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PubMed1995

Polymorphisms in angiotensin-converting-enzyme gene and progression of IgA nephropathy.

We have investigated the influence of the functional insertion (I) and deletion (D) polymorphism in intron 16 of the gene for angiotensin-converting enzyme (ACE) in a retrospective study of 100 patients with IgA nephropathy. There was no difference in genotype frequency compared with normal subjects. However, patients homozygous for the D allele tended to present at an earlier age (medians: DD, 33; ID, 34; II, 42 years) and to require renal replacement therapy at a younger age (medians 37, 42, and 48 years, respectively). The rate of progression was significantly worse in patients homozygous for the D allele. The DD genotype is associated with increased severity of disease in patients with IgA nephropathy.

Adult↗

PubMed1991

Detection of the common alpha-1-antitrypsin variants by denaturing gradient gel electrophoresis.

The well-characterized and highly polymorphic human alpha-1-antitrypsin (AAT) gene was used as a test locus to evaluate the general applicability of denaturing gradient gel electrophoresis (DGGE) for the detection of single base change polymorphisms. We report the resolution of all the major alleles, M1Ala, M1Val, M2, M3, S and Z and the identification of substantial genetic polymorphism in intron 3-4 by this technique. DGGE was found to be a quick and efficient method for the screening of multiple samples for the presence of genetic variation.

Alleles↗

PubMed2004

Interleukin-4 gene polymorphisms in Japanese and Caucasian patients with aggressive periodontitis.

OBJECTIVES: Recently, interleukin (IL) 4 gene polymorphisms have been analyzed in association with periodontitis. Genetic differences between Caucasian and Japanese patients with periodontitis have previously been detected. The aim of the present study was to analyze IL-4 genotypes in Caucasian and Japanese patients with aggressive periodontitis (AgP). MATERIAL AND METHODS: One hundred and twenty-four subjects were included in the study, 31 Japanese and 30 Caucasian patients with generalized AgP, plus 30 Japanese and 33 Caucasian healthy controls. IL-4 polymorphisms were determined by polymerase chain reaction. A logistic regression was used to investigate the possible association of the genotypes with the disease in both populations. Odds ratio (OR) estimates were analyzed for allele frequencies. RESULTS: No significant association of IL-4 polymorphisms with the risk of AgP was determined in either population. However, the allele frequencies showed different results between populations. The carriage of the polymorphism in intron 2 was higher in Caucasian patients compared with controls (OR: 2.0, 95% confidence interval: [1.0;4.2]. Furthermore, the frequency of the IL-4 promoter/intron 2 composite genotype (PP+/IP+) in patients and controls, respectively, was found to be approximately 25% and 60% higher in the Japanese population than in the Caucasian population. CONCLUSION: There was no evidence of an association of IL-4 genotypes and AgP in either population, although the frequencies of the IL-4 genotypes in the Japanese and the Caucasians were different.

Adult↗

PubMed2005

No Evidence for BRAF as a melanoma/nevus susceptibility gene.

Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.

Alleles↗

PubMed2003

Genetic variation at the scavenger receptor class B type I gene locus determines plasma lipoprotein concentrations and particle size and interacts with type 2 diabetes: the framingham study.

The scavenger receptor class B type I (SR-BI) is a key component in the reverse cholesterol transport pathway. We have previously reported three common polymorphisms associated with plasma lipids and body mass index. We hypothesized that diabetic status may interact with these polymorphisms in determining plasma lipid concentrations and particle size. We evaluated this hypothesis in 2463 nondiabetic (49% men) and 187 diabetic (64% men) participants in the Framingham Study. SR-BI and APOE genotypes, anthropometric, clinical, biochemical, and lifestyle variables were determined. After multivariate adjustment, we found a consistent association between the exon 8 polymorphism and high-density lipoprotein cholesterol concentration and particle size. Interaction effects were not significant for exon 8 and intron 5 polymorphisms. However, we found statistically significant interactions between SR-BI exon 1 genotypes and type 2 diabetes, indicating that diabetic subjects with the less common allele (allele A) have lower lipid concentrations. For low-density lipoprotein cholesterol, the adjusted means (+/-SE) were 3.31 +/- 0.03 and 3.29 +/- 0.04 mmol/liter for G/G and G/A or A/A in nondiabetics, respectively, compared with 3.19 +/- 0.10 and 2.75 +/- 0.01 mmol/liter for G/G and G/A or A/A in diabetics (P = 0.03 for interaction). Similar results were obtained for HDL(2)-C. In conclusion, SR-BI gene variation modulates the lipid profile, particularly in type 2 diabetes, contributing to the metabolic abnormalities in these subjects.

