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PubMed2004

Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn's disease.

BACKGROUND: Sacroiliitis is a common extraintestinal manifestation of Crohn's disease but its association with the HLA-B27 phenotype is less evident. Polymorphisms in the CARD15 gene have been linked to higher susceptibility for Crohn's disease. In particular, associations have been found with ileal and fibrostenosing disease, young age at onset of disease, and familial cases. OBJECTIVES: To investigate whether the presence of sacroiliitis in patients with Crohn's disease is linked to the carriage of CARD15 polymorphisms. METHODS: 102 consecutive patients with Crohn's disease were clinically evaluated by a rheumatologist. Radiographs of the sacroiliac joints were taken and assessed blindly by two investigators. The RFLP-PCR technique was used to genotype all patients for three single nucleotide polymorphisms (SNP) in the CARD15 gene. Every SNP was verified by direct sequencing. The HLA-B27 phenotype was determined. RESULTS: Radiological evidence of sacroiliitis with or without ankylosing spondylitis was found in 23 patients (23%), of whom only three were HLA-B27 positive. In contrast, 78% of patients with sacroiliitis carried a CARD15 variant v 48% of those without sacroiliitis (p = 0.01; odds ratio 3.8 (95% confidence interval, 1.3 to 11.5)). Multivariate analysis (logistic regression) showed that the association between sacroiliitis and CARD15 polymorphisms was independent of other CARD15 related phenotypes (ileal and fibrostenosing disease, young age at onset of disease, familial Crohn's disease) (p = 0.039). CONCLUSIONS: CARD15 variants were identified as genetic predictors of Crohn's disease related sacroiliitis. An association was demonstrated between these polymorphisms and an extraintestinal manifestation of Crohn's disease.

Adolescent↗
PubMed2004

Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland Homocysteine Study.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is involved in the metabolism of folate and homocysteine; a polymorphism in the MTHFR gene (677C-->T) has been associated with adverse outcomes of pregnancy. We studied whether two polymorphisms in the MTHFR gene (677C-->T and 1298A-->C) are associated with pregnancy complications, adverse outcomes, and birth defects. METHODS: MTHFR polymorphisms were determined in blood collected in 1992 and 1993 from 5883 women aged 40 to 42 years, and linked with 14,492 pregnancies in the same women recorded in the Medical Birth Registry of Norway from 1967 to 1996. RESULTS: The 677TT genotype in mothers was associated with increased risk of placental abruption (odds ratio [OR] = 2.6; 95% confidence interval [CI]: 1.4 to 4.8) compared with the CC variant. The risk of intrauterine growth restriction increased with number of T alleles (P for trend = 0.04). Compared with the 1298AA variant, the CC variant was associated with a reduced risk of very low birth weight infants (OR = 0.4; 95% CI: 0.2 to 0.8). No significant associations were found between MTHFR polymorphisms and birth defects. CONCLUSION: The maternal MTHFR 677C-->T polymorphism was a risk factor for placental abruption. The unexpected protective effect of the 1298A-->C polymorphism on very low birth weight needs further study.

Abruptio Placentae↗
PubMed2002

Increased risk of high-grade anal neoplasia associated with a human papillomavirus type 16 E6 sequence variant.

Expression of the E6 and E7 genes of human papillomavirus (HPV) type 16 have been implicated in the etiology of anogenital premalignant and malignant lesions. To evaluate whether variations in the HPV-16 E6 sequence were related to the incidence of high-grade anal neoplasia, 628 HPV-16-positive anal specimens from 193 human immunodeficiency virus (HIV)-positive and 59 HIV-negative participants were typed for variations in 15 E6 nucleotide positions. Although most participants were infected with a prototype strain, 15 (6%) carried the G131 variant, and 12 (5%) were infected with the Af1a variant. Two new variants not previously reported were identified as well. An elevated risk for high-grade anal squamous intraepithelial lesions was associated with infection by G131 variants, compared with the prototype strain (odds ratio, 3.4; 95% confidence interval, 1.1-10), after controlling for HIV status. These data provide further evidence for HPV strain variation as a factor in determining the natural history of anogenital neoplasia.

