients with AAA referred to the Unit of Vascular Surgery of the University of Florence compared with 250 truly healthy subjects with a negative history of vascular diseases. All subjects, patients, and controls, underwent duplex scanning examination, and to assess the presence of other atherosclerotic localizations, all patients underwent clinical and instrumental examinations. RESULTS: A significant difference in genotype distribution and allele frequency was observed for eNOS G894T but not for T-786C and 4a/4b polymorphisms. At the multivariate analysis after adjustment for traditional vascular risk factors and other atherosclerotic localizations, the eNOS 894T variant was significantly associated with AAA, according to dominant and recessive models (dominant model odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.21-3.93, P = .007; recessive model OR: 2.7, 95% CI: 1.42-5.20, P = .002). When patients with other atherosclerotic localizations were excluded from the analysis, the 894T variant still remained associated with the predisposition to AAA, according to the models considered (dominant model OR: 2.1, 95%CI: 1.23-3.92, P = .007; recessive model OR: 2.8, 95%CI: 1.45-5.24, P = .002). CONCLUSIONS: The present study showed that the eNOS G894T polymorphism is a mild modulator of the predisposition to AAA apart from traditional risk factors, suggesting a genetic influence on the molecular mechanisms responsible for this complex disease.

Aged↗
PubMed2000

Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.

Data Interpretation, Statistical↗
PubMed2000

Phenotypic differences between African and white patients with motor neuron disease: a case-control study.

There is increasing evidence that race may affect the phenotype in some neurodegenerative diseases. To investigate this in motor neuron disease a retrospective case-control study has been carried out on 15 negroid African and 45 white patients with the disease seen over 8 years. Each African was compared with three age and sex matched white patients with motor neuron disease. There were no statistically significant differences in age of onset or the mean duration of disease in the two groups. The chance of presenting with the "flail arm" variant of motor neuron disease was four times as high in the African group than the white group (odds ratio 4.33, p=0. 05, 95% confidence interval 0.99-18.92). Although no overall differences in survival were seen between the two groups, in those with the flail arm variant, four out of the six African patients had died whereas all six white arm patients were alive at the censoring date of 1 January 1999 (median follow up 38.5 months). It is concluded that race may influence the phenotype and progression of motor neuron disease.

Africa↗
PubMed2006

ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.

We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.

Alleles↗
PubMed2006

Genetic variants of UGT1A6 influence risk of colorectal adenoma recurrence.

PURPOSE: The UDP glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9) enzymes participate in the metabolism of nonsteroidal anti-inflammatory drugs, endogenous substances, and carcinogens. Functional polymorphisms of UGT1A6 (T181A and R184S) and CYP2C9 (R144C and I359L) have been reported to modify the protective effect of aspirin on colorectal adenoma risk. We aimed to further investigate the effect of these genetic variants on the development of colorectal neoplasia. EXPERIMENTAL DESIGN: We examined the relationship between UGT1A6 and CYP2C9 genotype and colorectal adenoma recurrence in 546 patients participating in a randomized placebo-controlled aspirin intervention trial. RESULTS: Although colorectal adenoma recurrence was not significantly influenced by CYP2C9 genotype, carriers of variant UGT1A6 alleles were at significantly reduced risk of colorectal neoplasia recurrence [relative risk (RR), 0.68; 95% confidence interval (95% CI), 0.52-0.89]. This risk reduction was also evident when the analysis was confined to advanced neoplasia recurrence (RR, 0.71; 95% CI, 0.47-1.09). When patients were stratified by genotype and aspirin intervention, those with variant UGT1A6 alleles were at reduced recurrence risk irrespective of whether they received aspirin or placebo (RR, 0.62; 95% CI, 0.42-0.92 and RR, 0.63; 95% CI, 0.44-0.91, respectively). CONCLUSIONS: These findings confirm that UGT1A6 variants influence colorectal carcinogenesis independent of aspirin intake and suggest that they may have clinical value in secondary prevention programs for patients diagnosed with colorectal adenoma.

