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PubMed2004

Splice-site genetic polymorphism of the human kallikrein 12 (KLK12) gene correlates with no substantial expression of KLK12 protein having serine protease activity.

The human kallikrein 12 (KLK12) gene is a new member of the KLK gene family, some members of which are implicated in the initiation and progression of cancer. In this study, we examined 50 non-cancerous tissues from Japanese patients with primary gastric cancer to determine the presence of genetic polymorphisms in the KLK12 gene using polymerase chain reaction (PCR)-single-strand conformation polymorphism and sequencing. Four different types of genetic polymorphisms were identified: one at a splice-donor site of intron 4 (c.457+2T>C), two in exon 6 (c.618_619delTG:p.Cys206fsX72 and c.735G>A:p.Met245Ile), and one in intron 3. The c.457+2T>C polymorphism was observed at a high frequency (allele frequency:0.63), compared to the frequencies of the two polymorphisms in exon 6 (allele frequency:0.01). Reverse transcriptase (RT)-PCR and Western blot analyses revealed that the c.457+2T>C polymorphism was associated with a splicing abnormality and that the expression of the human KLK12 protein (hK12), corresponding to the putative serine protease, was absent in individuals with a c.457+2C/C genotype but not in individuals with the T/T or T/C genotypes. We also found that recombinant His6-tagged hK12 has activity that cleaves chromogenic substrate (H-D-Pro-L-Phe-L-Arg-p-nitroaniline dihydrochloride), that is, serine protease activity. These results indicate that individuals with the c.457+2C/C genotype have no substantial expression of hK12 serine protease.

Carcinoma↗

PubMed2004

Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers.

Alterations in TGF-beta signaling appear to be associated with an altered risk of developing cancer, including breast cancer. We carried out a case-control study on 8 polymorphisms, including 5 in the TGF-beta1 gene (G-800A, C-509T, Leu10-->Pro, Arg25-->Pro and Thr263-->Ile), a polyalanine polymorphism (9A-->6A) in the TGF-betaRI gene and 2 (G-875A and A-364G) in the TGF-betaRII gene, using samples from 2 different populations, Polish familial and Finnish unselected breast cancer cases, together with ethnically and geographically matched controls. Additionally, familial breast cancer cases with respective controls from Sweden and Germany were studied in the Leu10-->Pro polymorphism, making the total number of familial cases 659. Allele, genotype and haplotype analysis on the TGF-beta1 gene as well as an analysis of the combinations of genotypes of the TGF-beta1 and its receptor genes in each individual were performed. Population differences in the allele and genotype distributions were found from 5 of the polymorphisms and 3 common haplotypes from the TGF-beta1 gene between the Finnish and other populations. However, no statistically significant difference between the breast cancer and healthy control groups was found for any of the 8 polymorphisms nor did the haplotype or genotype combination analysis reach statistical significance. Thus, none of the studied polymorphisms from the TGF-beta1 and its receptor genes was found to influence significantly susceptibility to breast cancer. The possible contribution of 6A/6A homozygosity in the TGF-betaRI gene to breast cancer needs to be confirmed in an independent study.

Activin Receptors, Type I↗

PubMed2005

Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico.

