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PubMed2004

Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer.

Inflammation plays a key role in the development of colorectal cancers. We have investigated the relationship between PTGS2 (COX2) polymorphisms and colorectal cancer risk in a hospital based case-control study. We recruited 292 patients with colorectal cancer and 274 controls from new patients admitted to Bellvitge Hospital, Barcelona, Spain, from 1996 to 1998. Subjects responded to a questionnaire on risk factors. Genotypes of the eight more frequent polymorphisms of PTGS2 were determined. Two polymorphisms are located in the promoter sequence, one in the untranslated region of exon 1, one in exon 3, one in intron 5, two in the untranslated region of exon 10, and one downstream of the last polyadenylation (poly-A) signal. Associations were analysed with logistic regression models assuming a dominant effect for rare variants to increase statistical power. An association was detected between colorectal cancer and a polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01. A nearby polymorphism downstream of the last poly-A signal also showed a nonsignificant increase in risk (OR 2.17, 95% CI 0.99-4.78, P=0.05). Analysis of haplotypes confirmed that individuals with these variants were at increased risk of colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97-4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti-inflammatory drugs and risk of colorectal cancer were also explored.

Adult↗

PubMed2007

Complement factor H polymorphism p.Tyr402His and cuticular Drusen.

OBJECTIVE: To determine the histidine frequency in patients with the cuticular drusen phenotype of age-related macular degeneration (AMD). METHODS: Fifty individuals were identified who met the criteria for the cuticular drusen phenotype using a standard threshold photograph. We genotyped DNA samples using a polymerase chain reaction-based restriction digest assay. Seven hundred individuals with typical AMD and 252 controls were also genotyped. Fisher exact test was used to analyze the significance of allele frequency differences. RESULTS: The histidine variant was present in 70% (frequency +/- SE, 0.70 +/- 0.05) of the cuticular cohort, 55% (frequency +/- SE, 0.55 +/- 0.01) of the more typical AMD cases, and 34% (frequency +/- SE, 0.34 +/- 0.02) of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = .003; odds ratio, 2.0; 95% confidence interval, 1.21-3.07; vs AMD cases P<.001; odds ratio 4.54; 95% confidence interval, 2.79-7.50; vs controls). Genotype distribution between the 3 groups was similarly significant (P<.001). CONCLUSION: The cuticular drusen phenotype is highly associated with the Tyr402His variant of the complement factor H (CFH) gene. The significantly higher histidine allele frequency in this group compared with the typical AMD cohort suggests that the complement cascade may play a greater role in the pathogenesis of the cuticular drusen subtype than in AMD as a whole. CLINICAL RELEVANCE: The c.1204T>C, p.Tyr402His allelic variant in the CFH gene is associated with a 3-fold increased risk for AMD. A high frequency of the histidine allele has also been noted in patients with membranoproliferative glomerulonephritis type II.

Adult↗

PubMed2006

Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan.

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both are implicated in carcinogenesis. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate cancer-predisposing factor. To evaluate the C677T and A1298C functional polymorphisms in the MTHFR gene and their associations with breast cancer risk, as well as the potential modifying effect by plasma folate status on the MTHFR-associated risk, a hospital-based case-control study was conducted on a Taiwanese population consisting of 146 histologically confirmed incident breast cancer cases and their 285 age-matched controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping and RIA was used to measure the plasma folate. Statistical evaluations were performed using logistic regression analysis. The plasma folate level was inversely associated with breast cancer risk with an adjusted odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.26-1.05] observed among women who were in the highest plasma folate tertile. The MTHFR 677T and 1298C variant alleles were associated with decreased risk for breast cancer [adjusted ORs were 0.81 (95% CI: 0.54-1.21) and 0.57 (95% CI: 0.36-0.89) for 677CT + TT genotypes and 1298AC + CC genotypes, respectively]. Furthermore, compound heterozygote and homozygote variants (677CT + TT and 1298AC + CC) had greater reduced risk (adjusted OR: 0.11, 95% CI: 0.03-0.43) among women with lower plasma folate levels. These results provide support for the important role of folate metabolism in breast tumorigenesis. Further mechanistic studies are warranted to investigate how MTHFR combined genotypes exert their effect on cancer susceptibility.

