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PubMed2026

Developmental genetic determinants of the human cerebrospinal fluid-ventricular system.

Primary enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the "hand-in-glove" development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Humans↗

PubMed2026

Clinically Relevant Pharmacogenomic Variant Frequencies in Kazakh, Russian, and Uzbek Population Groups Residing in Kazakhstan.

Central Asian populations remain underrepresented in pharmacogenomic research, limiting the availability of population-specific data for genotype-informed prescribing and precision medicine. This study analyzed clinically relevant pharmacogenomic variant frequencies in Kazakh, Russian, and Uzbek population groups residing in Kazakhstan using genome-wide genotype data from 1301 individuals: Kazakh (n = 1111), Russian (n = 156), and Uzbek (n = 34). ClinPGx, a PharmGKB-based clinical annotation framework that prioritizes variant-drug associations according to levels of evidence, was used to select variants with evidence levels 1A, 1B, and 2A. In total, 112 directly genotyped variants were retained for population-specific allele and genotype frequency analysis. All 112 variants were queried against the gnomAD v4.1 genome and exome reference datasets. Of these, matching allele-frequency data for the predefined reported allele were available in at least one of the two gnomAD datasets for 103 variants, whereas for 9 variants the VEP-based query did not return a matching gnomAD frequency for that allele. Frequencies were reported for the same predefined reported allele across all groups, and differences between the study groups were assessed using 95% confidence intervals, Fisher's exact tests, and false discovery rate correction. Genotype counts and the proportions of individuals carrying at least one copy of the reported allele were also summarized for all selected variants. Several pharmacogenomic variants showed population-specific frequency patterns, including NUDT15 rs116855232, SLCO1B1 rs4149056, VKORC1 rs9934438, and UGT1A1 rs10929302. Comparison with gnomAD showed that the observed frequencies were variant-specific and could not be consistently approximated by a single broad genetic ancestry group. Reference-based population structure analysis provided additional ancestry context and supported separate reporting by population group. The study did not evaluate clinical outcomes or make individual prescribing recommendations, and the small Uzbek sample size limits the precision of frequency estimates for this group, particularly for rare variants. Overall, this study provides a clinically prioritized pharmacogenomic frequency resource for underrepresented population groups in Kazakhstan and supports broader Central Asian representation in pharmacogenomic implementation research.

Central Asia↗

PubMed2004

T29C polymorphism in the transforming growth factor beta1 gene and postmenopausal breast cancer risk: the Multiethnic Cohort Study.

Laboratory studies suggest a dual role for the transforming growth factor-beta (TGF-beta) signaling pathway in breast cancer. The normal antiproliferative activity of TGF-beta in early breast tumor development is replaced by a promoting effect in later stages. A T29C transition polymorphism in the TGFB1 gene has been associated with higher circulating TGF-beta1 levels, and inconsistently with breast cancer risk in three recent studies. We tested the association of this variant with invasive breast cancer in a case-control study of 1123 cases and 2314 controls nested in the Multiethnic Cohort (MEC) Study. This study is a large prospective study being conducted in Hawaii and Los Angeles that includes Japanese, white, African American, Latino, and Native Hawaiian women who were predominantly postmenopausal at baseline. After adjustment for breast cancer risk factors, the odds ratio (OR) and 95% confidence interval (95% CI) for the TGFB1 29 CC genotype was 0.95 (95% confidence interval: 0.76-1.18), compared to the TT genotype. Analyses stratified by race/ethnicity, stage, or age category did not reveal any association of this variant with breast cancer. Given the strong biological rationale and the scarce and divergent epidemiologic data to date, additional investigations of the relationship between breast cancer and genetic variants in the TGF-beta signaling pathway appear warranted.

Aged↗

PubMed2006

Surfactant protein B gene variations and susceptibility to lung cancer in chromate workers.