Several cytokine gene polymorphisms have been associated with increased risk of distal gastric cancer (GC) and its precursor histological markers in Caucasian, Asian and Portuguese populations although little is known about their role in other ethnic groups. Our study investigates the role of the IL-1B-31, IL-1RN and TNF-A-308 gene polymorphisms as risk factors for the development of GC in a Mexican population. We studied 278 patients who were enrolled at the Hospital Universitario Dr. Jose Eleuterio Gonzalez, Universidad Autonoma de Nuevo Leon. The subjects were divided into 2 groups. Sixty-three patients with histologically confirmed distal GC (mean age = 58.8 years, range = 22-84, F:M = 0.56), and 215 patients with no evidence of distal or proximal GC (mean age = 56.1 years, range = 18-92, F:M = 1.17). The IL-1B-31 and the TNF-A-308 polymorphisms were determined by PCR-RFLP and pyrosequencing, respectively, in all cases and controls. The VNTR polymorphism in intron 2 of the 1L-1RN gene was typed by PCR in 25 cases and 201 controls. The H. pylori status was determined by histology, rapid urease test, culture and serology for non-cancer controls and by histology for the GC cases. The carriage of the proinflammatory IL-1B-31*C allele was associated with increased risk of distal GC (odds ratio [OR] = 7.63, 95% confidence interval [CI] = 1.73-46.94, p = 0.003). When cases and controls were matched by age and gender, the OR value was higher (OR = 8.05, 95% CI = 1.8-50.22, p = 0.001). When only H. pylori GC cases and controls were compared, the OR value was 7.8 (95% CI = 1.05-161.8, p = 0.04). No association was found between any of the other polymorphisms studied and distal GC. In this Mexican population, the IL-1B proinflammatory genotype increases the risk of distal GC. These findings are similar to previous reports in Caucasian populations and underscore the importance of cytokine gene polymorphisms in the development of distal GC.

Adolescent↗

PubMed1996

The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal Mexican-American women.

We examined the association of bone mineral density (BMD) with a polymorphism in the gene encoding the vitamin D receptor (VDR) that causes a change in the predicted protein sequence. The polymorphism results from a C-to-T transition and creates an initiation codon (ATG) three codons proximal to a downstream start site. The polymorphism can be defined by a restriction fragment length polymorphism (RFLP) using the restriction endonuclease FokI. The presence of a FokI site, designated f, allows protein translation to initiate from the first ATG. The allele lacking the site (designated F), initiates from a second ATG site. Thus, translation products from these alleles are predicted to differ by three amino acids with the f variant elongated. In a group of 100 postmenopausal Mexican-American Caucasian women, subjects with the ff genotype (15% of the study population) had a 12.8% lower BMD at the lumbar spine than FF subjects (37% of the population) (p = 0.01). Heterozygote (Ff) subjects (48% of the population) had an intermediate BMD. This association between BMD and genotype was not apparent at the femoral neck or forearm. Over a 2-year follow-up period, a decrease in BMD at the femoral neck was greater in ff compared with FF subjects (-4.7% vs. -0.5%, p = 0.005). This trend was not apparent at the lumbar spine or forearm. There were no differences between genotype groups in measurements of 25-hydroxyvitamin D (25(OH)D), calcitriol, parathyroid hormone (PTH), osteocalcin, or urinary pyridinolines. We conclude that the FokI polymorphism of the VDR gene correlates significantly with decreased BMD at the lumbar spine and with an increased rate of bone loss at the hip in ff subjects. We emphasize that these initial data should be interpreted with caution but that the utility of this polymorphism as a genetic marker to determine BMD and osteoporosis risk warrants further study in larger populations with subjects of diverse ethnic backgrounds.

Aged↗

PubMed1989

Interleukin-1 alpha gene intron containing variable repeat region coding for the SP1 transcription factor recognition sequence is polymorphic.

Interleukin-1 alpha (IL-1 alpha) is a cytokine produced by a number of cell types including macrophages, fibroblasts, keratinocytes, and mesangial cells. We were interested in identifying a DNA restriction fragment length polymorphism (RFLP) for the IL-1 alpha gene for use in studies of genetic alteration in various human cancers. Human genomic DNA from 32 unrelated individuals was digested with various restriction enzymes, alone and in combination, and subjected to Southern blot analysis. Hybridization to 32P-labeled IL-1 alpha cDNA revealed an insertion-deletion-type polymorphic pattern. After digestion with RsaI, insertion-deletion-type polymorphic bands with sizes of 3.4 kb, 3.1 kb, and 2.8 kb and one invariant band of 0.8 kb were observed. These three alleles, designated A1, A2, and A3, had relative frequencies of 0.18, 0.06, and 0.78 with heterozygosity observed in 38% of the unrelated individuals studied. Evaluation of nine related individuals for this RsaI polymorphism was consistent with a Mendelian inheritance. Comparison of restriction patterns following Southern analysis of DNA digested with several different enzymes showed that the polymorphic region resides within the sixth intron. Furthermore, this RFLP results from a variable length region containing multiple copies of a recognition sequence for SP1, an imperfect copy of viral enhancer elements, and an inverse and complementary sequence of the glucocorticoid receptor binding site. The identified polymorphism may be of value in analyses of chromosome 2 and may help to elucidate mechanisms by which IL-1 alpha transcription is regulated.