Adult↗

PubMed2007

Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors.

PURPOSE: There is a paucity of data quantifying the familial risk of colorectal cancer associated with mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories. EXPERIMENTAL DESIGN: Constitutional DNA from probands was systematically screened for MYH variants and those with cancers displaying microsatellite instability (MSI) for germ-line MMR mutations; diagnoses of familial adenomatous polyposis and juvenile polyposis were established based on clinical phenotype and mutational analysis. Familial colorectal cancer risks were enumerated from age-, sex-, and calendar-specific population incidence rates. Segregation analysis was conducted to derive a model of the residual familial aggregation of colorectal cancer. RESULTS: Germ-line predisposition to colorectal cancer was identified in 37 probands [3.4%; 95% confidence interval (95% CI), 2.4-4.6]: 29 with MLH1/MSH2 mutations, 2 with familial adenomatous polyposis, 1 with juvenile polyposis, and 5 with biallelic MYH variants. The risk of colorectal cancer in first-degree relatives of probands with MSI and MMR-stable cancers was increased 5.01-fold (95% CI, 3.73-6.59) and 1.31-fold (95% CI, 1.07-1.59), respectively. MSH2/MLH1 mutations were responsible for 50% of the overall excess familial risk and 80% of the risk associated with MSI cancers but 32% of the familial risk was unaccounted for by known loci. Genetic models based on major gene loci did not provide a better explanation of the residual familial aggregation than a simple polygenic model. CONCLUSIONS: The information from our analyses should be useful in quantifying familial risks in clinical practice and in the design of studies to identify novel disease alleles.

Adenomatous Polyposis Coli↗

PubMed1997

High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers.

Allelic variants at the catechol-O-methyltransferase (COMT) locus are candidates to contribute to genetic components of interindividual differences in vulnerability to substance abuse. COMT plays a prominent role in dopaminergic circuits important for drug reward, and COMT alleles encode enzymes whose activities vary from three- to four-fold. We compared COMT allele frequencies in control research volunteers reporting insignificant lifetime use of addictive substances with those in volunteers reporting substantial polysubstance use. Homozygosity for the high-activity COMT allele was found in 18% of controls, 31% of volunteers with high lifetime substance use, and 39% meeting DSMIII-R substance abuse criteria [odds ratio (relative risks) 2.0 (control vs. use; 95% confidence interval 1.2-3.5; P < 0.013) and 2.8 (control vs. DSM; 1.3-6.1; P < 0.008)]. Individuals with the high-activity COMT variant may have greater genetic vulnerability to drug abuse.

Alleles↗

PubMed2001

Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia.

Epidemiological studies have been inconsistent regarding a role for folate in the etiology of cervical dysplasia. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. A common variant of this enzyme, resulting from a 677C-->T (Ala-->Val) substitution in the gene, has been shown to have reduced activity and is associated with mild hyperhomocysteinemia. A multiethnic case-control study was used to examine the association of dietary folate and MTHFR genotype with the odds ratios (ORs) for cervical dysplasia among women identified from several clinics on Oahu, Hawaii, between 1992 and 1996. We collected blood samples for DNA extraction, cervical smears for cytological diagnosis, exfoliated cervical cells for human papillomavirus (HPV) DNA testing, and personal interviews from 150 women with squamous intraepithelial lesions (SILs) and from 179 women with cytologically normal (Pap) smears. We found a positive, monotonic trend (P = 0.02) in the ORs for cervical SILs associated with the number of variant MTHFR T alleles, after multivariate adjustment. Women with the heterozygous CT genotype had twice the risk of cervical SILs [OR, 2.0; 95% confidence interval (CI), 1.1-3.7], and women with the homozygous TT genotype had almost three times the risk of SILs (OR, 2.9; 95% CI, 1.0-8.8) compared to women with the homozygous MTHFR CC genotype. The dietary intakes of folate, vitamin B(6), and vitamin B(12) were inversely related to the ORs for cervical SILs, after adjustment for HPV DNA and other confounders. The OR among women in the highest quartile compared with women in the lowest quartile of folate intake was 0.3 (95% CI, 0.1-0.7; P for trend = 0.002). Women with the variant T allele and folate intakes below the median were at significantly elevated risk of cervical SILs (OR, 5.0; 95% CI, 2.0-12.2) compared to women with CC alleles and folate intakes above the median. HPV infection was a strong risk factor for cervical dysplasia, particularly among women with the variant T allele (OR, 46.6; 95% CI, 15.9-136.2). All associations of MTHFR genotype with the ORs for cervical SILs were independent of other risk factors under study. These findings suggest that the MTHFR T allele and reduced dietary folate may increase the risk for cervical SILs.

