CCM2 gene polymorphisms in Italian sporadic patients with cerebral cavernous malformation: a case-control study

Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Among our group of CCM Italian patients, we selected a cohort of sporadic cases negative for mutations in CCM genes. In this cohort, five variants in CCM2 gene were detected, which proved to be the known polymorphisms in intronic regions (IVS2-36A>G and IVS8 +119 C>T) and in coding sequence (c.157 G>A in exon 2, c.358 G>A in exon 4 and c.915 G>A in exon 8). Therefore, we undertook a case-control study to investigate the possible association of these polymorphisms with sporadic CCMs. The five polymorphisms were identified in 91 CCM sporadic patients and in 100 healthy controls by direct sequencing methods using lymphocyte DNA. Polymorphisms IVS2-36A>G and c.915 G>A showed statistically significant differences in frequencies between patients and controls [(χ2, 6.583; P<0.037); (χ2, 14.205; P<0.001)]. The prevalence of the wild-type genotype was significantly lower in the CCM group than in the control sample. Patients with the A/G and G/G genotypes (IVS2-36A>G) had a significant increase for CCM risk (OR, 3.08; 95% CI, 1.5-5.9 and OR, 4.3; 95% CI, 1.4-22.6) and the same was observed for the polymorphism c.915 G> A (genotype G/A OR, 6.1; 95% CI, 3.0-12.6 and genotype A/A OR, 2.79). In addition, the polymorphisms c.358 G>A in exon 4 (χ2, 15.977; P<0.04) and c.915 G>A in exon 8 (χ2, 18.109; P<0.02) were significantly associated with different types of symptoms. Haplotype analysis, performed only on polymorphisms c.358 G>A (p.Val120Ile), c.915 G>A (p.Thr305 Thr) and IVS2-36A>G, shows that haplotype GAG (+--) significantly increased among CCM sporadic patients compared to the control group. Significant differences between patients and controls were observed only for IVS2-36A>G and c.915 G>A polymorphisms indicating their possible association with sporadic CCMs and an increased risk of CCM. On the other hand, polymorphisms c.358 G>A and c.915 G>A were associated with a more benign course of the disease. These data were confirmed by the haplotype GAG (+--) frequencies.     

The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder

Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) locates. GABA is one of the major neurotransmitters that may be involved in the pathogenesis of bipolar disorder. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in a Japanese population. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with control subjects. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57, 95% confidence interval: 0.44-0.73). These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder.     

Identification of polymorphisms in the XIAP gene and analysis of association with lung cancer risk in a Korean population

The X-linked inhibitor of apoptosis protein (XIAP) is a potent mammalian IAP, and has been shown to play an important role in development and progression of cancer. Polymorphisms in the XIAP gene may influence XIAP production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we first screened for polymorphisms in the XIAP gene by direct sequencing of genomic DNA samples from 27 healthy Korean women and then performed a case-control study to evaluate the association between the polymorphisms and the risk of lung cancer. The XIAP genotypes were determined by polymerase chain reaction amplification and melting curve analysis in 582 lung cancer patients and in 582 healthy control subjects who were frequency-matched for age and sex. We identified 12 single nucleotide polymorphisms (SNPs), one novel SNP [30051C>G (A321G) in exon 3] and the following 11 known SNPs: 192G>C (rs5956578), 262C>T (rs28382699), 318C>T (rs5958318), and 374C>T (rs12687176) in the putative promoter; 26615A>G (rs2355676) in intron 1; 41725A>G (rs5958338) in intron 5; 42009A>C (Q423P, rs5956583) in exon 6; 48162T>C (rs17334739) and 48228C>T (rs28382739) in intron 6; and 48542A>G (rs28382740) and 49333G>T (rs28382742) in 3'-UTR. Four of these 12 SNPs were selected for large-scale genotyping based on their frequencies and haplotype tagging status: 262C>T, 318C>T, 374C>T, and 42009A>C. The four XIAP polymorphisms and their haplotypes exhibited no apparent relationship with the risk of lung cancer. In addition, we observed no evidence of effect modification by age, sex, smoking history, or tumor histology. These results suggest that XIAP polymorphisms do not significantly affect susceptibility to lung cancer in Koreans.     

