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PubMed2006

Common polymorphisms in the promoter of the visfatin gene (PBEF1) influence plasma insulin levels in a French-Canadian population.

The adipokine visfatin (PBEF1) exhibits insulin-mimetic effects and correlates strongly with visceral adiposity. We sequenced visfatin gene exons and 1,480 bp of the promoter in 23 individuals, including 18 individuals from the Quebec Family Study (QFS) with varying degrees of abdominal visceral fat, assessed by computed tomography, and 5 individuals from the Saguenay-Lac-Saint-Jean region of Québec. We identified a synonymous polymorphism in exon 7 (SER301SER) but no nonsynonymous mutations. We observed an additional 10 polymorphisms, including 5 intronic, 4 within the promoter, and 1 within the 3' untranslated region. Further promoter sequencing (816 bp) identified five additional single nucleotide polymorphisms (SNPs) in the QFS population. To investigate the role of visfatin gene variants in obesity-related phenotypes, we genotyped a total of 13 SNPs in the promoter region of the gene. From these, we analyzed the seven common SNPs in the QFS sample (918 participants from 208 families). A significant association was found between two SNPs (rs9770242 and rs1319501), in perfect linkage disequilibrium, and fasting insulin levels (P = 0.002). These SNPs were also associated with fasting glucose (P <or= 0.02). In addition, a more distal SNP (rs7789066) was significantly associated with the apolipoprotein B component of VLDL (P = 0.012).

Adult↗

PubMed2000

Angiotensin-converting enzyme polymorphism and the risk of coronary heart disease in the Saudi male population.

OBJECTIVE: To determine the relevance of angiotensin I-converting enzyme (ACE) gene polymorphism for coronary artery disease (CAD) in the Saudi population. METHODS AND RESULTS: DNA of 84 male Saudi patients with established CAD, 36 male controls who underwent angiography, and 327 healthy Saudi male blood donors was amplified by polymerase chain reaction, using oligonucleotide primers flanking the insertion (I)/deletion (D) sites in the polymorphic region of intron 16 of the ACE gene. Polymerase chain reaction amplification resulted in 490-bp (II), 190-bp (DD), or 490- and 190-bp (ID) fragments. The genotype II distribution was 16.7% in the control group, 7.3% in the blood donor group, and 7.2% in the patients with CAD, and the distribution for DD was 58.3%, 47.1%, and 41.0%, respectively. Notably, 61.9% (P <.0001) of CAD patients presented with angina on admission, and 52.4% had diabetes mellitus. CONCLUSIONS: The results show no increased risk of CAD in association with either the II or DD genotypes in the Saudi population. However, further investigation of genotype II as a predictor for atherosclerosis rather than increased risk of coronary heart disease may be indicated.

Adult↗

PubMed1995

Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome.

To investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)n repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis.

Abnormalities, Multiple↗

PubMed2006

Low protein Z levels and risk of occurrence of deep vein thrombosis.

BACKGROUND: Protein Z (PZ) serves as a cofactor for activated factor X inhibition by the PZ-dependent protease inhibitor. In vivo and in vitro studies aimed at investigating the role of PZ levels in venous thombosis have produced conflicting results. OBJECTIVES: We investigated whether reduced PZ levels and PZ gene common variants are associated deep vein thrombosis (DVT). PATIENTS AND METHODS: In 197 patients with DVT and in 197 age-matched and sex-matched controls, PZ plasma levels and gene polymorphisms were evaluated by means of an enzyme-linked immunosorbent assay and direct cycle sequence analysis. RESULTS: Similar PZ levels were found in controls (1.44; SD 0.63 microg mL-1) and in patients (1.44; SD 0.96 microg mL-1). The incidence of PZ levels below the 5.0 (0.52 microg mL-1) or the 2.5 percentile of controls (0.47 microg mL-1) was higher in patients (10.2% and 8.7%, respectively) than in controls {4.1% [odds ratio (OR) 2.7, 95% confidence interval (CI) 1.2-7.3], and 2.0% (OR 4.6, 95% CI 1.5-13.9), respectively}. This relationship was independent of the effect of age, sex, and factor V Leiden and FII A(20210) alleles [OR 2.8 (95% CI 1.1-7.3), and OR 4.9 (95% CI 1.4-17.3)]. PZ levels were associated with the intron C G-42A and the intron F G79A polymorphisms in cases (r2=0.129) and in controls (r2=0.140). However, frequencies of the PZ gene polymorphisms were similar in the two groups and were not associated with very low PZ levels. CONCLUSIONS: The present data suggest an association between very low PZ plasma levels and the occurrence of DVT, with PZ gene polymorphisms contributing little to this relationship.