Adult↗

PubMed2003

The I1307K adenomatous polyposis coli gene variant does not contribute in the assessment of the risk for colorectal cancer in Ashkenazi Jews.

Ashkenazi Jews with the I1307K adenomatous polyposis coli gene variant were suggested to confer a higher risk for colorectal cancer (CRC). We assessed the clinical importance of this polymorphism in Israeli Jews at average and elevated risk for CRC. Among 1,370 consecutive subjects that were examined, 975 Ashkenazi Jews were stratified into those at average risk (no personal or family history of colorectal neoplasia) and those at high risk. DNA was obtained from peripheral leukocytes and amplified by PCR, with primers designed to detect the I1307K variant. Overall, I1307K polymorphism was found in 7.1% (9.1% among Ashkenazi and 1.7% among non-Ashkenazi Jews). The carrier rate was 8.3 and 9.3% in average and high-risk Ashkenazim, respectively (P = 0.65). The overall odds ratio for neoplasia in carriers was 1.43 (95% confidence interval, 0.89-2.30). Age, gender, and the histopathological features of adenomas and cancers did not differ between carriers and noncarriers. No interaction on the CRC risk was found between I1307K variant and lifestyle modifiers (such as cigarette smoking, alcohol consumption, high body mass index, low physical activity, and vitamins/antioxidant intake). The I1307K adenomatous polyposis coli gene variant is not an important marker for increased risk for CRC. It confirms previous reports of a slight nonsignificant increase (OR, 1.4) in the risk of CRC in these carriers. There is no interaction effect on the risk of colorectal neoplasia between the I1307K variant and various lifestyle risk factors. The usual recommended screening and surveillance strategies should be used for carriers of this polymorphism.

Adenomatous Polyposis Coli Protein↗

PubMed2005

Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer.

BACKGROUND & AIMS: Overexpression of cyclooxygenase-2 (COX-2) is implicated in many steps of cancer development. Single nucleotide polymorphisms (SNPs) in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. This study sought to identify functional SNPs in the COX-2 promoter and evaluated their effects on the risk of developing esophageal squamous cell carcinoma (ESCC). METHODS: Thirty individual DNA samples were sequenced to search for SNPs, and the function of the SNPs was examined by a set of biochemical assays. Genotypes and haplotypes were analyzed in 1026 patients and 1270 controls, and odds ratios and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: Three SNPs, -1290A-->G, -1195G-->A, and -765G-->C, were identified; the frequencies of variant alleles were 0.04, 0.51, and 0.02, respectively. The -1195G-->A change creates a c-MYB binding site and displays a higher promoter activity. The -1195A-containing haplotypes had significantly increased luciferase expression and COX-2 messenger RNA levels in esophageal tissues compared with the -1195G-containing counterparts. A case-control analysis showed a 1.72-fold (95% CI, 1.35-2.20) and 2.24-fold (95% CI, 1.59-3.16) excess risk of developing ESCC for the -1195AA or -765CC genotype carriers compared with noncarriers. A greater risk of developing ESCC was observed for A(-1195)-C(-765)-containing haplotypes compared with G(-1195)-G(-765)-containing haplotypes, suggesting an interaction between the -1195G-->A and -765G-->C polymorphisms in the context of haplotype. CONCLUSIONS: These findings indicate that genetic variants in COX-2 may play a role in mediating susceptibility to esophageal cancer.