Amino Acid Sequence↗
PubMed2004

Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers.

We reported previously that subjects homozygous for the cytochrome P450 2A6 (CYP2A6) (*)4 have a lower risk of lung cancer. The purpose of this study was to clarify whether or not the alterations of smoking behavior and risk for lung cancer could be found in subjects possessing novel CYP2A6 variants discovered recently. An epidemiological study was performed with 1094 cases and 611 controls in male Japanese smokers. It was found that the amounts of daily cigarette consumption in subjects who harbored CYP2A6(*)4/(*)7, (*)4/(*)10, (*)7/(*)7, (*)7/(*)9 and (*)4/(*)4 genotypes were significantly less than those in subjects carrying the (*)1/(*)1 genotype (P < 0.01). Even after adjustment with cigarette consumption, the adjusted odds ratios (ORs) for lung cancer were significantly lower in subjects who harbored CYP2A6(*)1/(*)4, (*)1/(*)7, (*)1/(*)9, (*)1/(*)10, (*)4/(*)4, (*)4/(*)7, (*)4/(*)9, (*)7/(*)7 and (*)7/(*)9 genotypes than those who possessed the (*)1/(*)1 genotype (P < 0.05). When participants were classified into four groups according to the CYP2A6 genotypes, group 1 ((*)1/(*)1), group 2 (heterozygotes for the (*)1 and a variant allele), group 3 (heterozygotes and homozygotes for variant alleles except for (*)4/(*)4) and group 4 ((*)4/(*)4), lung cancer risk was found to be less in subjects with the variant of CYP2A6 alleles [group 2, OR of 0.59 [95% confidence interval (CI), 0.44-0.79]; group 3, OR of 0.52 (95% CI, 0.37-0.72); group 4, OR of 0.30 (95% CI, 0.16-0.57)]. The reduced risk for lung cancer was seen more clearly in heavy smokers than in light smokers. Additional stratification analysis showed that the ORs for squamous cell carcinoma (OR of 0.07) and small cell carcinoma (OR of 0.10) were lower than that of adenocarcinoma (OR of 0.39) in group 4. These results suggest that the CYP2A6 is one of the principal determinants affecting not only smoking behavior but also susceptibility to tobacco-related lung cancer.

Adenocarcinoma↗
PubMed2005

NOD2/CARD15 and TNFA, but not IL1B and IL1RN, are associated with Crohn's disease.

BACKGROUND: NOD2/CARD15 was described as the first susceptibility gene to Crohn's disease (CD). Polymorphisms in the TNFA gene and in the IL1 gene cluster, which are associated with an enhanced chronic inflammatory response, may also play a role in the development of CD. The aim of this study was to determine the association of polymorphisms in the CARD15, TNFA, IL1B, and IL1RN genes with risk of development of CD and with the clinicopathological profile of CD patients. METHODS: In a case-control study including 235 CD patients and 312 controls (929 controls for TNFA genotyping), the CARD15 (R702W, G908R, and 1007fs), TNFA (-308G/A and -857C/T), IL1B (-511C/T), and IL1RN (intron 2 variable number of tandem repeats) polymorphisms were genotyped. RESULTS: We observed a significant association between CD and the CARD15 polymorphisms, with an odds ratio (OR) of 2.9 [95% confidence interval (CI), 1.9 to 4.6] for carriers of 1 variant allele and an OR of 11.8 (95% CI, 3.5 to 40.4) for carriers of 2 variant alleles. Patients with CARD15 polymorphisms had more frequently ileal or ileocolonic disease location, stricturing phenotype, abdominal surgery, and no extraintestinal manifestations. The TNFA-308A/A genotype was associated with susceptibility to CD with an OR of 3.0 (95% CI, 1.2 to 7.2). TNFA-308A/A homozygotes showed a higher frequency of erythema nodosum and arthritis, colonic disease location, and absence of abdominal surgery. No associations were found with the TNFA-857, IL1B-511, and the IL1RN VNTR polymorphisms. CONCLUSIONS: These findings suggest that CARD15 and TNFA-308 genetic polymorphisms are associated with increased risk of CD displaying distinct clinicopathological profiles.