Adenoma↗
PubMed2005

A promoter polymorphism (-77T>C) of DNA repair gene XRCC1 is associated with risk of lung cancer in relation to tobacco smoking.

X-ray repair cross complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base-excision repair pathway. Functional Polymorphisms in the XRCC1 gene may lead to decreased DNA repair capacity and thus confer inherited predisposition to cancer risk. In this case-control study of 710 patients with incident lung cancer and 710 cancer-free controls who were frequency matched on age, sex and residential area, we genotyped a novel T>C transition at the promoter region (-77T>C) of XRCC1 and other two common non-synonymous polymorphisms (Arg194Trp and Arg399Gln) to determine their associations with risk of lung cancer. We found that compared with the -77TT wild-type homozygote, the variant genotypes were associated with significantly increased risk of lung cancer [adjusted odds ratio (OR)=1.51; 95% confidence interval (CI)=1.17-1.94 for -77TC; OR=2.98; 95% CI=0.93-9.59 for -77CC; and OR=1.55; 95% CI=1.21-1.98 for -77TC/CC]. By contrast, no significant associations were observed between the other two exonic variants (Arg194Trp and Arg399Gln) and lung cancer risk. Furthermore, we observed a 9.82-fold increased risk (95% CI=5.66-17.02) for heavy smokers carrying the -77C variant (-77TC/CC) and a 4.07-fold increased risk (95% CI=2.85-5.81) for heavy smokers not carrying the variant. However, the interaction between the -77T>C variant and cumulative smoking was not statistically significant (P=0.1560). These findings indicate that the new XRCC1 -77T>C polymorphism may contribute to the aetiology of lung cancer. Further functional studies are warranted to elucidate the underlying molecular mechanisms of the association.

Adenocarcinoma↗
PubMed2005

Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma.

To test the hypothesis that aberrations of DNA repair contribute to susceptibility for the progression of gastroesophageal reflux disease (GERD) into Barrett esophagus (BE) and esophageal adenocarcinoma (EADC), we studied the frequency of polymorphisms of selected DNA repair genes in patients with GERD (n = 126), BE (n = 125) and EADC (n = 56) enrolled in a 2-year prospective case-control study. Controls comprised 95 strictly asymptomatic healthy individuals. Using genomic DNA extracted from blood samples, we identified wild-type and polymorphic variants of XPD (Arg156Arg and Lys751Gln), XRCC1 (Arg194Trp and Arg399Gln) and XRCC3 (Thr241Met), and the poly (AT) insertion/deletion of XPC (PAT). Allelic frequencies were compared between cases and controls using logistic regression to calculate age, gender, smoking and alcohol-adjusted odds ratios (OR) and 95% confidence intervals (CI). Patients with EADC demonstrated a significantly higher frequency of the XPC PAT homozygous variant genotype compared with asymptomatic controls (OR = 3.82; 95% CI = 1.05-13.93). Significantly reduced frequencies were seen for the XPD Lys751Gln homozygous variant genotype in patients with EADC (OR = 0.24; 95% CI = 0.07-0.88), and for the XRCC1 Arg399Gln homozygous variant genotype in patients with BE (OR = 0.38; 95% CI = 0.12-0.64) and GERD (OR = 0.29; 95% CI = 0.12-0.66). We conclude that the malignant phenotype probably results from a summation of polymorphic nucleotide excision repair genes showing opposing effects (an increased risk of XPC versus a protective effect of XPD). The protective effect of the homozygous variant of XRCC1 Arg399Gln for GERD and BE suggests that base excision repair alterations may occur early in progression to EADC, likely in response to GERD-induced endogenous oxidative or inflammatory DNA damage. As GERD and BE are highly prevalent in the general population, this protective effect may well explain why only a fraction of individuals with GERD and BE progress into invasive EADC.

Adenocarcinoma↗
PubMed1999

Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal membranes.