BACKGROUND: Hexavalent chromium has been extensively investigated regarding its mutagenicity and carcinogenicity; however, its mechanism for initiating and enhancing the development of lung cancer is still obscure. Biomarkers of exposure, effect or susceptibility are required for risk assessment and for epidemiologic research studies especially in occupational settings. Since the surfactant protein system (SP) is very important for normal lung function and for mediating local airway conditions and in the clearance of the upper respiratory tract from the occupational and environmental dusts, we hypothesize that SP genes may represent good candidates to study susceptibility for lung cancer. METHODS: Using PCR genotyping methods with gel electrophoresis and confirmation of results with precise DNA fragment size measurement on microchip electrophoresis, we analyzed SP-B intron-4 polymorphism in 230 subjects who were classified into groups; chromate-related lung cancer, control chromate workers who had not developed lung cancer, control individuals with non chromate-related adenocarcinoma or squamous cell carcinoma of the lungs, or healthy Japanese control individuals. RESULTS: Our results indicated that the SP-B variants (deletion/insertion) were significantly overrepresented (61.3%) in the chromate-related lung cancer group than other groups (X2 = 47.6; DF = 4, P = 0.0001). There was a significant difference between the chromate lung cancer group and both of the control groups, healthy individuals and chromate workers who did not develop lung cancer, showing odds ratios (OR) with 95% confidence intervals (CI) of 21.9 (7.3-65.7) and 19.0 (3.78-95.4), respectively. Compared with 46 non chromate-related SCC of the lung, the SP-B variants were significantly overrepresented in the chromate-related SCC (18/28; 64.3%) than the non-chromate SCC (11/46; 23.9%) of the lung samples (X(2) = 10.27, P = 0.01), OR with 95% CI is 5.73 (2.05-16.01). CONCLUSION: These findings indicate a very strong association of the SP-B intron-4 variants with mechanisms that may enhance lung cancer susceptibility, especially in workers who are employed in chromate industry. Moreover, confirmation of such results may help to suggest adding the SP-B intron-4 typing to be one of the screening tests of the pre-placement medical examination to confirm that the worker has no variations of the SP-B gene before being engaged in a chromium-related industry, with the intention of providing proper medical counseling.

Carcinogens, Environmental↗

PubMed1996

Rates of Down syndrome at livebirth by one-year maternal age intervals in studies with apparent close to complete ascertainment in populations of European origin: a proposed revised rate schedule for use in genetic and prenatal screening.

Precision and accuracy in determining rates of Down syndrome at livebirth are indispensible to algorithms which determine eligibility for prenatal cytogenetic diagnostic services. We derived Down syndrome rates by single year of maternal age which we propose as a revised rate schedule for background risk. Data on European-origin populations were obtained from 5 sources judged most likely to have complete ascertainment of cases. A "constant plus exponent" regression model and variants extending the analysis to higher powers of maternal age were applied to several ranges of maternal age. Confidence intervals about the rates were calculated. This analysis results in rates significantly higher than those in widespread use though the confidence intervals show a need for caution in assuming precision. Sources of variation in rates are also considered.

Adolescent↗

PubMed2003

NURR1 promoter polymorphisms: Parkinson's disease, schizophrenia, and personality traits.

We have previously identified mutations in exon three in NURR1 (NR4A2) in two patients with schizophrenia (SZ) and one patient with bipolar disease with psychotic symptoms. In the present study we analyzed the promoter region of NURR1 and identified five polymorphic sites: three were found to be in strong linkage disequilibrium with a previously identified polymorphic site in the sixth intron. One polymorphism of this haplotype and the two other independent polymorphisms were investigated for their possible association with SZ and Parkinson's disease (PD) by comparing their frequencies in a Swedish material consisting of 134 subjects with SZ and 207 matched controls and 108 subjects with PD and 125 matched controls. Exon 1 was also investigated in our Parkinson and control material but no variances were found. The distributions of the two most informative polymorphisms in the promoter were investigated in an American material as well consisting of 141 subjects with SZ and 139 matched controls. Furthermore, the identified markers were screened for association with putative endophenotypes of SZ in the Swedish material. The distribution of sequence variants among the Swedish controls matched for SZ was investigated with regard to personality. No significant genotype or allelic association of the three sequence variants with SZ or PD was found. Several comparisons regarding endophenotypes or personality indicated association at the 5% confidence level, although correction for multiple testing rendered none of these findings significant. We conclude that the identified polymorphic sites in the human NURR1 are unlikely to be involved in conferring susceptibility for SZ or PD in our patient material.