Alleles↗

PubMed2004

Calsquestrin 1 (CASQ1) gene polymorphisms under chromosome 1q21 linkage peak are associated with type 2 diabetes in Northern European Caucasians.

Genome-wide scans in multiple populations have identified chromosome 1q21-q24 as one susceptibility region for type 2 diabetes. To map the susceptibility genes, we first placed a dense single nucleotide polymorphism (SNP) map across the linked region. We identified two SNPs that showed strong associations, and both mapped to within intron 2 of the calsequestrin 1 (CASQ1) gene. We tested the hypothesis that sequence variation in or near CASQ1 contributed to type 2 diabetes susceptibility in Northern European Caucasians by identifying additional SNPs from the public database and by screening the CASQ1 gene for additional variation. In addition to 15 known SNPs in this region, we found 8 new SNPs, 3 of which were in exons. A single rare nonsynonymous SNP in exon 11 (A348V) was not associated with type 2 diabetes. The associated SNPs were localized to the region between -1,404 in the 5' flanking region and 2,949 in intron 2 (P = 0.002 to P = 0.034). No SNP 3' to intron 2, including the adjacent gene PEA15, showed an association. The strongest associations were restricted to individuals of Northern European ancestry ascertained in Utah. A six-marker haplotype was also associated with type 2 diabetes (P = 0.008), but neither transmission disequilibrium test nor family-based association studies were significant for the most strongly associated SNP in intron 2 (SNP CASQ2312). An independent association of SNPs in introns 2 and 4 with type 2 diabetes is reported in Amish families with linkage to chromosome 1q21-q24. Our findings suggest that noncoding SNPs in CASQ1 alter diabetes susceptibility, either by a direct effect on CASQ1 gene expression or perhaps by regulating a nearby gene such as PEA15.

Calsequestrin↗

PubMed2003

Congenital bilateral absence of the vasa deferentia and related respiratory disease.

In a meaningful proportion of cases, CBAVD has been recognised as a probable consequence of cftr gene mutations. This lead to a further enlargement of the spectrum of clinical pictures due to "cftr deficiency". More recently, the identification of a polymorphism in intron 8 regulating the level of correct cftr transcription, shed new light on the genotype-fenotype correlation of cftr mutations. Unfortunately, little information is still available on the clinical manifestations of CBAVD other than infertility. History, clinical picture, sweat test and genotype were carefully evaluated in a series of 21 patients affected by CBAVD, selected on the basis of otherwise unexplained obstructive azoospermia. History collection was especially addressed to respiratory symptoms. Family history was always negative for CF. Nevertheless, personal history showed respiratory symptoms in 18 cases (86%) 9/21 (43%) patients suffered from chronic sinusitis and one of these had had a pneumothorax. Other 9 (43%) patients had chronic nasal obstruction, due to recurrent nasal poliposis in two cases. Sweat test was clearly abnormal in 15/21 (71%) and borderline in the remaining 6 patients (29%). Genetic analysis allowed detection of one mutation in 15/21 patients (71%). Our data show that respiratory symptoms may be present in CBAVD patients, so that CBAVD cannot be merely considered a "genital form" of CF.

Adult↗

PubMed2000

Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis.

The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis are not fully understood. Recent studies suggest that apoptosis is involved in the abnormal neural death that occurs in this devastating disease. Presenilin-1, a transmembrane protein, seems to be implicated in apoptosis. To determine whether presenilin-1 intron 8 polymorphism has an influence in the course of amyotrophic lateral sclerosis, we examined this polymorphism genotypes in a large group of patients (n = 72) with amyotrophic lateral sclerosis and in a random sample of 213 healthy individuals. The results showed a significant difference in genotype (P < 0.04) and allele (P < 0.03) distribution between patients controls. These results suggest a possible intervention of presenilin-1 in the pathogenesis of amyotrophic lateral sclerosis.

Adult↗

PubMed2000

Characterization of the alternate allelic forms of human PAX7.

Six different allelic forms of the human neurogenic and myogenic developmental gene, PAX7, have been identified. They are distinguished by the number of tandem tetranucleotide, GAAG, repeats at a polymorphic site within the second intron of the paired box. Within the same intron, a second polymorphic site was found to have variable numbers of a dinucleotide TG repeat. The alleles are identified by a PCR-based method with oligo primers that span the variable regions of the intron. Several of the alleles include a duplicate copy of the entire paired box. Segregation studies demonstrate that the PAX7 alleles are inherited in a Mendelian fashion and that the duplicate copies of the PAX7 paired box region present in some of the alleles are closely linked. This initial study identified differences in the distribution of PAX7 alleles in DNA from patients with the skeletal muscle myopathy, dermatomyositis. Recognition of genetic polymorphism of PAX7 allows new approaches to understanding the role of PAX7 in myogenesis, neurogenesis, and neuromuscular disorders.