OBJECTIVE: The rarer allele of a polymorphism within the promoter region at position -308 of the gene for tumor necrosis factor alpha is associated with increased gene transcription. In this study we tested the hypothesis that this rarer allele is associated with spontaneous preterm birth. STUDY DESIGN: We conducted a case-control study of women admitted to our labor and delivery unit. To assess data from a single racial group with a high incidence of preterm birth we restricted our analysis to African American women, who contributed 73.6% of the samples collected during the study period. Case patients (n = 55) were defined as women who were delivered before 37 weeks' gestation after idiopathic preterm labor or preterm premature rupture of membranes. Control subjects (n = 110) included women who were delivered after 37 weeks' gestation and had no history of preterm delivery. We also performed subgroup analyses of women with idiopathic preterm labor and delivery (n = 29) and women who were delivered preterm after preterm premature rupture of the fetal membranes (n = 26). RESULTS: Although carriers (homozygotes plus heterozygotes) of the rarer allele of the polymorphism at position -308 in the gene for tumor necrosis factor alpha were not significantly more common among women who were delivered preterm (n = 24/55, 44%) than among control subjects (n = 33/110, 30%, P =.08, odds ratio 1.81, 95% confidence interval 0.92-3.54), carriers of the rarer allele were more common among women who were delivered preterm after preterm premature rupture of membranes (n = 15/26, 58%) than among control subjects (P =.008, odds ratio 3.18, 95% confidence interval 1.33-7.83). CONCLUSIONS: Our results demonstrate an association between allelic variants of the polymorphism at position -308 in the gene for tumor necrosis factor alpha and preterm birth after preterm premature rupture of the fetal membranes. We hypothesize that host susceptibility to environmental factors, such as hyperresponsiveness of the gene for tumor necrosis factor alpha to genital tract infection, may promote preterm premature rupture of the fetal membranes and subsequent preterm delivery.

Adolescent↗
PubMed1999

Prevalence of temporomandibular joint disk displacement in infants and young children.

OBJECTIVE: The purpose of this study was to determine the prevalence of temporomandibular joint disk displacement in infants and young children. STUDY DESIGN: Magnetic resonance images were obtained of the temporomandibular joints in 30 infants and young children ranging in age from 2 months to 5 years (median age, 3 years; mean age, 2.5 years). RESULTS: All joints had normal superior disk position. The computed 95% confidence interval was 0.00-0.06, which implies a minimal probability that disk displacement would occur in this age group. CONCLUSIONS: The result contradicts previous suggestions that temporomandibular joint disk displacement could represent a congenital normal anatomic variant.

Argentina↗
PubMed2005

Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis.

Several studies have identified the PTPN22 allelic variant 1858 C/T that encodes the R620W amino-acid change as a putative susceptibility factor in autoimmune diseases. The current study was undertaken to examine a large cohort of Finnish rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) subjects using both population control and, importantly, family-based association methods. The latter is particularly important when, as is the case for the 1858 C/T polymorphism, the frequency of the variant allele (T) differs in both major ancestral populations and in subpopulations. The analysis of rheumatoid factor-positive 1030 RA probands from Finland provides strong support for association of this variant in both population studies (allele specific odds ratio (OR)=1.47, 95% confidence interval (CI)=1.27-1.70, P=3 x 10(-7)) and in family studies (P<10(-6)). In contrast, no allelic association was seen with JIA (230 probands) and only weak evidence for a genotypic effect of 1858T homozygotes was observed in this population.