Caspase 9 promoter polymorphisms and risk of primary lung cancer

Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [-1263A>G, -905T>G, -712C>T and -293_-275delCGTGAGGTCAGTGCGGGGA (-293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the -1263 AA genotype or combined -1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42-0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46-0.97, P=0.01, respectively]. For the -712C>T polymorphism, individuals with at least one -712T allele were at a significantly increased risk of lung cancer compared with those harboring the -712 CC genotype (adjusted OR=1.42, 95% CI=1.06-1.89, P=0.02). Consistent with the results of genotype analyses, the -1263G/-712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47-0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45-0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17-0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; P(trend)<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the -1263G/-712T and -1263A/-712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.     

Novel intronic polymorphisms in the RET proto-oncogene and their association with Hirschsprung disease

Germline mutations of the RET proto-oncogene have been found in familial and sporadic forms of Hirschsprung disease (HSCR), but also in the autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes, which comprise the medullary thyroid carcinoma (MTC) as an obligatory feature. Besides mutations various polymorphisms of the RET proto-oncogene are associated with the HSCR. In this study, we have characterized seven intronic RET polymorphisms (IVS2+9G>A, IVS4+48A>G, IVS12+47C>T, IVS14-24G>A, IVS19+47T>C, IVS20+96C>T, 3'UTR+124A>G) and investigated these variants by DNA sequencing in populations of 76 HSCR patients and 40 sporadic MTC patients as well as in a control population. Variants of four of these seven polymorphisms have a strong association with the HSCR phenotype. In contrast, none of the investigated polymorphisms show a significant difference in the genotype distribution and the allele frequencies in patients with sporadic MTC when compared to controls. These findings support the hypothesis that specific RET haplotypes cause or modify the HSCR phenotype.     

Analysis of the PTCH coding region in human rhabdomyosarcoma

Inherited mutations of the human tumor suppressor gene Patched (PTCH) lead to an autosomal dominant disorder known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS). The syndrome is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Tumors in patients with NBCCS include basal cell carcinoma, medulloblastoma, fibroma and rhabdomyosarcoma (RMS). RMS are also present in 15 % of mice haplodeficient for Ptch. To investigate whether mutations in PTCH are a general feature in rhabdomyosarcomagenesis we sequenced the protein-coding region in sporadic human cases of these tumors. For this purpose we first determined the distribution and frequency of polymorphisms in 23 exons of PTCH in 48 healthy caucasians. Ten new polymorphisms were identified (IVS11 + 15-17del AAA; IVS14 + 25T>C; 2485G>A; IVS15 + 9G>C; IVS17 + 21A>G; 3033T>C; 3149T>C; 3387T>C; 3617G>A; 4080C>T). Next, the PTCH coding region in 14 RMS was sequenced. Whereas one case with LOH at the PTCH locus was detected, none of the cases showed nonsense or missense mutations in the coding region of PTCH. These data do not support the existence of frequent mutations in the protein-coding region of PTCH in RMS.     

Two ATM variants and breast cancer risk

The ATM gene is mutated in ataxia-telangiectasia (AT). Heterozygote female relatives of AT cases have a 2-7fold increased risk of breast cancer. We previously reported high risks of breast cancer associated with certain ATM variants. To estimate the risks more precisely, we have examined two ATM variants, c.1066-6T>G (IVS10-6T>G) and c.4258C>T (p.Leu1420Phe), in additional cases and controls from the same Australian cohorts previously used to estimate the risk of breast cancer associated with c.1066-6T>G. A total of 775 and 84 population-based controls were genotyped for the c.1066-6T>G and c.4258C>T ATM variants respectively, as were index cases from 378 and 373 non-BRCA1/2 breast cancer families. Penetrance was estimated by Bayes factor analysis. The allele frequencies of ATM c.1066-6T>G and c.4258C>T estimated from controls were 0.005 (95% CI=0.002 to 0.009) and 0.012 (95% CI=0.001 to 0.042), respectively. We identified three new breast cancer families with c.1066-6T>G, and seven families with c.4258C>T. Combining with the two c.1066-6T>G families previously reported, the estimated penetrance to age 70 of c.1066-6T>G was 17.2% (95% CI=4.7% to 37.5%). For c.4258C>T, the estimated average penetrance was 4.8% (95% CI 1.7% to 10.1%). In conclusion, we found no evidence that the ATM c.4258C>T variant increases breast cancer risk, and little evidence that c.1066-6T>G confers an elevated risk. Analysis of additional families will be necessary to define more precisely the risk, if any, associated with c.1066-6T>G.     