Adult↗

PubMed2004

Leptin responsiveness to energy restriction: genetic variation in the leptin receptor gene.

Serum leptin concentrations are an important afferent signal in energy balance homeostasis. It has been speculated that the leptin responsiveness to energy restriction is affected by the functionality of the leptin receptor. The purpose of this analysis was to explore the effect of polymorphisms in the LEPR gene on the acute decline in leptin after 4 days of 65% energy restriction. Leptin concentrations of the study group (n = 44; all men) declined by 2.3 +/- 1.5 micro g/L [-39.4% (95% confidence interval: -43.6 to -34.9)]. Leptin responses did not statistically differ between noncarriers and carriers of three mutant variants of the polymorphisms: Lys109/Lys109 (-41.4%) vs. Arg109/+ (-37.0%) (p = 0.33); Gln223/Gln223 (-41.5%) vs. Arg223/+ (-37.8%) (p = 0.40); Lys656/Lys656 (-39.5%) vs. Asn656/+ (-39.3%) (p = 0.96). No effect of the assessed polymorphisms in the LEPR gene on the acute decline in leptin after energy restriction was observed. Power calculations are provided for future studies on the leptin responsiveness to energy restriction.

Adult↗

PubMed1997

Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility.

We describe here a case-control study to identify associations between polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) and cytochrome P-450 1A1 (CYP1A1) genes and susceptibility to endometrial cancer. Accordingly, genotype frequencies in 80 endometrial carcinoma patients were compared with frequencies in 60 controls. DNA analysis suggest a significantly increased endometrial cancer risk with an alanine to valine substitution at nucleotide 677 of MTHFR gene with an odds ratio of 2.8 (95% confidence interval: 1.36-6.14, P = 0.002). Moreover, the tumors from patients with the valine allele were more undifferentiated (P = 0.03). On the other hand, a recently described mutation in exon 7 of CYP1A1 gene (threonine exchanged to asparagine in codon 461) showed a strong association with endometrial cancer risk with an odds ratio of 6.36 (95% confidence interval: 1.99-26.5, P = 0.0004). Thus, this study suggests that polymorphisms at MTHFR and a novel CYP1A1 variant could influence susceptibility to endometrial cancer, although larger sample sizes would be required to corroborate these findings.

Carcinoma↗

PubMed1998

A pilot study testing the association between N-acetyltransferases 1 and 2 and risk of oral squamous cell carcinoma in Japanese people.

Risk of oral cancer has been associated with exposure to tobacco smoke, alcohol and with genetic predisposition. The aromatic amines and their metabolites, a class of carcinogens present in tobacco smoke, undergo metabolism (activation or detoxification) through an N- or O-acetylation pathway by the polymorphic enzymes, N-acetyltransferases (NAT)1 or NAT2. The genes that encode these enzymes, NAT1 and NAT2, have a variety of high and low activity alleles and we analyzed these genetic polymorphisms in 62 oral squamous cell carcinoma cases, and 122 healthy control subjects from Japan. NAT1 alleles tested were NAT1*3 (C1095A), NAT1*4 (functional reference allele), NAT1*10 (T1088A,C1095A), NAT1*11(9 bp deletion), NAT1*14 (G560A), NAT1*15 (C559T) and NAT1*17 (C190T). No low activity alleles (NAT1*14, NAT1*15 and NAT1*17) were observed in these Japanese subjects. We observed significantly increased risk [odds ratio 3.72; 95% confidence interval (CI) 1.56-8.90; P < 0.01] associated with the NAT1*10 allele, an allele that contains a variant polyadenylation signal. Stratifying by smoking status we found odds ratios of 5.9 (95% CI 1.13-30.6; P < 0.05) for non-smokers with the NAT1*10 allele and 3.1 (95% CI 1.09-9.07; P < 0.05) for smokers, but these risks were not significantly different from each other. Thus, we did not observe that NAT1*10 alleles confer differential risk among smokers and non-smokers. NAT2 rapid acetylation genotype was not a significant risk factor for oral cancer in this Japanese study population. This is the first study to test for oral cancer risk associated with polymorphism in the NAT1 and NAT2 genes, and these positive findings in our pilot study, while based on small numbers, suggest that the NAT1*10 allele may be a genetic determinant of oral squamous cell carcinoma among Japanese people.