Adult↗

PubMed1993

Short report: insertion variant in intron 9, but not microsatellite in intron 2, of the insulin receptor gene is associated with essential hypertension.

OBJECTIVE: To determine whether a microsatellite polymorphism of the insulin receptor gene (INSR) is associated with essential hypertension, as has been demonstrated previously for an Rsal restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic hypertensive patients whose parents were both hypertensive, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the hypertensive and normotensive groups, or between obese and non-obese subgroups of hypertensives. This is in contrast to the significantly higher frequency seen for the R1- allele of an Rsal RFLP of INSR: 0.71 in the hypertensive group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of hypertensives and did not differ between obese and non-obese subgroups. The non-obese hypertensives also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the hypertension-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the hypertension-associated variants of INSR as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron.

Adult↗

PubMed2000

A recombination hotspot delimits a wild-species quantitative trait locus for tomato sugar content to 484 bp within an invertase gene.

In nature, genetic variation usually takes the form of a continuous phenotypic range rather than discrete classes. The genetic variation underlying quantitative traits results from the segregation of numerous interacting quantitative trait loci (QTLs), whose expression is modified by the environment. To uncover the molecular basis of this variation, we characterized a QTL (Brix9-2-5) derived from the green-fruited tomato species Lycopersicon pennellii. The wild-species allele increased glucose and fructose contents in cultivated tomato fruits in various genetic backgrounds and environments. Using nearly isogenic lines for the QTL, high-resolution mapping analysis delimited Brix9-2-5 to a single nucleotide polymorphism-defined recombination hotspot of 484 bp spanning an exon and intron of a fruit-specific apoplastic invertase. We suggest that the differences between the Brix9-2-5 alleles of the two species are associated with a polymorphic intronic element that modulates sink strength of tomato fruits. Our results demonstrate a link between naturally occurring DNA variation and a Mendelian determinant of a complex phenotype for a yield-associated trait.

Alleles↗

PubMed2001

[Molecular diagnosis of multiple type 2 endocrine neoplasia].

The paper reviews the data on the molecular structure of the protooncogene RET encoding for receptor-type protein kinase, on the mechanism of transformation of the normal protooncogene RET to a dominant transforming oncogene, and on RET mutations detected in patients with the MEN-2 syndrome. Moreover, it presents the authors' own findings. The familial medullary thyroid carcinoma burdened genealogy shows a new point mutation TCG(Ser)-->GCG(Ala) in codon 891, in the exon 15 of the protooncogene RET. This mutation was not detected in the chromosomes of healthy individuals. Analyzing the linkage with two known and two new polymorphic markers showed that there was a cisaggregation of informative polymorphic markers, phenotypic manifestation of the disease, and mutations in the genealogy in question. In the protooncogene RET, there were two new polymorphisms: G/A at position 24 in intron 14 and C/T in codon 836 (exon 14). The rate of the polymorphism encountered in codon 836 proved to be similar for the Russians and the Germans (0.96%), which was also seen for two earlier described polymorphisms in codon 691 (0.80 and 0.81, respectively) and in codon 904 (0.21 and 0.22). At the same time, there were statistically significant differences in the rates of intron 14 polymorphism (0.87 and 0.77, respectively). In a family having MEN 2, a proband displayed TGC-->CGC mutation in codon 634 of the gene RET in the heterozygous state. The mutation results in substitution of cysteine amino acid residue in the cysteine-rich extracellular domain of protein kinase encoded by the gene RET for arginine. The results of molecular analysis were used to confirm its clinical diagnosis and to indicate that effective care should be delivered in MEN 2a.

Alleles↗

PubMed2005

Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy.