RET基因调控区遗传变异与先天性巨结肠患病风险研究

目的先天性巨结肠（HSCR）是一种复杂的先天性疾病,RET是其主要的易感性基因。本研究对RET非编码区单核甘酸多态性（SNP）-5G〉A（rs10900296）,-1A〉C（rs10900297）和intron1 C〉T（rs2435357）进行分型分析,评估RET基因调控区SNPs及单倍型与先天性巨结肠之间的相关性。方法选取115名病例组病人和139名对照组正常人群,应用聚合酶链反应（PCR）技术和直接测序的方法进行基因分型。回归模型中使用OR值和95%置信区间（CI）作为基因型危险性的评价指标。结果 -5G〉A,-1A〉C,intron1C〉T各基因型频率在病例和对照人群的分布具有显著差异。-5 AA（OR=6.26,95%CI=3.62-10.83）,-1 CC（OR=7.54,95%CI=2.06-27.66）和intron1 TT（OR=19.22,95% CI=7.54-48.99）基因型均能显著增加HSCR发病的风险。单倍型A-C-T（OR=6.28,95% CI=3.77-10.46）和双体型A-C-T/A-C-T（OR=13.62,95% CI=3.48-53.30）分析同样表明与HSCR发病风险存在较强的相关性,并呈现出一定的累积效应。结论 RET基因调控区的基因多态性可能与HSCR的发病易感性有关,支持RET通路的常见变异在HSCR的发展过程中起着重要的作用的假设。     

Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population

BACKGROUND: Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T(H)2 inflammation. OBJECTIVE: We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. METHODS: A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. RESULTS: The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance (P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 (P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients (P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). CONCLUSIONS: The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.     

Adiponectin and resistin gene polymorphisms in association with their respective adipokine levels

Single nucleotide polymorphisms (SNPs) at the adiponectin and resistin loci are strongly associated with hypoadiponectinemia and hyperresistinemia, which may eventually increase risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS), and cardiovascular disease. Real-time PCR was used to genotype SNPs of the adiponectin (SNP+45T>G, SNP+276G>T, SNP+639T>C, and SNP+1212A>G) and resistin (SNP-420C>G and SNP+299G>A) genes in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40 and 70 years old. The genotyping results for each SNP marker was verified by sequencing. The anthropometric clinical and metabolic parameters of subjects were recorded. None of these SNPs at the adiponectin and resistin loci were associated with T2DM and MS susceptibility in Malaysian men. SNP+45T>G, SNP+276G>T, and SNP+639T>C of the adiponectin gene did not influence circulating levels of adiponectin. However, the G-allele of SNP+1212A>G at the adiponectin locus was marginally associated (P= 0.0227) with reduced circulating adiponectin levels. SNP-420C>G (df = 2; F= 16.026; P= 1.50×10(-7) ) and SNP+299G>A (df = 2; F= 22.944; P= 2.04×10(-10) ) of the resistin gene were strongly associated with serum resistin levels. Thus, SNP-420C>G and SNP+299G>A of the resistin gene are strongly associated with the risk of hyperresistinemia in Malaysian men.     

Evidence of a single origin for the most frequent mutation (R402W) causing glutaryl-CoA dehydrogenase deficiency: identification of 3 novel polymorphisms and haplotype definition

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia, biochemically by excretion of glutaric and 3-hydroxyglutaric acids in urine, and pathologically by neural degeneration of the caudate and putamen. To date, over 70 mutations in GCDH gene have been identified, single prevalent mutations have been found in communities in which GA I is particularly common, but generally GA I is heterogeneous. The most frequent mutation in Caucasians, R402W, has been identified in 12-16% of alleles. Here we report the frequency of mutation R402W in GA I Spanish patients, the characterization of three novel GCDH polymorphisms (IVS2+48T>C, IVS2-82T>G and 3'UTR 1518A>G) which, in combination with the two polymorphisms previously described (IVS2+64G>C, 1209G>T) gave rise to the first definition of GCDH haplotypes and their frequencies in control population. Linkage disequilibrium has been found between mutation R402W and a specific haplotype, suggesting a single origin for this mutation. Hum Mutat 15:207, 2000.     