Binding Sites↗

PubMed1992

Neuromuscular function and polymorphism of the acetylcholine receptor gamma gene.

Examination of inbred and wild mice has shown that the gene coding for the acetylcholine receptor gamma subunit is polymorphic and the polymorphism correlates with differences in neuromuscular function tested by two different methods. Polymorphism of the AChR gamma gene was demonstrated after digestion of genomic DNA with Pstl and Xbal. These two restriction enzymes demonstrated RFLP patterns specific for C57Bl/6J (PSXS) and C3H/HeJ (PRXR) mice, respectively. Examination of F1 (C3H/HeJ x C57Bl/6J) and F2 hybrid populations, and other murine inbred strains, showed the inheritance and strain specificity of the RFLPs. Testing wild mice demonstrated that the PSXS form of the AChR gamma gene is the most common in the wild. The AChR gamma and AChR delta subunits are closely linked and carried on the same chromosome as several contractile proteins. Because these genes are essential for correct neuromuscular development and activity, we investigated the possibility that the observed AChR gamma polymorphisms mark a haplotype which correlates with variations in neuromuscular function. Analysis of exercise times showed a correlation between AChR gamma polymorphism and neuromuscular function. To our knowledge, this is the first description of AChR polymorphism cosegregating with variations in neuromuscular function.

Animals↗

PubMed2000

Linkage disequilibrium testing of four interleukin-1 gene-cluster polymorphisms in Danish multiplex families with insulin-dependent diabetes mellitus.

The molecules of the interleukin 1 (IL-1) system have been suggested to play a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM), and polymorphisms in the genes encoding IL-1beta (IL1B), the IL-1 Type 1 receptor (IL1RTI) and the IL-1 receptor antagonist (IL1RN) molecules have been associated with IDDM in case-control studies. It can be difficult to exclude selection biases in case-control studies leading to spurious association. This risk is eliminated when using the transmission disequilibrium test (TDT). Hence, by means of the TDT we have investigated four intragenic IL-1 gene-cluster polymorphisms, the IL1B AvaI, the IL1B TaqI, the IL1RTI PstI and the IL1RN 2(nd)intron polymorphisms, for linkage and intra-familial association with IDDM in Danish IDDM multiplex family material comprising 245 families. We found no evidence for overall linkage or intra-familial association between any of the polymorphisms and IDDM. In addition, we did not find linkage between any of the polymorphisms and IDDM in HLA-DR3/4 heterozygous or HLA-non-DR3/4 heterozygous IDDM subjects, respectively. In conclusion, by means of intra-familial TDT analysis we found no linkage or intra-familial association between IDDM and the four IL-1 gene-cluster polymorphisms in Danish IDDM multiplex family material.

Denmark↗

PubMed2002

The use of DNA polymorphisms in genetic mapping.

The introduction of molecular markers has revolutionized genetics. The range of polymorphisms that are available is increasing and the advent of large-scale cDNA and genomic sequencing is a source of an ever-increasing set of available markers. The ease with which any particular marker type can be applied to an experimental system depends, to some extent, on the amount of genomic information available for that system. However, comparative genomics is enabling a wider range of marker technology to be applied to relatively information-poor systems. The types of markers that are available include restriction fragment length polymorphisms, amplified fragment length polymorphisms, ransom amplified polymorphic DNAs, simple sequence repeats, single nucleotide polymorphisms and small insertions/deletions. The types of questions that can be addressed with these molecular markers include the generation of genetic and physical maps for the identification of interesting loci, the development of marker-based gene tags, map-based cloning of agronomically important genes, synteny mapping, marker-assisted selection and quantitative trait analysis. The continued development of technology including new high throughput methods, for example those being applied to single nucleotide polymorphisms, will change the ease with which current questions can be answered as well as enable new analyses that are presently impossible to undertake.