Alleles↗

PubMed2000

Polymorphisms of tryptophan hydroxylase gene and the symptomatology of schizophrenia: an association study.

Serotonergic neurotransmission may be involved in the etiology of schizophrenia. We systematically searched for human tryptophan hydroxylase (TPH) coding polymorphisms, and detected a novel pentanucleotide repeat deletion polymorphism (GTTTT)4/5 in TPH intron 1b. We also confirmed A779C intron 7. Neither polymorphism showed a significant association with schizophrenia (182 patients with schizophrenia, 148 controls). A significant association, however, between A779C genotypes and the total Manchester Scale (MS) scores was found in male patients (P = 0.045). Subsequently, a significant association was also found between A779C genotypes and the MS negative symptoms scores in male patients (P = 0.030). These results suggest that the TPH gene may play a role in the negative symptoms in male patients with schizophrenia.

Alleles↗

PubMed1998

The nature of polymorphism of the HLA-DRB intron sequences is lineage specific.

The sequence database of HLA-DRB genes is mainly derived from mRNA analysis or has focused exclusively on the polymorphism of the 2nd exon. Little is known about the non-coding sequences of the different DRB alleles which represent about 94% of the genes. In this study we have determined the sequence of the 3' 500 bp intron 1 fragment adjacent to exon 2 in all serologically defined HLA-DRB genes and their most frequent allelic subtypes. The intron sequences turned out to be highly polymorphic. Similar to the class I introns, this variability was not characterized by random point mutations but by a highly systematic diversity reflecting the lineage-specific relationship of the HLA-DR alleles. With a few exceptions in DRBI*15, 13 and 08 as well as DRB4 and 5, the variability mirrors the serological diversity. As well as delivering insight into the genetic relationship between the different DRB alleles, these sequences will provide an extremely valuable basis for developing advanced DRB sequencing strategies for clinical purposes.

B-Lymphocytes↗

PubMed2000

Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes.

The products of proliferating cell nuclear antigen (PCNA) and flap endonuclease (FEN1) genes are multifunctional proteins that are involved in DNA replication and damage repair. Yeast models suggest association of mutant forms of PCNA and FEN1 with genomic instability. In our study, we have determined the single nucleotide polymorphisms in human PCNA and FEN1 genes. We sequenced the coding region and adjacent noncoding region of both the PCNA and FEN1 genes in 120 alleles (60 individuals). In the PCNA gene, we detected 9 sequence variants with Hardy-Weinberg allele frequency ranging from 0.008 to 0.088. No polymorphism was detected in the FEN1 gene. The sequence variants in the PCNA gene included 7 intronic single nucleotide polymorphisms (SNP) and 2 synonymous exonic SNPs. All the intronic SNPs were located in introns 1 and 4, which contain several regulatory elements involved in the control of PCNA gene expression. Six of the 7 intronic SNPs showed complete linkage disequilibrium. We confirmed this allelic linkage disequilibrium by allele-specific PCR sequencing. We genotyped 117 additional individuals belonging to 3 population subgroups using the PCR-RFLP method. Finally, to see if the detected polymorphisms are associated with any cancer type, we genotyped cases with melanomas (37 cases), breast cancers (118 cases) and lung cancers (100 cases). We did not find statistical difference in frequency of polymorphism in any cancer type compared with healthy controls, although in breast cancer the frequency was low. Our results suggest that the coding regions of the PCNA and FEN1 genes are highly conserved when compared with other DNA repair genes. The potential of some of the detected intronic polymorphisms to effect regulation of the PCNA gene expression remains to be determined.

Alleles↗

PubMed1991

Oligonucleotide fingerprinting using simple repeat motifs: a convenient, ubiquitously applicable method to detect hypervariability for multiple purposes.