Adult↗

PubMed2006

Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer.

Impaired base-excision repair (BER) function can give rise to the accumulation of DNA damage and initiation of cancer. We evaluated whether genetic variation in six BER pathway genes (XRCC1, ADPRT, APEX1, OGG1, LIG3, and MUTYH) is associated with breast cancer risk in two large population-based case-control studies in the United States (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). A detailed evaluation was first done in a subset of 1,898 cases and 1,514 controls with mouthwash DNA samples in the U.S. study. Significant findings were followed up in the remainder of the U.S. study population that provided cytobrush DNA samples and in the Polish study. Using data from U.S. study participants with mouthwash DNA, we found no significant overall association between breast cancer risk and XRCC1 R280H and R194W, ADPRT V726W, APEX1 D148E, OGG1 S326C, LIG3 R780H, or MUTYH 5' untranslated region. These data suggested a decreased risk for XRCC1Q399R homozygous variants compared with homozygous wild-type in premenopausal women, but these findings were not confirmed when data from cytobrush DNA samples were added [combined odds ratio (OR), 0.8; 95% confidence interval (95% CI), 0.6-1.1] or in the Polish study (OR, 1.0; 95% CI, 0.7-1.5). Meta-analyses based on our data and published data from studies of two single nucleotide polymorphisms in XRCC1 showed no evidence of an overall association between breast cancer risk and homozygous variants versus wild-type for Q399R (OR, 1.1; 95% CI, 1.0-1.2) or R194W (OR, 1.0; 95% CI, 0.7-1.8), although there was a suggestion for an association in Asian populations for Q399R (OR, 1.6; 95% CI, 1.1-2.4; P = 0.02). In conclusion, our results do not support that the polymorphisms evaluated in six BER pathway genes play a major role in breast carcinogenesis, particularly in Caucasian populations.

Adult↗

PubMed2004

Variation of the McKusick-Kaufman gene and studies of relationships with common forms of obesity.

Obesity is a prominent feature of the Bardet-Biedl syndrome (BBS), one subset of which, BBS6, is due to mutations in the chaperonin-like gene termed the McKusick-Kaufman syndrome (MKKS) gene. We tested whether variation in MKKS contributes to common and probably polygenic forms of obesity by performing mutation analysis of the coding region in 60 Danish white men with juvenile-onset obesity. Five variants were identified, including two synonymous mutations (Pro(39)Pro and Ile(178)Ile) and three nonsynonymous variants (Ala(242)Ser, Arg(517)Cys, and Gly(532)Val). Furthermore, the rare Ala(242)Ser was identified in two families and showed partial cosegregation with obesity. The Pro(39)Pro, Ile(178)Ile, and Arg(517)Cys variants are in complete linkage disequilibrium and defined a prevalent haplotype. In a case-control study, the Arg(517)Cys polymorphism allele prevalence was 11.4% [95% confidence interval (CI), 9.7-13.0] among 744 men with juvenile-onset obesity and 9.3% (CI, 7.9-10.7) among 867 control subjects (P = 0.048). However, among middle-aged men the allelic prevalence was 9.7% (CI, 7.9-11.4) among 523 obese men and 12.2% (CI, 10.8-13.6) among 1051 lean men (P = 0.037). In conclusion, it is unlikely that MKKS variants play a major role in the pathogenesis of nonsyndromic obesity, although in rare cases the A242S allele may contribute to obesity.

Adolescent↗

PubMed2000

Association of the TNF-alpha-308 (G-->A) polymorphism with self-reported history of childhood asthma.