Chromosome Mapping↗

PubMed1994

Polymorphisms of the apolipoprotein and angiotensin converting enzyme genes in young North Karelian patients with coronary heart disease.

The genes encoding apolipoproteins (apos) A-I, B, C-III and E as well as that encoding the angiotensin converting enzyme (ACE) have been proposed as candidate genes for coronary heart disease (CHD). We determined the common polymorphisms of the apo genes, previously found to influence serum lipid levels at the population level, and the insertion/deletion polymorphism of the ACE gene, recently reported to reflect the risk of myocardial infarction, in 82 very young (mean, 41 years) North Karelian Finns with symptomatic CHD and 50 controls of similar age. Patients with familial hypercholesterolemia had been excluded from this material. None of the polymorphisms examined, including the apo A-I promoter MspI, apo C-III SstI and apo B XbaI restriction fragment polymorphisms, a common variation of apo E (epsilon 2, epsilon 3 and epsilon 4 alleles) and an ACE insertion/deletion (I/D) polymorphism, was significantly associated with the risk of premature CHD. Patients with CHD had a higher mean serum LDL cholesterol/HDL cholesterol ratio than controls (3.15 +/- 1.30 vs 2.72 +/- 0.98, P < 0.05), but no significant associations between the common apo gene polymorphisms and serum lipid levels were disclosed in either group. It is possible that other genetic loci than those proposed to be associated with accelerated atherosclerosis may be more important as risk factors of symptomatic CHD at the age of 40 years.

Adult↗

PubMed1986

Restriction fragment length polymorphism (RFLP) of the human insulin receptor gene in Japanese: its possible usefulness as a genetic marker.

Restriction fragment length polymorphism of the human insulin receptor gene was analyzed with a 4.2 Kb cDNA probe in Japanese normal subjects and Type 2 (non-insulin-dependent) diabetic patients. Restriction endonuclease Rsa I digestion showed polymorphism of the human insulin receptor gene, with a band at 6.7 Kb, 6.2 Kb or 3.6 Kb. The frequency of the 6.7 Kb band was less than that in Caucasians. Furthermore, 15% of all the Japanese subjects examined lacked a 3.6 Kb band, which is commonly found in Caucasians. We have also detected restriction fragment length polymorphism in the human insulin receptor gene by Pvu II or Stu I digestion. Although no significant association of restriction fragment length polymorphism with Type 2 diabetes was found in the present study, our results suggest that the restriction fragment length polymorphism in the human insulin receptor gene varies among ethnic groups, and that the restriction fragment length polymorphism linked to the human insulin receptor gene might be a useful marker for the linkage study of the genes located close to the human insulin receptor gene on chromosome 19.

Adult↗

PubMed1991

Polymorphisms in the human X-linked pyruvate dehydrogenase E1 alpha gene.

Pyruvate dehydrogenase E1 alpha deficiency is an X-chromosome-linked disorder, often with fatal consequences. We have searched for genetically useful polymorphisms in or near this gene. No restriction fragment length polymorphisms were detected using a battery of 36 different restriction enzymes and probing with a full-length cDNA fragment, or two single-copy genomic fragments located within intron 8, and 15 kb 3' of the coding region, respectively. The chemical cleavage method was then applied to the detection of base changes in or near the gene. One polymorphism was found in exon 8 of the coding region. However, no base changes were detected in intron 3 or in the part of intron 8 covered by fragment gB2. Three blocks of microsatellite DNA containing variable numbers of CA-repeats were isolated from the 5' end of the gene and characterized. Length polymorphisms in these microsatellite DNAs were analysed using the polymerase chain reaction. Although the three loci are tightly linked, the polymorphisms appear not to be in disequilibrium, making them useful markers in linkage studies of the pyruvate dehydrogenase E1 alpha gene. Of 31 females analysed 12(39%) were heterozygous for at least one length polymorphism of the three (CA)n alleles.

Autoradiography↗

PubMed2003

High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR.