Adolescent↗
PubMed2005

Identification and functional analysis of genetic variants of the human beta-glucuronidase in a German population sample.

The deleterious consequences of total beta-glucuronidase deficiency, leading to symptomatic mucopolysaccharidosis type VII (MPS VII), have been firmly established. However, the question of whether sequence variations in beta-glucuronidase of non-MPS VII patients affect expression of the enzyme, thereby explaining the wide inter-individual expression, has not been addressed in a systematic manner. In the present study, a population of 965 subjects were screened for enzyme activity and relevant fractions of the beta-glucuronidase gene were sequenced in those individuals belonging to the highest or lowest decile of activity. The study showed a substantial inter-individual variability of beta-glucuronidase in plasma (range 0.5-150.2 micromol/min) and confirmed the association of beta-glucuronidase activity with gender (P < 0.001), age (r = 0.218; P < 0.001) and body mass index (r = 0.311; P < 0.001). We were able to identify six beta-glucuronidase single base substitutions (-1026A > G, -72G > T, -12G > A, +7728C > T, +14 209C > T and +14 604A > G) in 193 non-MPS VII patients at a rate of one single nucleotide polymorphism (SNP) per 520 bp sequenced. The GG genotype of +14 604A > G and the CT genotype of +14 209C > T were associated with higher beta-glucuronidase activity (P < 0.05). Subsequently, reporter gene assays were carried out to elucidate the effects of the SNPs -1026A > G, -72G > T and -12G > A, and the combined genotype -1026A > G and -12G > A observed in one of the subjects. Variant -12G > A reduced the promoter activity (75%; 95% confidence interval 70-84%, P < 0.05). The present study demonstrates that three of the described SNPs influence the activity and/or expression of beta-glucuronidase. Taken together, the data indicate a rather limited influence of genetic factors on inter-individual variability in beta-glucuronidase activity.

Cross-Sectional Studies↗
PubMedDate not supplied

Intestinal malrotation in children: a problem-solving approach to the upper gastrointestinal series.

Intestinal malrotation, which is defined by a congenital abnormal position of the duodenojejunal junction, may lead to midgut volvulus, a potentially life-threatening complication. An evaluation for malrotation is part of every upper gastrointestinal (GI) tract examination in pediatric patients, particularly neonates and infants. Although the diagnosis of malrotation is often straightforward, the imaging features in approximately 15% of upper GI tract examinations are equivocal and lead to a false-positive or false-negative interpretation. The clinical manifestations and upper GI tract findings of malrotation in older children and adults are less specific than are those in younger patients, and for this reason diagnosis of the condition may be more difficult. Successful differentiation between a normal variant and malrotation requires the use of optimal techniques in acquiring and interpreting the upper GI series. Familiarity with the upper GI series appearance of both normal and abnormal anatomic variants allows the radiologist to increase both diagnostic accuracy and confidence in the diagnosis of malrotation.

Diagnosis, Differential↗
PubMed2004

Vitamin D receptor gene polymorphisms and breast cancer risk.