Asthma is a complex disease involving genetic and environmental aetiology. The tumour necrosis factor-alpha (TNF-alpha) and angiotensin-converting enzyme (ACE) genes have been implicated in asthma pathogenesis. This study investigated the association of a G-308A variant of TNF-alpha and an insertion/deletion (I/D) variant of ACE with a self-reported history of childhood asthma, in two population groups. At Northwick Park Hospital, London, 1,811 pregnant women attending for antenatal care were recruited. Participants with a self-reported history of childhood asthma, determined by a researcher-administered questionnaire, and controls with no personal or family history of asthma, of UK/Irish (cases n=20; controls n=416) and South Asian (cases n=6; controls n=275) origin were used in this study. Participants were genotyped for the TNF-alpha-308 and ACE I/D variants by a PCR-RFLP and PCR approach. The TNF-alpha-308 allele 2 (-308A) was significantly associated with self-reported childhood asthma in the UK/Irish (Odds ratios (OR): 2.6; 95% confidence intervals (CI): 1.1-6.2; P=0.03) but not in the South Asian population. The ACE DD genotype was not associated with childhood asthma in either population group. Gametic phase disequilibrium between the TNF-alpha-308 and ACE I/D variants was significantly different from zero in UK/Irish cases (delta=0.09; P=0.034). The TNF-alpha308 allele 2 or a linked major histocompatibility complex (MHC) variant may be a genetic risk factor for childhood asthma in the UK/Irish sample.

Adenine↗

PubMed2024

Increased risk of hearing loss associated with MT-RNR1 gene mutations: a real-world investigation among Han Taiwanese Population.

BACKGROUND: Previous studies have implicated inherited mutations in mitochondrial DNA (mtDNA) in sensorineural hearing loss (SNHL). However, the definitive association between mitochondrial 12S rRNA (MT-RNR1) variants and hearing loss in the population has not been well established, particularly in Asia. The objective of this retrospective cohort study was to assess the association between MT-RNR1 variants and the risk of SNHL in patients in Taiwan. METHODS: The cohort included 306,068 participants from Taiwan between January 2003 and December 2020. Participants were classified based on genetic variants, particularly mitochondrial mutations (rs267606618, rs267606619, rs267606617). MT-RNR1 variant cases were matched 1:10 with non-mutant patients by age, gender, and visit year, excluding those with pre-existing hearing loss. The primary endpoint was SNHL, identified using specific ICD-TM codes with a 90% positive predictive value. Medication exposure history was determined via self-report or electronic medical records in the hospital. Cox proportional hazard regression models were used to assess the association between MT-RNR1 variants and hearing loss, adjusting for various covariates. Kaplan-Meier survival curves and log-rank tests compared hearing loss incidence between groups. RESULTS: The mean age of the mtDNA variants group is 32.4 years, with a standard deviation of 19.2 years. The incidence density of hearing loss for the mutation group was 36.42 per 10,000 person-years (95% Confidence Interval [CI], 27.21-47.73), which was higher than the 23.77per 10,000 person-years (95% CI, 21.32-26.42) in the wild-type group (p = 0.0036). Additionally, diabetes mellitus was associated with an increased risk of developing SNHL in individuals with MT-RNR1 variants (adjusted hazard ratio = 1.76 [95% CI, 1.00-3.09], p < 0.05). CONCLUSION: This study highlights the increased risk of hearing loss in patients carrying MT-RNR1 variants, particularly those with diabetes mellitus. Future research that integrates genetic and clinical data is crucial for developing more precise interventions to monitor and treat hearing loss in this vulnerable population.

Adolescent↗

PubMed2005

Variation in the alpha2B-adrenergic receptor gene (ADRA2B) and its relationship to vascular response in vivo.