The recently described family of Toll-like receptors (TLRs) plays a major role in innate immunity by mediating inflammatory reactions against a wide array of pathogens. TLR-2 is reported to interact with various bacterial partial structures including lipoproteins, peptidoglycan, and lipoteichoic acid. Two polymorphisms of the TLR-2 gene have recently been described: Arg753Gln, correlated with the incidence of sepsis in a white population, and Arg677Trp, correlated with the incidence of lepromatous leprosy in an Asian population. Both polymorphisms, when inserted into expression vectors encoding for human TLR-2, reduced stimulation of Chinese hamster ovary cells by synthetic lipopeptides. We furthermore developed a rapid and inexpensive method for the detection of both single nucleotide polymorphisms based on restriction fragment length polymorphism. While no individuals carrying the Arg677Trp SNP were identified in a large group of whites, 9.4% of the study population were found to be heterozygous for the Arg753Gln polymorphism. This ratio is significantly higher than previously reported, and therefore detection of this polymorphism among patients may yield important information for the assessment of risk profiles regarding susceptibility to bacterial infections.

Alleles↗

PubMed1996

Effects of apoE gene polymorphism on Lp(a) concentrations depend on the size of apo(a): a study of 466 white men.

Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P = 0.05). Lp(a) was highest in the apoE genotypes epsilon 2 epsilon 3 and epsilon 3 epsilon 3 and lowest in genotype epsilon 3 epsilon 4, and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P = 0.04) in apoE genotype epsilon 2 epsilon 3 than in genotype epsilon 3 epsilon 3. Lp(a) concentrations did not differ among the XbaI (P = 0.65) or SP 24/27 (P = 0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P < 0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors.

Apolipoproteins A↗

PubMed2004

Bone mineral density of the lumbar spine is associated with TNF gene polymorphisms in early postmenopausal Japanese women.

We investigated the relationships between tumor necrosis factor (TNF) gene polymorphism, circulating TNF-alpha (TNF-alpha) concentrations, and bone mineral density (BMD) in the lumbar spine. TNF gene polymorphisms studied were the Nco I polymorphism within the first intron of TNF-beta (TNF-beta) and three single nucleotide polymorphisms in the promoter region of the TNF-alpha gene, at positions -857, -863, and -1031. Allelic variants of the TNF gene were identified using restriction fragment length polymorphism (RFLP) analysis in 177 postmenopausal Japanese women within 10 years after menopause, aged 56.4 +/- 4.5 years (mean +/- SD). A significantly higher prevalence of the alleles TNF-alpha-863A (20.3% versus 9.9%) and TNF-alpha-1031C (21.3% versus 12.4%) was seen in the low BMD group (Z-score < 0, n = 91) than in the high BMD group (0 < Z-score, n = 86). In genotype analysis, although difference did not reach a significant level, women with the rarest allelic variants, i.e., homozygous TNFbl, TNF-alpha-863A, and TNF-alpha-1031C, showed the lowest BMD Z-scores. Women with another rarest allelic variant, TNF-alpha-857T/T had significantly lower BMD Z-scores than did women with TNF-alpha-857C/T or -857C/C. The BMD Z-score decreased significantly with an increase in the total number of such rare alleles. Serum concentrations of TNF-alpha did not differ significantly among groups divided by genotypes. Multiple linear regression analysis revealed that the total number of rare alleles, in addition to the body mass index and the number of years since menopause, was an independent predictor of the BMD. These presumptive functional polymorphisms of the TNF gene may be associated with the lumbar spine BMD in early postmenopausal Japanese women.

Absorptiometry, Photon↗

PubMed2004

p53 codon 72 polymorphism and susceptibility malignancy of colorectal cancer in Taiwan.