PURPOSE: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The actions of 1,25-dihydroxyvitamin D3 are mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in a United Kingdom Caucasian population. EXPERIMENTAL DESIGN: In a retrospective case-control study, female breast cancer patients (n = 398) and control women (n = 427) were recruited, and three VDR polymorphisms were determined. RESULTS: The 3' VDR polymorphisms BsmI and variable-length poly(adenylate) sequence were both significantly associated with breast cancer risk; odds ratios (adjusted for age menopausal status and hormone replacement therapy usage) for bb genotype versus BB genotype = 1.92 (95% confidence interval, 1.20-3.10; P < 0.01) and for LL versus SS = 1.94 (95% confidence interval, 1.20-3.14; P < 0.01). A 5' VDR gene variant, FokI, was not associated with breast cancer risk when analyzed in isolation (P > 0.05). However, FokI did modulate the increased risk associated with the bb/LL genotype such that possession of one or more F alleles together with the bb/LL genotype augmented breast cancer risk. Furthermore, the highest proportion of bb and FFLL/FfLL genotypes occurred in women with metastatic breast cancer. CONCLUSIONS: VDR polymorphisms are associated with breast cancer risk and may be associated with disease progression. Additional investigations into how different genotypes may affect the functional mechanisms of the VDR will provide a better strategy for identifying women at risk of breast cancer and for developing improved treatments.

Adult↗
PubMed2001

Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma.

Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C-->T and MTHFR1298 A-->C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A-->G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospital-based case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. Further studies to confirm the association and detailed biologic mechanisms are now required.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2006

A functional polymorphism in the glucocorticoid receptor gene and its relation to cardiovascular disease risk in familial hypercholesterolemia.

CONTEXT: Individuals with the functional ER22/23EK variant in the glucocorticoid receptor gene are relatively resistant to the downstream consequences of glucocorticoids. Evidence suggests that carriers have a more favorable cardiovascular risk profile, but the relationship between this ER22/23EK variant and cardiovascular disease has not been hitherto assessed. OBJECTIVE: We, therefore, determined whether carriership of the ER22/23EK improves cardiovascular disease risk in patients with severe hypercholesterolemia. DESIGN, SETTING, AND PARTICIPANTS: In a multicenter cohort study, 2024 patients with heterozygous familial hypercholesterolemia, aged 18 yr and older, were genotyped for the ER22/23EK polymorphism. Patients were identified at lipid clinics throughout The Netherlands between 1989 and 2002. MAIN OUTCOME MEASURES: The primary outcome measure was cardiovascular disease. RESULTS: Seventy-six (7.8%) of 977 men and 72 (6.9%) of 1047 women were carriers of the ER22/23EK variant. A total of 395 men and 247 women had a cardiovascular event. In contrast to expected results, we observed no significant association of the ER22/23EK variant with cardiovascular disease risk (men: relative risk, 0.75; 95% confidence interval, 0.50-1.14; P = 0.2; women: relative risk, 1.37; 95% confidence interval, 0.82-2.28; P = 0.2). However, we found a significant interaction between gender and the polymorphism on cardiovascular disease (P = 0.02). CONCLUSIONS: In this large cohort of individuals with very high risk of cardiovascular disease, the association between the functional ER22/23EK polymorphism and cardiovascular risk was not significant overall, although it varied significantly by gender.

Adult↗
PubMed2002

Polymorphism in intron 2 of islet amyloid polypeptide gene is associated with lower low-density lipoprotein cholesterol in nondiabetic subjects and in type 2 diabetic patients.