A panel of simple repetitive oligonucleotide probes has been designed and tested for multilocus DNA fingerprinting in some 200 fungal, plant and animal species as well as man. To date at least one of the probes has been found to be informative in each species. The human genome, however, has been the major target of many fingerprinting studies. Using the probe (CAC)5 or (GTG)5, individualization of all humans is possible except for monozygotic twins. Paternity analyses are now performed on a routine basis by the use of multilocus fingerprints, including also cases of deficiency, i.e. where one of the parents is not available for analysis. In forensic science stain analysis is feasible in all tissue remains containing nucleated cells. Depending on the degree of DNA degradation a variety of oligonucleotides are informative, and they have been proven useful in actual case work. Advantages in comparison to other methods including enzymatic DNA amplification techniques (PCR) are evident. Fingerprint patterns of tumors may be changed due to the gain or loss of chromosomes and/or intrachromosomal deletion and amplification events. Locus-specific probes were isolated from the human (CAC)5/(GTG)5 fingerprint with a varying degree of informativeness (monomorphic versus truly hypervariable markers). The feasibility of three different approaches for the isolation of hypervariable mono-locus probes was evaluated. Finally, one particular mixed simple (gt)n(ga)m repeat locus in the second intron of the HLA-DRB genes has been scrutinized to allow comparison of the extent of exon-encoded (protein-) polymorphisms versus intronic hypervariability of simple repeats: adjacent to a single gene sequence (e.g. HLA-DRB1*0401) many different length alleles were found. Group-specific structures of basic repeats were identified within the evolutionarily related DRB alleles. As a further application it is suggested here that due to the ubiquitous interspersion of their targets, short probes for simple repeat sequences are especially useful tools for ordering genomic cosmid, yeast artificial chromosome and phage banks.

Animals↗

PubMed2005

Polymorphisms of TNFalpha, IL1beta, and IL1RN genes in chronic obstructive pulmonary disease.

It is recognized that genetic factors play a role in the susceptibility to COPD. COPD is characterized by airflow limitation. Chronic inflammation causes small airway disease and parenchymal destruction, leading to the airflow limitation. Polymorphisms in pro-inflammatory cytokine genes may confer a risk for the development of COPD. A case-control association study was performed in Japanese population (88 COPD patients and 61 controls) and Egyptian population (106 patients and 72 controls). Genotype and allele frequencies of the TNFalpha -308 G/A and +489 G/A polymorphisms, the IL1beta -511 C/T, -31 T/C, and +3954 C/T polymorphisms, and a VNTR polymorphism in intron 2 of the IL1RN gene were investigated. In addition, pairwise haplotype frequencies were analyzed. When studied independently, none of the polymorphisms were associated with the development of COPD in both populations. However, in the Egyptian population, the distributions of the haplotype (IL1beta -31 T/C : IL1beta +3954 C/T) were significantly different between the COPD patients and the controls (p(corr)=0.0037). Our findings suggest that this haplotype within the IL1beta gene may be involved in the pathogenesis of COPD and that the genetic factors of COPD susceptibility might be different between different populations.

Aged↗

PubMed2006

Investigation of A218C tryptophan hydroxylase polymorphism: association with familial suicide behavior and proband's suicide attempt characteristics.

According to WHO, suicide accounts for about 1,000,000 deaths worldwide every year. In view of these dramatic data, several studies have tried to identify possible biological mechanisms and markers of suicide. Genes encoding for proteins involved in the serotonergic transmission are major candidates in association studies of suicidal behavior. The gene that codes for tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, is one of these candidates. Two polymorphisms in intron 7 of this gene (A218C and A779C) have been described, but their role in suicidal behavior remains uncertain. TPH A218C polymorphism was analyzed in a sample of 248 psychiatric patients and 63 healthy controls. In addition, at least one close relative member was interviewed to assess family suicidal behavior history. Our research confirmed that a positive history of suicide attempts in a family member is associated with the chance of an individual to attempt suicide. Furthermore, we demonstrated that familial suicide attempts are more lethal and frequently more violent. We were not able to find significant differences of the TPH genotype frequencies between patients and controls. The TPH A218C genotypes were not associated with a history of suicide attempt and the lethality of the most lethal lifetime suicide attempt and suicide attempt method. The authors conclude that the A218C polymorphism of the TPH gene may not be a susceptibility factor for suicidal behavior in this group of psychiatric patients but confirm that a family suicidal behavior history increases the proband's suicide attempt risk.

Adult↗

PubMedDate not supplied

A previously unknown polymorphism located within the RB1 locus only present in Asian individuals.

Although the retinoblastoma susceptibility locus (RB1) spans some 180 kb in the human and has been fully sequenced, few polymorphisms within the locus have been identified and none have been shown to vary in allelic frequency in different populations. We have identified a previously unknown polymorphism within intron 18 of the retinoblastoma susceptibility gene that is present in Asians but not in the other ethnic groups examined. This polymorphism eliminates a Tsp5091 restriction enzyme site, making it easily detectable for use in linkage analysis and genetic population studies.

Asia↗

PubMed2006

Vitamin D-binding protein (DBP) gene polymorphism is associated with Graves' disease and the vitamin D status in a Polish population study.