Acetylation↗

PubMed2003

Gene interactions and stroke risk in children with sickle cell anemia.

Stroke is a devastating complication of sickle cell anemia (SCA), affecting up to 30% of children with the disease. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Because stroke in SCA is likely a multifactorial disease, analysis of the combined effect of multiple genetic variants may prove more successful than evaluation of individual candidate genes. We genotyped 230 children with SCA for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. Patients were phenotyped based on magnetic resonance imaging/angiography (MRI/MRA) findings into large-vessel (LV) versus small-vessel (SV) disease stroke subgroups. Specific polymorphisms in the IL4R 503, TNF (-308), and ADRB2 27 genes were independently associated with stroke susceptibility in the LV stroke subgroup, while variants in the VCAM1 (-1594) and LDLR NcoI genes were associated with SV stroke risk. The combination of TNF (-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to LV stroke (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 2.3-13.1). We show that several candidate genes may play a role in predisposition to specific stroke subtypes in children with SCA. If confirmed, these results provide a basis for population screening and targeted intervention to prevent stroke in SCA.

Adolescent↗

PubMed2006

A common genetic variant in XPD associates with risk of 5q- and 7q-deleted acute myeloid leukemia.

Numerous structural genetic abnormalities observed in acute myeloid leukemia (AML) illustrate the heterogeneity of this disease, which likely has contributed to difficulty in identifying susceptibility alleles for AML. We previously reported that carriers of the glutamine-encoding allele at codon 751 of the xeroderma pigmentosum group D (XPD) DNA repair gene were significantly more likely to have a karyotype associated with a less favorable prognosis, and hypothesized that this observation was driven by an association between the codon 751 variant and risk of developing AML with specific structural abnormalities. Using a case series of 927 patients with AML, we show here that the XPD codon 751 glutamine-encoding variant significantly associates with risk of developing AML with a chromosome 5q deletion (odds ratio [OR] 2.09; 95% confidence interval [CI] 1.14-3.81; n=69; P=.02) or a chromosome 7q deletion (OR 2.27; 95% CI 1.09-4.71; n=47; P=.03), but not with any other commonly recurring cytogenetic lesion.

Acute Disease↗

PubMed2006

PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease.

We analysed relationships between the PTPN22 1858 polymorphism and antibodies to cyclic citrullinated peptide (CCP), rheumatoid factors (RFs) and the shared epitope (SE) gene (HLA-DRB1*0404 or 0401) and determined their combined predictive value for rheumatoid arthritis (RA) in individuals who subsequently developed RA. This case-control study was nested within the Medical Biobank of Northern Sweden. Patients with RA (n = 92) were identified from amongst blood donors antedating onset of disease by a median of 2.4 (interquartile range 1.2 to 4.9) years. Matched controls were selected randomly from the same cohorts (n = 368). Anti-CCP antibodies and RFs were determined using enzyme-linked immunoassays. Genotyping was performed using an ABI PRISM 7900HT instrument and HLA-SE genes were identified using PCR sequence-specific primers. The 1858T allele and also carriage of T were associated with future onset of RA (odds ratio (OR) = 2.29, 95% confidence interval (CI) 1.45-3.61 and OR = 2.64, 95% CI 1.56-4.47, respectively). The combination of the 1858T variant and anti-CCP antibodies gave 100% specificity for the disease. None of the 368 controls expressed this combination. The PTPN22 1858T variant and anti-CCP antibodies were clearly associated (OR = 3.80, 95% CI 1.51-9.57). A combination of the PTPN22 1858T variant and anti-CCP antibodies gave a much higher relative risk (>132.03) for developing RA than the combination of the T variant and HLA-SE (OR = 7.85). The PTPN22 1858T variant was associated with future development of RA. There was an association between the T variant and anti-CCP antibodies and their combination, found only among pre-patients, gives a very high relative risk for development of RA. The combination gave a specificity of 100% for diagnosing RA.

Arthritis, Rheumatoid↗

PubMed2007

Surgically relevant normal and variant renal parenchymal and vascular anatomy in preoperative 16-MDCT evaluation of potential laparoscopic renal donors.