The aim of this study was to investigate the presence of mutations in the islet amyloid polypeptide (IAPP) gene in a Spanish population with type 2 diabetes and gestational diabetes mellitus (GDM). Using polymerase chain reaction single-stranded conformation polymorphism, we examined the coding region and the 5'-untranslated region (UTR) of the IAPP gene in 177 unrelated type 2 diabetic patients, 110 healthy control subjects, 38 women with GDM, and 38 gestational control subjects. Mutations were confirmed by DNA sequencing. A heterozygous C-to-A nucleotide substitution at +79 bp in intron 2 of the IAPP gene was detected. The frequencies of the +79-bp polymorphism (A allele) were 6.8% in type 2 diabetic patients, 7.7% in nondiabetic control subjects, 11.8% in women with GDM, and 9.2% in gestational control subjects. No AA genotypes were detected. Nondiabetic subjects and patients with type 2 diabetes bearing the CA genotype had lower low-density lipoprotein (LDL) cholesterol levels than subjects bearing wild genotype. Multivariate logistic regression analysis showed an independent association (p < 0.001; odds ratio: 0.33; 95% confidence interval: 0.17-0.63). We did not detect any sequence variant within exons 1 or 2. One diabetic patient was heterozygous for a silent mutation at codon 31 of exon 3 (Asn31 AAC --> AAT). Our findings indicate that the presence of the +79-bp polymorphism of the IAPP gene in nondiabetic subjects and in patients with type 2 diabetes is associated with lower levels of LDL cholesterol. Furthermore, abnormalities of the coding regions or the 5'-UTR of the IAPP gene are not associated with type 2 diabetes or GDM in the Spanish population.

Aged↗
PubMed2001

Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients.

Sequence variations have been identified in a number of DNA repair genes, including XPD, but the effect of these polymorphisms on DNA repair capacity (DRC) is uncertain. We therefore examined XPD polymorphisms at Lys751Gln and Asp312Asn in 341 white lung cancer cases and 360 age-, sex-, ethnicity-, and smoking-matched controls accrued in a hospital-based molecular epidemiological study of susceptibility markers for lung cancer. As previously reported, DRC was statistically significantly lower in the cases than in the controls (7.8% versus 9.5%; P < 0.001), which represents an average 18% reduction among the cases. The variant Lys751Gln and Asp312Asn allele frequencies were 0.36 and 0.29, respectively, for the cases and 0.33 and 0.27, respectively, for the controls. For subjects homozygous for the variant genotype at either locus, the adjusted odds ratio [95% confidence interval (CI)] was 1.84 (1.11-3.04; P = 0.018, for trend). Both cases and controls with the wild-type genotypes exhibited the most proficient DRC. The risk (95% CI) for suboptimal DRC (defined as less than the median DRC value among the controls) was 1.57 (0.74-3.35) for those with the Gln/Gln751 genotype. For cases with the Asn/Asn312 genotype, the risk (95% CI) was 3.50 (1.06-11.59). For cases who were homozygous at either locus, the risk was 2.29 (1.03-5.12; P = 0.048, for trend). The pattern was less evident among the controls, although there was a nonsignificant 41% increase in the risk of suboptimal DRC for controls who were homozygous at either locus. These results suggest that the two XPD polymorphisms have a modulating effect on DRC, especially in the cases.

Case-Control Studies↗
PubMed2003

Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis.

PURPOSE: The association of BRCA2 polymorphisms at codon 372 [Asn (N)/His (H)]and codon 784 [Met (M)/Val (V)] with breast cancer risk was evaluated in Japanese women. In addition, the prognostic significance of these polymorphisms was studied in breast cancer patients. EXPERIMENTAL DESIGN: A case-control study was conducted to examine the association of the BRCA2 N/H372 polymorphism and M/V 784 polymorphism with breast cancer risk (cases = 149, controls = 154). The prognostic significance of these polymorphisms was evaluated in 139 patients with primary breast cancer. RESULTS: No significant association was observed between the N/H372 polymorphism and breast cancer risk. In contrast, a significant increase in breast cancer risk (odds ratio, 2.03; 95% confidence interval, 1.07-3.87) was observed in carriers of the variant allele (V784) of the M/V784 polymorphism as compared with noncarriers after adjustment for the classical risk factors, age, family history, parity, body mass index, and so forth. Among breast cancer patients, various clinicopathological parameters including menopausal status, tumor size, lymph node status, histological grade, and estrogen-receptor status were not significantly different between the carriers and noncarriers of the variant allele with regard to both N/H372 and M/V784 polymorphisms. The N/H 372 polymorphism was not significantly associated with patient prognosis. On the other hand, breast cancer patients carrying the variant allele of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year disease-free survival rate (63%) than noncarriers (92%). Multivariate analysis has revealed that the M/V784 polymorphism is a significant prognostic factor, being independent of the other conventional prognostic factors such as lymph node status and estrogen receptor status. CONCLUSION: These results suggest that the M/V784 polymorphism, but not the N/H372 polymorphism, would be useful in the selection of women at high risk for developing breast cancer and would also serve as a clinically useful prognostic factor in breast cancer patients.