OBJECTIVE: Vitamin D-binding protein (DBP) genetic variants have an influence on vitamin D status and, therefore, they may contribute to the development of autoimmune diseases. In this case-control study, we investigated the association of DBP gene polymorphisms with susceptibility to Graves' disease (GD) in a Polish population. Furthermore, we analyzed the distribution of DBP genotypes in GD patients divided according to the clinical (gender, age of onset, ophthalmopathy, family history, smoking habits) and genetic parameters (CTLA4 49G and HLA-DRB1*03 alleles), as well as the vitamin D serum levels. METHODS: 332 polish patients with GD and 185 healthy controls were genotyped for the DBP gene single nucleotide polymorphisms (SNPs) at codon 420 ACG --> AAG (Thr --> Lys) and at codon 416 GAT --> GAG (Asp --> Glu) by the PCR-RFLP method. The variable (TAAA)N repeat polymorphism in the intron 8 was analyzed in 332 patients and 164 controls by the PCR amplification followed by the PAGE. In addition, 25(OH)D3 serum levels were measured in 110 patients. RESULTS: In patients with GD, the frequency of the Lys allele (34.2% vs. 25.7%, p = 0.005; OR = 1.50; 95% CI: 1.13-1.99) at codon 420 was significantly higher compared to controls. The distribution of codon 420 genotypes also differed significantly (p = 0.01), with the frequency of the Lys/Lys homozygotes (9.3% vs. 5.9%; OR = 1.63; 95% CI: 0.80-3.32) being higher in GD. The distribution of codon 416 alleles and genotypes did not differ in both studied groups (p = 0.59 and p = 0.81, respectively). Analysis of the intron 8 (TAAA)N repeat polymorphism led to the identification of a novel variant in the Polish population, described as 7 repeats, but no association between the intron 8 alleles and GD was observed. The 420 Lys allele was associated with lower 25(OH)D3 serum levels (p = 0.01). No correlation between the DBP genotypes and other susceptibility alleles or the GD clinical phenotype was observed. CONCLUSIONS: (i) The DBP gene Lys allele at codon 420 confers susceptibility to GD in the Polish population, (ii) the codon 416 alleles and intron 8 (TAAA)N variants are not associated with susceptibility to and clinical phenotype of GD, and (iii) the codon 420 Lys allele correlates with lower 25(OH)D3 serum concentration.

Adolescent↗

PubMed2005

Application of multiplex ARMS and SSCP/HD analysis in molecular diagnosis of cystic fibrosis in Indian patients.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The most severe, DeltaF508, mutation accounts for nearly 70% of CF cases worldwide. Besides DeltaF508, there are other point mutations, namely G542X, G551D, R553X, N1303K, and 621+1(G-->T), which are common among Caucasians. Additionally, a polyT polymorphism in intron 8 is also involved in the pathogenesis of CF. However, neither the prevalence nor the types of mutations causing CF in India are known. In this study, we aimed at estimating the frequency of the above common mutations and polymorphism in clinically suspected CF cases. We also carried out partial analysis of the CFTR gene, limited to exons 10 and 11, to identify other variations in these exons. METHODS: The multiplex amplification refractory mutation system (ARMS) test was applied for rapid simultaneous analysis of six most common CF mutations, in 100 normal and 39 elevated sweat chloride cases. The scanning of exons 10 and 11 was carried out by single-stranded conformation polymorphism/heteroduplex (SSCP/HD) analysis, followed by DNA sequencing in 50 normal and 37 elevated sweat chloride cases. A single ARMS-polymerase chain reaction assay was used to distinguish the 5T, 7T, and 9T alleles in 100 normal and 33 elevated sweat chloride cases. RESULTS: The multiplex ARMS analysis identified the DeltaF508 mutation at an allele frequency of 24% in Indian CF cases. However, the other predominant CF mutations were found to be absent. The 7T polyT variant was observed to be the most common allele, followed by the 9T, and 5T, which was the lowest. The DeltaF508 mutation was observed in all instances with the 9T variant. The SSCP/HD and DNA sequencing additionally revealed a known polymorphism (M470V, exon 10) and a known mutation [1525-1(G-->A), intron 9]. The 1525-1(G-->A) mutation, observed in a single 4-year-old male, is predicted to code for a class II defective CFTR protein. CONCLUSION: The findings of this study suggest a difference in relative frequencies and spectrum of CFTR mutations in Indian CF cases. A larger screening study of the entire CFTR gene in clinically well defined CF cases is required to delineate common mutations in the CFTR gene and enable molecular diagnosis of CF in India.

Amino Acid Substitution↗