Alleles↗
PubMed2003

BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy that starts in adolescence. A major JME susceptibility locus (EJM1) was mapped to chromosomal region 6p21 in three independent linkage studies, and association was reported between JME and a microsatellite marker in the 6p21 region. The critical region for EJM1 is delimited by obligate recombinants at HLA-DQ and HLA-DP. In the present study, we found highly significant linkage disequilibrium (LD) between JME and a core haplotype of five single-nucleotide-polymorphism (SNP) and microsatellite markers in this critical region, with LD peaking in the BRD2 (RING3) gene (odds ratio 6.45; 95% confidence interval 2.36-17.58). DNA sequencing revealed two JME-associated SNP variants in the BRD2 (RING3) promoter region but no other potentially causative coding mutations in 20 probands from families with positive LOD scores. BRD2 (RING3) is a putative nuclear transcriptional regulator from a family of genes that are expressed during development. Our findings strongly suggest that BRD2 (RING3) is EJM1, the first gene identified for a common idiopathic epilepsy. These findings also suggest that abnormalities of neural development may be a cause of common idiopathic epilepsy, and the findings have implications for the generalizability of proposed pathogenetic mechanisms, derived from diseases that show Mendelian transmission, to their complex counterparts.

Adolescent↗
PubMed2006

Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma.

The caspase proteins are essential for the regulation of normal B cell development and regulation of apoptosis. We investigated five single nucleotide polymorphisms in four key caspase genes, CASP3 [Ex8-280C>A (rs6948) and Ex8+567T>C (rs1049216)], CASP8 Ex14-271A>T (rs13113), CASP9 Ex5+32G>A (rs1052576) and CASP10 Ex3-171A>G (rs3900115) to determine whether they alter risk for non-Hodgkin lymphoma (NHL) in a population-based case-control study of women in Connecticut (461 cases and 535 controls). Variants in CASP3 and CASP9 were significantly associated with a decreased risk for NHL, particularly follicular lymphoma [e.g. CASP3 Ex8+567T>C odds ratio (OR)(CC+TC) = 0.4, 95% confidence interval (CI) = 0.3-0.7; and CASP9 Ex5+32G>A OR(AA+AG) = 0.6, 95% CI = 0.4-1.0]. Further, variants in CASP3, CASP8 and CASP10 were associated with a decreased risk of marginal zone lymphoma and variants in CASP3 and CASP10 were associated with a lower risk of chronic lymphocytic leukemia and related subtypes. The striking protective associations observed for polymorphisms in all four genes for NHL and/or one or more subtypes suggest that genetic variation in CASP genes may play an important role in the etiology of NHL.

Adult↗
PubMed2004

In vitro evolution predicts that the IMP-1 metallo-beta-lactamase does not have the potential to evolve increased activity against imipenem.

In vitro evolution was used to predict whether the IMP-1 metallo-beta-lactamase has the potential to evolve an increased ability to confer resistance to imipenem. Screening of eight libraries containing 9.8 x 10(6) +/- 1.4 x 10(6) (mean +/- standard error) variants per library, with an average of 1.2 mutations per variant, detected no increased resistance to imipenem. The results predict, with >99.9% confidence, that even under intense selection the IMP-1 beta-lactamase will not evolve to confer increased resistance to imipenem.

Biological Evolution↗
PubMed2006

Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer.

The Ala(222)Val single nucleotide polymorphism (SNP) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in one-carbon metabolism, has been associated with colorectal cancer risk. Many enzymes are involved in one-carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-carbon metabolism pathway in relation to the risk of colorectal cancer in a case-control study nested in the Nurses' Health Study and the Health Professionals Follow-up Study cohorts. Among 376 men and women with colorectal cancer and 849 controls, a reduced risk of colorectal cancer was observed for Val/Val versus Ala carriers of MTHFR Ala(222)Val [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.43-1.00]. An increased risk was suggested for the variant carrier genotypes versus homozygous wild-type for betaine hydroxymethyltransferase Arg(239)Gln (OR, 1.40; 95% CI, 1.07-1.83) and two linked SNPs in methionine synthase reductase, Ser(284)Thr (OR, 1.85; 95% CI, 1.05-3.27) and Arg(415)Cys (OR, 2.03; 95% CI, 1.15-3.56). The other SNPs were not associated with colorectal cancer risk. Also, none of the SNPs were associated with risk in subgroups of dietary methyl status or were jointly associated with colorectal cancer risk in combination with another SNP, except possibly SNPs in methionine synthase and transcobalamin II. However, these analyses of gene-diet interactions were limited in statistical power. Our results corroborate previous findings for MTHFR Ala(222)Val and suggest that other genes involved in one-carbon metabolism, particularly those that affect DNA methylation, may be associated with colorectal cancer risk.