Clinical, immunological and molecular characteristics of 37 Iranian patients with X-linked agammaglobulinemia

BACKGROUND: X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency characterized by an early onset of recurrent bacterial infections, a profound deficiency of all immunoglobulin isotypes and a markedly reduced number of peripheral B lymphocytes. Eighty-five percent of the patients with this phenotype have mutations in Bruton's tyrosine kinase (BTK) gene. METHODS: To provide an informative outlook of clinical and immunological manifestations of XLA in Iran, 37 Iranian male patients with an age range of 1-34 years, followed over a period of 25 years, were studied. Twenty-four of the 37 patients were screened for BTK gene mutation using PCR-SSCP followed by direct sequencing. BTK protein expression assay was done by flow cytometry in 9 families. RESULTS: All patients first presented with infectious diseases, the most common of which were respiratory tract infections. Eighteen different mutations were identified, 13 of which were novel: IVS1+5G>C, 1896G>A, 349delA, 1618C>T, 1783T>C, 2084A>G, 1346delT, 1351delGAG, 587A>G, IVS14-1G>A, IVS3+2T>C, 1482G>A, 1975C>A. CONCLUSION: The fact that we found a great number of novel mutations in a relatively limited number of patients underlines the heterogeneity of BTK mutations in the Iranian population. The large number of new mutations indicates that extended studies in this region would be rewarding.     

Allelic variants of CD40 and CD40L genes interact to promote antibiotic‐induced cutaneous allergic reactions

Background The danger hypothesis provides a new perspective of the mechanisms underlying drug allergy. In this study, we evaluated associations between variations in the genes involved in danger signal pathways and antibiotic‐induced cutaneous allergic reactions (AICARs). Methods Two hundred cases with urticaria, angio‐oedema, maculopapular rash, and erythema multiforme caused by antibiotics were extracted from the database of the Adverse Drug Reaction Research Group in Korea. All cases were confirmed by an allergy specialist. Causative antibiotics included penicillin, cephalosporin, quinolone, and others (approximately 40 different types). Ten single nucleotide polymorphisms (SNPs) in seven genes (?318C>T, +49A>G, and +6230G>A in CTLA4, IVS+17T>C in CD28, ?3479T>G and I170V in CD86, ?1C>T in CD40, ?3458A>G in CD40LG, ?308G>A in TNF, and ?31T>C in IL1B) were scored for cases and for healthy subjects without a history of AICARs. Results Our analysis failed to reveal differences in the distribution of the 10 SNPs between cases and controls. However, we could find a gene–gene interaction between ?1C>T in CD40 and ?3458A>G in CD40L using multifactor dimensionality reduction analysis. Subjects with minor alleles of both SNPs showed a significant risk for developing AICARs [P=0.017, odds ratio (OR) (95% confidence interval)=2.93 (1.20–7.97)]. Conclusion Our findings suggest that a genetic interaction between CD40 and CD40L favours the development of AICARs.     

Association of the osteoprotegerin gene polymorphisms with bone mineral density in postmenopausal women