OBJECTIVE: Using 16-MDCT, we describe and quantify the frequency and types of renal anatomic variants and findings relevant for preoperative evaluation and surgical planning for potential laparoscopic renal donors. MATERIALS AND METHODS: On 16-MDCT, 126 consecutive potential donors underwent scanning before contrast administration and after i.v. power injection of nonionic contrast material during the arterial, nephrographic, and excretory phases. On a 3D workstation, CT images were evaluated retrospectively in consensus by three abdominal imagers. The number and branching pattern of bilateral renal arteries and veins, including anomalies of the inferior vena cava and lumbar-gonadal axis, were categorized along with the frequency of incidental findings of the renal parenchyma and collecting system. RESULTS: Major arterial variants including supernumerary and early branching arteries were present in 16% and 21%, respectively, of left kidneys and 22% and 15%, respectively, of right kidneys. Major and minor venous variants were detected in 11% and 58% of left kidneys and 24% and 3% of right kidneys. Late confluence of the venous trunk was identified in 17% of left kidneys and 10% of right kidneys. Incidental parenchymal and urothelial abnormalities, most commonly cysts and calyceal calcifications, were identified in 30% of the kidneys. Other relevant incidental findings included focal infarcts, cortical scars, atrophic scarred kidney, and bilateral papillary necrosis. Urothelial variants included bilateral simple ureteroceles and rightsided complete duplicated collecting system. CONCLUSION: 16-MDCT angiography and urography allow confident detection and classification of a variety of anatomic and incidental anomalies relevant to the preoperative selection of potential laparoscopic renal donors and to surgical planning.

Adolescent↗

PubMed2000

Glutathione S-transferase M1, T1, and P1 polymorphisms as risk factors for renal cell carcinoma: a case-control study.

Renal cell carcinoma (RCC) has known environmental risk factors, notably smoking, and enzymes that biotransform carcinogens have high levels of activity in the kidney. However, a possible role of polymorphisms in these enzymes in RCC etiology has received little study. We investigated glutathione S-transferase (GST) polymorphisms in a population-based case-control study of RCC. Subjects completed a structured interview, and DNA was isolated from pathological material or buccal cells for 130 cases, and from blood for 505 controls. Genotypes for GSTM1 and GSTT1 were determined by multiplex PCR, and for GSTP1 by oligonucleotide ligation assay. The frequency of GSTM1 null genotype was 50.0% in cases and 50.5% in controls, with an adjusted odds ratio (OR) of 1.0 [95% confidence interval (CI), 0.6-1.6]. For GSTP1, the frequencies of genotypes AA, AG, and GG representing the Ile104Val variant were: cases, 44.6%, 43.1%, and 12.3%; controls, 43.4%, 44.0%, and 12.6%; OR for AG and GG, 1.0 (95% CI, 0.6-1.6). An excess of the GSTT1 null genotype was observed in cases compared with controls, 28.6% versus 18.5% (OR, 1.9; 95% CI, 1.1-3.4). The association with GSTT1 was present among both smokers and nonsmokers, but was modified by body mass index, a recognized risk factor for RCC; among subjects in the lowest tertile of body mass index, the OR for GSTT1 null was 4.8 (95% CI, 1.8-13.0). The association between GSTT1 null and increased RCC risk in this population-based study suggests that activity of the GSTT1 enzyme protects against RCC. This contrasts with a recent report of reduced risk of RCC associated with GSTT1 null in a cohort of trichloroethene-exposed workers and suggests that specific chemical exposures alter the effect of GSTT1 on cancer risk.

Adult↗

PubMed2003

Genetic polymorphisms in GSTM1, -P1, -T1, and CYP2E1 and the risk of adult brain tumors.