PURPOSE: The p53 tumor suppressor gene plays two important roles in genomic stability: blocking cell proliferation after DNA damage until it has been repaired, and starting apoptosis if the damage is too critical. A recent report suggests that a polymorphism of the p53 tumor suppressor gene that results in the substitution of a proline residue with an arginine residue at position 72 of the p53 protein might act as a risk factor in the malignant transformation of colorectal adenoma to cancer. METHODS: In our study, the samples consisted of 150 patients were analyzed for the mutation in the p53 gene. The age of 150 patients (46 women and 104 men) ranged from 30 to 91 years (mean age 68.46 years). RESULTS: The polymorphism showed 52.04% mutant in the codon 72 of exon 4 in the Taiwanese population. Both of the chi-square for trend test (chi-square = 4.97, p = 0.034) and logistic regression (p = 0.037, odds ratio = 1.699) showed significant differences in the distribution of polymorphism of codon 72 in the p53 gene and Dukes classification of colorectal cancer. CONCLUSIONS: There were significant relationship between the polymorphism of codon 72 and the malignancy of colorectal cancer in Taiwanese population. There is 1.70 times in each grade change (Dukes A-D) more risk of CCC polymorphism than that of CCG polymorphism of codon 72 of exon 4.

Adult↗

PubMed2002

Influence of interleukin-12 receptor beta1 polymorphisms on tuberculosis.

Host genetic factors may be important determinants of susceptibility to tuberculosis, and several candidate gene polymorphisms have been shown to date. A series of recent reports concerning rare human deficiencies in the type-1 cytokine pathway suggest that more subtle variants of relevant genes may also contribute to susceptibility to tuberculosis at the general population level. To investigate whether polymorphisms in the interleukin-12 receptor (IL-12R) gene predispose individuals to tuberculosis, we studied these genes by single-strand conformational polymorphism analysis and direct sequencing. Although no common polymorphisms could be identified in the IL-12R beta 2 gene ( IL-12RB2), we confirmed four single nucleotide polymorphisms (SNPs; 641A-->G, 684C-->T, 1094T-->C, and 1132G-->C) causing three missense variants (Q214R, M365T, G378R) and one synonymous substitution in the extracellular domain of the IL-12R beta 1 gene ( IL12RB1). All SNPs were in almost perfect linkage disequilibrium (D'=0.98), and two common haplotypes of IL12RB1(allele 1: Q214-M365-G378; allele 2: R214-T365-R378) were revealed. Polymerase chain reaction/restriction fragment length polymorphism and sequence analyses were used to type IL12RB1polymorphisms in 98 patients with tuberculosis and 197 healthy controls in Japanese populations. In our case-control association study of tuberculosis, the R214-T365-R378 allele (allele 2) was over-represented in patients with tuberculosis, and homozygosity for R214-T365-R378 (the 2/2 genotype) was significantly associated with tuberculosis (odds ratio: 2.45; 95% CI: 1.20-4.99; P=0.013). In healthy subjects, homozygotes for R214-T365-R378 had lower levels of IL-12-induced signaling, according to differences in cellular responses to IL-12 between two haplotypes. These data suggest that the R214-T365-R378 allele, i.e., variation in IL12RB1, contribute to tuberculosis susceptibility in the Japanese population. This genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial dysfunction of interferon-gamma-mediated immunity.

Adult↗

PubMed1996

Novel polymorphisms and haplotypes in the human coagulation factor XIII A-subunit gene.

Novel polymorphic sites within the coding region of the human coagulation factor XIII A-subunit (F13A) gene and their haplotypic combinations with the other polymorphic sites thus far reported are presented. Polymorphic bands were detected in exons 2, 5, 8, 12 and 14 by using single strand conformational polymorphism analysis and antithetic forms of the polymorphic exons were linked with each other, cosegregating as distinct sequence haplotypes. In Finnish, German, and Russian populations a total of 18 haplotypes were observed of possible 72 haplotypic combinations of the 5 exons. Ten of the haplotypes detected were found to have no novel mutations but to be only combinations of preexisting mutations. No tightly associated combinations in pairwise comparisons between antithetic forms of the polymorphic exons were observed, indicating that there may be recombinational hotspots within the F13A gene region.

Amino Acid Sequence↗

PubMed2005

ATM polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) age of onset (United States).

OBJECTIVE: We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families. MATERIALS AND METHODS: We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis. RESULTS: The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population. CONCLUSIONS: Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Adaptor Proteins, Signal Transducing↗