OBJECTIVES: Osteoprotegerin (OPG) is a recently discovered member of the tumour necrosis factor receptor superfamily. It plays a crucial role in the control of bone resorption and its gene could therefore be a good candidate gene for osteoporosis. The aim of our work was to find polymorphisms in the OPG gene and to investigate their possible contribution to the genetic susceptibility to osteoporosis by testing for their association with bone mineral density (BMD). METHODS: The whole OPG gene coding region was screened for the presence of polymorphisms in a group of 60 osteoporotic women by single-strand conformation polymorphism analysis (SSCP) approach. Association of the discovered polymorphisms with bone mineral density was investigated in 136 Slovenian postmenopausal women. RESULTS: We detected eight OPG gene polymorphisms that were confirmed by direct DNA sequencing, deletion 4752_4753delCT and nucleotide substitutions 1181G>C, 1217C>T, 1284G>A, 4501C>T, 6893A>G, 6950A>C and 8738T>A. Nucleotide substitutions 1284G>A and 8738T>A have not been previously described. Polymorphisms 4752_4753delCT, 6893A>G and 6950A>C were in complete linkage and the same was true for 1217C>T and 4501C>T. The association with BMD was found only for polymorphism 1181G>C. Subjects with genotype 1181GG had significantly lower lumbar spine BMD than subjects displaying 1181GC. CONCLUSIONS: By our approach we detected eight polymorphisms in the OPG gene. According to our analysis polymorphism 1181G>C is associated with BMD and could therefore be considered as an element of genetic susceptibility to osteoporosis.     

Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes

Mutations in the proteolipid protein 1 (PLP1) gene cause the X-linked dysmyelinating diseases Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). We examined the severity of the following mutations that were suspected of affecting levels of PLP1 and DM20 RNA, the alternatively spliced products of PLP1: c.453G>A, c.453G>T, c.453G>C, c.453+2T>C, c.453+4A>G, c.347C>A, and c.453+28_+46del (the old nomenclature did not include the methionine codon: G450A, G450T, G450C, IVS3+2T>C, IVS3+4A>G, C344A, and IVS3+28-+46del). These mutations were evaluated by information theory-based analysis and compared with mRNA expression of the alternatively spliced products. The results are discussed relative to the clinical severity of disease. We conclude that the observed PLP1 and DM20 splicing patterns correlated well with predictions of information theory-based analysis, and that the relative strength of the PLP1 and DM20 donor splice sites plays an important role in PLP1 alternative splicing.     

Identification of novel SNPs in the interleukin 6 receptor gene (IL6R)

The human interleukin-6 receptor (IL6R) is responsible for signal transduction of IL6 that might have associations with immune diseases and various infectious diseases. We have sequenced all 10 exons including the putative splicing site to identify single nucleotide polymorphisms in IL6R. Seven novel single nucleotide polymorphisms (SNPs) were identified; one SNP in the promoter region (-183G>A), one synonymous SNP in exon 2 (24013G>A: Ala31Ala), one non-synonymous SNP in exon 9 (48892A>C: Asp358Ala) and four in introns (29753A>C, 42700T>C, 48869T>A and 59818C>T). The frequencies of each SNP in the Korean population (n=300) were 0.48 (-183 G>A), 0.13 (24013 G>A), 0.41 (29753A>C), 0.41 (42700T>C), 0.1 (48869T>A), 0.42 (48892A>C), and 0.07 (59818C>T), respectively. Haplotypes and their frequencies were estimated by the EM algorithm. Linkage disequilibrium coefficients (/D'/) between each SNP pair were also calculated. The information on SNPs and haplotypes in IL6R would be useful for genetic studies of this gene.     

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.     

Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women

Maternal impairments in folate metabolism and elevated homocysteinemia are known risk factors for having a child with Down syndrome (DS) at a young age. The 80G>A polymorphism of the reduced folate carrier gene (RFC-1) has been recently demonstrated to affect plasma folate and homocysteine levels, alone or in combination with the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. We performed the present study on 80 Italian mothers of DS individuals, aged less than 35 at conception, and 111 Italian control mothers, to study the role of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C genotypes to the risk of a DS offspring at a young maternal age. When polymorphisms were considered alone, both allele and genotype frequencies did not significantly differ between DS mothers and control mothers. However, the combined MTHFR677TT/RFC-1 80GG genotype was borderline associated with an increased risk (OR 6 (CI 95%: 1.0-35.9), P = 0.05), and to be MTHF1298AA/RFC-1 80(GA or AA) was inversely associated with the risk (OR 0.36 (CI 95%: 0.14-0.96), P = 0.04). Present results seem to indicate that none of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C polymorphisms is an independent risk factor for a DS offspring at a young maternal age; however, a role for the combined MTHFR/RFC-1 genotypes in the risk of DS pregnancies among young Italian women cannot be excluded.