GST and CYP2E1 genes are involved in metabolism of several compounds (e.g., solvents) that may play a role in brain cancer etiology. We evaluated associations between polymorphisms in these genes and adult brain tumor incidence. Cases were 782 patients with brain tumors diagnosed from 1994 to 1998 at three United States hospitals. Controls were 799 patients admitted to the same hospitals for nonmalignant conditions. DNA was extracted from blood samples that had been collected from 1277 subjects (80% of all subjects; 604 controls; 422 gliomas, 172 meningiomas, and 79 acoustic neuromas), and genotyping was successfully conducted for GSTM1 null, GSTT1 null, GSTP I105V, GSTP A114V, CYP2E1 RsaI, and CYP2E1 Ins96. The GSTP1 105 Val/Val genotype was associated with increased glioma incidence [odds ratio (OR), 1.8; 95% confidence limits (CLs), 1.2, 2.7], with the estimated effect following a trend of increasing magnitude by number of variant alleles (Ile/Ile: OR, 1.0; Ile/Val: OR, 1.3; Val/Val: OR, 2.1). The CYP2E1 RsaI variant was weakly associated with glioma (OR, 1.4; 95% CL, 0.9, 2.4) and acoustic neuroma (OR, 2.3; 95% CL, 1.0, 5.3), with some indication of stronger associations among younger subjects. Estimated effects of the gene variants differed by glioma subtype. There was evidence of supermultiplicativity of the joint effect of GSTP1 I105V and CYP2E1 RsaI variants on both glioma and acoustic neuroma, even following adjustment of estimates toward a common prior distribution using hierarchical regression models. Previously reported associations between the GSTT1 null genotype and overall glioma incidence were not replicated, but an association with meningioma was observed (OR, 1.5; 95% CL, 1.0, 2.3). These findings may provide clues to both genetic and environmental determinants of brain tumors.

Adult↗

PubMed2005

[Association of two genetic polymorphisms in the 5'untranslated region of exon 2 of the p73 gene and risk of lung cancer].

OBJECTIVE: To study the relationship between two potential functional polymorphisms in exon 2 of the p73 gene and the susceptibility of lung cancer. METHODS: Genotypes were determined by polymerase chain reaction-single stand conformation polymorphism (PCR-SSCP) method in 425 histologically-confirmed lung cancer cases and 588 cancer-free controls, frequency-matched by age and sex. RESULTS: The two polymorphisms were in complete linkage disequilibrium and the frequencies of variant p73 AT haplotype (A4T14) were less commonly seen in the cases (0.225) than in the controls (0.287) (P = 0.0018). Compared with the p73 GC/GC homozygotes, both the AT/AT variant homozygotes and GC/AT heterozygotes were associated with a significantly decreased risk [adjusted odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.26 - 0.80 and OR = 0.70, 95% CI = 0.53-0.92, respectively]. CONCLUSION: These results suggested that this p73 dinucleotide polymorphism might have had a role to play in the susceptibility of lung cancer.

5' Untranslated Regions↗

PubMed2006

The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage.

X-ray repair cross-complementing 1 (XRCC1) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5'-untranslated region (5'-UTR) variant -77T-->C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders, and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The -77T-->C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wild-type allele other positions) was associated with increased BC risk [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.12-3.23] and the H3 haplotype (wild-type allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, -77C, wild-type allele codons 194, 280, 399) (OR, 0.39; 95% CI, 0.16-0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival (P=0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 h following IR exposure. These results suggest that the -77T-->C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.

Breast Neoplasms↗

PubMed2002

Analysis of the RNASEL gene in familial and sporadic prostate cancer.

The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (chi(2) trend test = 1.42; P=.23) or the Asp541 variant (chi2=1.52; P=.22). However, significant differences were detected for the Arg462Gln genotypes (chi2=5.20; P=.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32-0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis </=64 years) (P=.0008; OR=0.29; 95% CI = 0.13-0.66), in node-negative patients (P=.01; OR=0.48; 95% CI 0.27-0.84), patients with stage T(1)/T(2) disease (P=.008; OR=0.39; 95% CI 0.2-0.75), and patients with low-grade disease (P=.01; OR=0.40; 95% CI 0.20-0.78). To evaluate whether this variant was also associated with sporadic PC, we genotyped an additional 499 patients with sporadic PC. Differences in frequency were not detected between patients with sporadic disease and control subjects. However, the same association was observed between patients with familial disease and patients with sporadic disease for the entire group (chi2=4.82; P=.03), as well as in the subset analyses. These results suggest that polymorphic changes within the RNASEL gene may be associated with increased risk of familial but not sporadic PC.

Adult↗