Alleles↗
PubMed2004

Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease.

Consistent deficits in the cholinergic system are evident in Alzheimer's disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95, P=0.019). These data suggest that this variant warrants further examination in large case-control series.

Aged↗
PubMed2001

Studies of genetic variability of the glucose transporter 2 promoter in patients with type 2 diabetes mellitus.

This study was performed to test the hypothesis that genetic variation in the promoter of the glucose transporter 2 (GLUT2) might predispose to prediabetic phenotypes or type 2 diabetes. A total of 1611 bp comprising the minimal promoter region of the GLUT2 gene were examined by combined single-strand conformational polymorphism and heteroduplex analysis followed by direct sequencing of identified variants on genomic DNA from 96 randomly recruited Danish type 2 diabetic patients. We identified 4 nucleotide variants, -447g-->a, -149c-->a, -122t-->c, and -44g-->a. None of the variants were positioned in known or presumed transcription factor binding sites, TATA-box, or transcriptional start site. Association studies of the -149c-->a, -122t-->c, and -44g-->a variants revealed that the variants were as prevalent in 320 type 2 diabetic patients [11.0% (95% confidence interval, 8.4-13.6), 9.8% (7.4-12.2), and 29.0% (24.4-33.6), respectively] as in 241 age-matched glucose-tolerant subjects [13.1% (9.8-16.4), 11.2% (8.3-14.1), and 33.4% (28.8-38.0), respectively]. The -447g-->a mutation was only identified in a single diabetic patient and did not show cosegregation with diabetes in the family of the proband. The three common variants showed in a primary genotype-phenotype study comprising 241 glucose-tolerant middle-aged subjects association to increased plasma glucose levels during an oral glucose tolerance test. However, this result could not be replicated in a second sample of 298 60-yr-old glucose-tolerant subjects. In conclusion, we found no evidence supporting the hypothesis that genetic variability in the minimal promoter of the GLUT2 is associated with type 2 diabetes or prediabetic phenotypes in the Danish population.

Adult↗
PubMed2005

Polymorphisms of vitamin D receptor gene protect against the risk of head and neck cancer.

Vitamin D has potent anti-tumour properties. Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including human squamous cells of the head and neck. Several polymorphisms of the vitamin D receptor (VDR) gene have been described, including a FokI restriction fragment-length polymorphism (RFLP) in exon 2 and an adjacent TaqI RFLP in exon 9. We hypothesized that the VDR FokI and TaqI polymorphisms are associated with the risk of developing squamous cell carcinoma of the head and neck (SCCHN). We conducted a hospital-based, case-control study of 719 SCCHN cases and 821 cancer-free controls (all non-Hispanic Whites) to assess the association between VDR polymorphisms and SCCHN risk. The cases and controls were frequency-matched on age, sex and ethnicity. Polymorphisms at the TaqI and FokI restriction sites were determined from genomic DNA by polymerase chain reaction-RFLP methods. Both homozygous variant genotypes (ff and tt) were associated with a decreased risk of SCCHN [odds ratio (OR)=0.72, 95% confidence interval (CI)=0.53-0.98 and OR=0.64, 95% CI=0.47-0.87, respectively] compared to the common FF and TT genotypes. The VDR variant genotypes were associated with a decreasing risk of SCCHN in a variant allele dose-dependent manner, and the decreasing trend in OR was statistically significant, particularly for the combined genotypes (Ptrend<0.001). These data suggest that the VDR f and t alleles and their genotypes may protect against SCCHN. However, further studies are warranted to confirm these findings.