The alpha2B-adrenergic receptor (ADRA2B) plays an important role in vasoconstriction and blood pressure regulation. One common variant in the ADRA2B gene (del 301--303) has been identified, and results in markedly decreased receptor desensitization in vitro but does not alter vascular sensitivity in vivo. Therefore, we fully characterized genetic variations in ADRA2B and related them to phenotype in vivo. We examined 5812 bp of contiguous sequence of ADRA2B (promoter, exonic, and 3'-untranslated region; 3'-UTR) using the polymerase chain reaction to amplify the genomic target followed by bidirectional sequencing (n=68). Haplotypes were inferred using an expectation maximization algorithm. Vasoconstriction in response to increasing doses of the highly selective alpha2-adrenergic receptor agonist, dexmedetomidine (0.01--1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) was determined for each subject from the individual dose--response curves. ED50 and Emax were compared in subjects with and without variant alleles and haplotypes of interest. We identified 24 variable sites, 12 in the promoter region, five in the coding region (including two previously described as non-synonymous variants) and seven in the 3'-UTR region. Four haplotypes were inferred, representing approximately 95% of the cohort. One haplotype, characterized by two single nucleotide polymorphisms in the promoter region, and one in the 3'-UTR, occurred in seven of 38 African-Americans, and was associated with a lower Emax, 61.3% [95% confidence interval (CI) 39.5--83.0, n=7] compared to 78.1% (CI 73.8--82.5) in wild-types (n=61) (P=0.02). There was no association between the nine common variants and dexmedetomidine ED50. We have described novel variants and haplotypes of the ADRA2B gene. These do not alter sensitivity to a selective alpha2-adrenergic receptor agonist but some may decrease maximal venoconstriction in vivo.

Adolescent↗

PubMed1999

Evidence for differences in MT2 cell tropism according to genetic subtypes of HIV-1: syncytium-inducing variants seem rare among subtype C HIV-1 viruses.

Non-syncytium-inducing (NSI) variants seem to be more readily transmitted than syncytium-inducing (SI) variants, and the switch from NSI to SI during HIV-1 infection seems to be a key determinant to the evolution of AIDS. We investigated eventual differences in the SI capacity on MT-2 cells according to genetic subtypes of HIV-1 and correlated this observations with CD4 counts and duration of HIV infection. In total, 86 patients, most with known date of HIV contamination and infected with different genetic subtypes, have been studied: 11 subtype A, 46 subtype B, 22 subtype C, and 7 subtype E. Multivariate analysis used a Cox's proportional hazards regression. The number and percentage of patients infected with an SI strain were as follows: 3 of 11 (27%) for subtype A, 15 of 46 (33%) for subtype B, 0 of 22 (0%) for subtype C, and 5 of 7 (71%) for subtype E. After adjustment for time after seroconversion and CD4 counts, significantly fewer SI variants were observed in patients infected with subtype C (p < .002) and it was found that subjects infected with subtype E had a higher risk of being infected with an SI strain (rate ratio [RR] = 12.39%; 95% confidence interval [CI] 1.55-98.67; p < .001). Most of the subtype E-infected patients from our study switched from an NSI to SI phenotype early after seroconversion (<4 years). To predict the in vitro presence of SI variants, we scanned V3-loop sequences for mutations at positions 11 and/or 25. Overall, 54 of 55 (98.2%) NSI strains in vitro were predicted NSI, and only 4 of 12 (33.3%) of SI viruses were predicted SI. For patients in whom a switch from an NSI to an SI virus was observed, the SI phenotype could be detected earlier in vitro than by the corresponding V3-loop sequence. No SI strains were observed among patients infected with subtype C; however, longer follow-up is needed to see whether the appearance of SI variants in subtype E or the absence of SI variants in subtype C-infected patients is also associated respectively with a faster or slower progression to AIDS as described for subtype B.

Amino Acid Sequence↗

PubMed2005

Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites.

OBJECTIVE: To confirm the association of 2 variants of the Frizzled-related protein gene (FRZB) with osteoarthritis (OA) of the hip, and to investigate whether these variants also associate with other heritable generalized OA phenotypes. METHODS: An association analysis of 2 variants (R200W and R324G) of FRZB was performed in a random sample of 1,369 subjects (ages 55-70 years) from a population-based cohort (the Rotterdam Study) scored for radiographic characteristics of OA in the hip, hand, spine, and knee and in a patient population of Caucasian probands (ages 40-70 years) and their siblings selected for the presence of primary symptomatic OA at multiple sites. RESULTS: The allele frequency of the 2 variants was not significantly different between subjects with hip radiographic OA (ROA) and controls. The frequency of the G allele of the R324G variant was significantly increased in subjects with generalized ROA from the Rotterdam Study (0.10) and in subjects from the Genetics, osteoARthritis and Progression study (0.11) compared with that in controls from the Rotterdam Study (0.08). Carriers of this G allele had increased susceptibility for generalized ROA (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 0.9-1.9, P = 0.10) or familial symptomatic OA at multiple sites (OR 1.6, 95% CI 1.1-2.3, P = 0.02). CONCLUSION: Our results confirm that the R324G variant of the FRZB gene is involved in OA and indicate a role of this variant in several generalized OA phenotypes. A more extended OA phenotype may indeed be expected from genetic variation in an essential pathway of skeletal development such as Wnt signaling.