Adult↗
PubMed2006

Lack of association between inherited thrombophilic risk factors and idiopathic sudden sensorineural hearing loss in Italian patients.

OBJECTIVES: We investigated the presence of congenital thrombophilic risk factors in a population of consecutive Italian patients affected by idiopathic sudden sensorineural hearing loss (SSNHL). METHODS: We investigated 48 patients with idiopathic SSNHL for the presence of congenital thrombophilic risk factors. The factor V Leiden G1691A, the prothrombin G20210A allele, and methylenetetrahydrofolate reductase (MTHFR) C677T genotypes were investigated. Allele frequencies and genotype distribution of all factors found in patients were compared to those of 48 healthy subjects of the same ethnic background by Chi2 and odds-ratio analysis. Odds ratios and 95% confidence intervals were calculated for allele and genotype frequencies of all thrombophilia variants. Statistical significance was accepted with a p value of less than .05. We also performed the following blood tests: hemacytometric analysis including platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, erythrocyte sedimentation rate, C-reactive protein, protein S, protein C, antithrombin III, and activated protein C resistance. RESULTS: In our series, we did not find an association between SSNHL and abnormal levels of antithrombin III, protein C, protein S, D-dimer, or fibrinogen; activated protein C resistance; or factor V G1691A, prothrombin G20210A, or MTHFR C677T mutations. CONCLUSIONS: At present, the few studies regarding genetic polymorphisms of congenital thrombophilic factors in SSNHL are not conclusive. According to our data, factor V G1691A, prothrombin G20210A, and MTHFR C677T variants should be not considered risk factors for SSNHL. Further large prospective studies are needed to provide currently lacking information and to improve our knowledge in the field before we recommend the determination of genetic polymorphism in SSNHL as routine practice.

Adolescent↗
PubMed2005

Genotypes and haplotypes of the methyl-CpG-binding domain 2 modify breast cancer risk dependent upon menopausal status.

INTRODUCTION: MBD2, the gene encoding methyl-CpG-binding domain (MBD)2, is a major methylation related gene and functions as a transcriptional repressor that can specifically bind to the methylated regions of other genes. MBD2 may also mediate gene activation because of its potential DNA demethylase activity. The present case-control study investigated associations between two single nucleotide polymorphisms (SNPs) in the MBD2 gene and breast cancer risk. METHODS: DNA samples from 393 Caucasian patients with breast cancer (cases) and 436 matched control individuals, collected in a recently completed breast cancer case-control study conducted in Connecticut, were included in the study. Because no coding SNPs were found in the MBD2 gene, one SNP in the noncoding exon (rs1259938) and another in the intron 3 (rs609791) were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate cancer risk associated with the variant genotypes and the reconstructed haplotypes. RESULTS: The variant genotypes at both SNP loci were significantly associated with reduced risk among premenopausal women (OR = 0.41 for rs1259938; OR = 0.54 for rs609791). Further haplotype analyses showed that the two rare haplotypes (A-C and A-G) were significantly associated with reduced breast cancer risk (OR = 0.40, 95% CI = 0.20-0.83 for A-C; OR = 0.47, 95% CI = 0.26-0.84 for A-G) in premenopausal women. No significant associations were detected in the postmenopausal women and the whole population. CONCLUSION: Our results demonstrate a role for the MBD2 gene in breast carcinogenesis in premenopausal women. These findings suggest that genetic variations in methylation related genes may potentially serve as a biomarker in risk estimates for breast cancer.

Binding Sites↗