Adult↗
PubMed2005

CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma.

Polymorphisms in the selected genes controlling carcinogen metabolism (CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1, GSTT1) considered separately or in different combinations, were investigated for an association with tobacco smoke-associated squamous cell carcinoma (SCC) of the larynx. The case-control study was performed in 289 patients with laryngeal SCC and in 316 cancer-free controls; all were Caucasian males from the same region of Poland and current tobacco smokers. The DNA samples were genotyped using PCR-RFLP and multiplex PCR. The variants' frequencies in both groups were compared; odds ratios and their 95% confidence intervals were calculated by logistic regression analyses. The CYP1A1*1/*4, CYP2D6*4/*4, NAT2*4/*6A genotypes, as well as the CYP1A1*4, CYP2D6*4 and NAT2*4 alleles, were found at significantly higher frequencies in cases than in controls indicating their role as "risk-elevating" factors in laryngeal SCC. Combined genotypes, characterized by the presence of the "risk-elevating" variants at more than one locus, often occurred together with the null variant of the GSTM1 gene and homozygous XPD A/A (Lys751Gln, A35931C) genotype. Furthermore, we identified some "protective" variants, found more frequently in controls than in cases, i.e. the NAT2*6A/*6A and NAT2*5B/*6A genotypes. A distribution of "risk" or "protection" genotypes/alleles seems to be connected with age as an occurrence or risk genes was more frequent in the group of "young" cases (< or = 49 years). Accumulation of certain alleles or genotypes of the CYP1A1, NAT2, GSTM1 and XPD seems to be associated with either increased or decreased risk to develop laryngeal SCC. Therefore, polymorphisms in these genes may play a role in the laryngeal cancer etiology.

Adult↗
PubMed2005

p53 Codon 72 polymorphism predicts the pathologic response to neoadjuvant chemotherapy in patients with breast cancer.

PURPOSE: Recent studies have highlighted that the p53 codon 72 polymorphism plays a crucial role in modulating wild-type p53 apoptotic capacity, and as such may influence the response to chemotherapy. Thus, the purpose of this study was to investigate whether the p53 codon 72 polymorphism might influence pathologic response to neoadjuvant chemotherapy in primary breast cancer. EXPERIMENTAL DESIGN: One hundred and ten operable breast cancer patients received anthracycline-based neoadjuvant chemotherapy and p53 codon 72 polymorphism status was analyzed by PCR-RFLP. RESULTS: The distribution of initial clinical stage, tumor size, estrogen receptor or progesterone receptor status, menopausal status, or erbB2 expression was not significantly different among the polymorphic variants. However, we found that only 13% (3 of 23) of patients with the Pro/Pro variant had a good pathologic response, defined as a complete pathologic response or minimal residual disease. In comparison, 40% (22 of 55) or 37.5% (12 of 32) of patients with the Pro/Arg or Arg/Arg variant had a good pathologic response (P = 0.019). Moreover, patients with the Pro/Pro variant were more likely to have a positive axillary lymph node status than those with the Pro/Arg or Arg/Arg variant (P = 0.007). Furthermore, in multivariate analysis, p53 codon 72 polymorphism was found to be a strong predictor of pathologic response (odds ratio 6.7, 95% confidence interval, 1.4-31.2; P = 0.016). CONCLUSION: Our study indicates that breast cancer patients with the Pro/Pro variant may be less sensitive to anthracycline-based treatment than those with the Pro/Arg or Arg/Arg variant and suggests that analysis of p53 codon 72 polymorphism may provide a simple predictive marker for selecting the right breast cancer patients to anthracycline-based neoadjuvant chemotherapy in clinical setting.

Adult↗