Adult↗

PubMed1989

Nasal cerebral heterotopia: the so-called nasal glioma or sequestered encephalocele and its variants.

Twenty two nasal cerebral heterotopias were compared with 11 nasal encephaloceles. No histological feature was found that would allow a communication with the brain to be confidently identified or excluded. Even laminated cerebral cortex with neurones and ependymal canals, suggestive of encephalocele, were found in heterotopias. Distinction required radiological and surgical evidence. However, CT scan could be misleading, in one infant suggesting a cribriform plate defect when none was found at craniotomy. Three children had multiple extracranial glial lesions, two with both heterotopia and encephalocele in the same patient. In a few older children it was extremely difficult to identify brain tissue because of marked replacement by fibrous tissue (up to 95%), leading to one misdiagnosis as fibroma, and considerable fibrosis occurred also in five of six recurrences and in a longstanding small encephalocele. In two heterotopias, cellularity in places approached that of low-grade neoplastic glioma. One nasopharyngeal heterotopia contained multiple mesenchymal tissues suggestive of teratoma. Two midline nasopharyngeal encephaloceles showed adjacent epithelium, possibly vestiges of Rathke's pouch.

Brain↗

PubMed2002

Waf-1 (p21) and p53 polymorphisms in breast cancer.

p53 is a transcription factor for Waf-1/p21, a cyclin-dependent kinase inhibitor. Certain polymorphic variants of Waf-1 and p53 have been evaluated for their association with cancer risk. Previous studies indicated that certain p53 polymorphisms confer an increased risk of breast cancer [odds ratios (ORs) and 95% confidence intervals (CIs) = 2.9, 1.4-6.3 Carcinogenesis (Lond.), 17: 1313, 1996; 2.5, 1.3-4.8 Cancer Epidemiol. Biomark. Prev., 6: 105, 1997; and 1.5, 1.1-2.0, Anticancer Res., 18: 2095, 1998). The primary objectives of this study were to test the hypotheses that the serine variant (codon 31 polymorphism) of Waf-1 is also involved in this process and that there is an interaction between Waf-1 and p53 polymorphisms. To do this, Waf-1 and p53 genotypes were determined for women enrolled in a breast cancer case-control study (Caucasians, African-Americans and Latinas; 487 Waf-1 and 504 p53 genotypes were obtained). Multivariate logistic regression was used to evaluate possible associations between Waf-1 and p53 polymorphisms, race, and menopause. The primary aim was to determine whether an interaction between Waf-1 and p53(1-2-1) existed. Whereas multivariate analysis suggested associations between breast cancer and inheritance of Waf-1(ser31) in African-Americans (OR, 2.32; 95% CI = 0.66-5.60; n = 37 cases and 65 controls) and Latinas (OR, 2.22; 95% CI = 0.71-6.89; n = 30 cases and 75 controls), and inheritance of p53(1-2-1) in Caucasians (OR, 3.15; 95% CI = 1.14-8.89; n = 93 cases and 187 controls), we did not see an interaction between Waf-1(ser31) and p53(1-2-1). Consistent with the finding that p53(1-2-1) is a risk factor for Caucasian women was the observation of a strong interaction between race and p53 (P < 0.01).

Adult↗

PubMed1999

A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk.

We previously reported (J. Chen et al., Cancer Res., 56: 4862-4864, 1996; J. Ma et al., Cancer Res., 57: 1098-1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27-1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