Angiotensin-converting enzyme (ACE) activity is considered to be of major importance for the conversion of angiotensin (Ang) I to Ang II. Recently, a second ACE, named ACE2, has been identified. Experimental data provide evidence that ACE2 might be involved in modulating cardiac structure and function. In the present explorative study, we assessed whether polymorphisms in the ACE2 gene are related to echocardiographically determined parameters of left ventricular mass, structure or function in the general population. Five intronic single nucleotide polymorphisms (SNPs) were genotyped using the 5'-exonuclease activity (TaqMan) assay in the echocardiographic substudy of the third MONICA Augsburg survey. As ACE2 is located on the X chromosome, women and men were analysed separately. Four SNPs showed high pairwise linkage disequilibrium (rs4646156, rs879922, rs4240157 and rs233575). The minor alleles of these four SNPs were associated with higher left ventricular mass index (LVMI) and higher septal wall thickness (SWT) in men. Likewise, male carriers of a common haplotype (frequency 29.9%) consisting of the minor alleles of these four SNPs displayed higher values for LVMI and SWT than non-carriers (LVMI: TGGC 98.8+/-1.52 vs non-TGGC 94.8+/-0.99 g/m(2), p=0.027; SWT: TGGC 11.5+/-0.14 vs non-TGGC 11.1+/-0.09 mm, p=0.019). Furthermore, this haplotype was associated with an increased odds ratio (OR) for left ventricular hypertrophy (OR 3.10, p=0.006). In women, similar but less pronounced and consistent trends were observed. No association was observed between any of these SNPs and parameters of left ventricular systolic or diastolic function nor with blood pressure levels. This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, SWT and left ventricular hypertrophy in hemizygous men.

Adult↗

PubMed2001

[HindIII polymorphism of lipoprotein lipase gene and risk of myocardial infarction].

The purpose of this study was to determine whether HindIII restriction polymorphism found in intron 8 of lipoprotein lipase gene is associated with the onset of myocardial infarction (MI) in Russians and Tartars living in Bashkortostan. HindIII polymorphism was investigated by the polymerase chain reaction in myocardial infarction survivors (males aged under 55 years (98 Russians and 68 Tartars) and in controls (53 Russians and 80 Tartars). The distribution of genotypes and allele frequencies in the controls were as follows: the frequencies of genotypes HindIII(-/-), HindIII(+/-), and HindIII(+/+) in Russians (3.77, 49.06, and 47.17%, respectively) did not differ from those in Tartars (7.50, 51.24, and 41.25%, respectively), while the frequency of HindIII(-) allele was 28.30% in Russians and 33.13% in Tartars. Among Tartars, the HindIII(+/+) genotype was more common in myocardial infarction survivors than in controls (OR 2.03). In the Russians this genotype was not associated with the risk of MI. The frequencies of HindIII(+/+) genotype and allele HindIII(+) were significantly higher (OR 8.96 and 6.71, respectively) and frequencies of HindIII(+/-) genotype and allele HindIII(-) were lower (OR 0.13 and 0.15) in Russian patients with repeated MI. These findings indicate that HindIII polymorphism may be a genetic risk factor for MI before 55 years of age in the Tartars and for repeated MI in Russians. This association prompts genotyping of HindIII polymorphism for predicting MI recurrence in Russian survivors after MI.

Asian People↗

PubMed2005

A DNA sequence polymorphism in the endoglin gene is not associated with intracranial aneurysm or aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Endoglin is a member of the transforming growth factor beta family of proteins and plays a central role in vascular growth and development. There have been conflicting reports that polymorphic variation in the endoglin gene is a risk factor for intracranial aneurysms (IAs). We sought to further investigate the intron 7 5'-TCCCCC-3' endoglin polymorphism as a risk factor for IA and subarachnoid hemorrhage (SAH) in a population of patients from western Pennsylvania. METHODS: We genotyped 98 IA patients and 191 unaffected controls for a length polymorphism in intron 7 using PCR-based methods. RESULTS: The endoglin polymorphism was not associated with IA or the incidence of aneurysm rupture and SAH. No association was found when data were stratified by smoking and hypertension. CONCLUSION: These data, from a population recruited in western Pennsylvania, support recent findings in Japanese and German populations that, despite earlier observation to the contrary, endoglin is not associated with IA. Furthermore, our study extends previous observations by demonstrating no association between endoglin and either IA or SAH regardless of whether data were stratified for modifiable risk factors such as smoking and hypertension.

Adult↗

PubMed2003

BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer.

Germline mutations in the BRCA2 gene have been shown to be associated with familial female and male breast cancer. Mutations occur throughout the entire coding region of the gene, and there is considerable ethnic and geographical diversity in the deleterious mutations detected in different populations. No data exist on the role of the BRCA2 gene in the Cypriot population. In this study we present the results of characterizing mutations in the BRCA2 gene, in 26 Cypriot families with multiple cases of breast/ovarian cancer. The entire coding region, including splice sites, of BRCA2 were sequenced using cycle sequencing. In total 29 BRCA2 variants were detected which include 3 truncating mutations, 8 missense mutations, 6 polymorphisms and 12 intronic variants. The 3 truncating mutations are frameshift mutation 8984delG (exon 22), and two nonsense mutations, namely C1913X (exon 11) which is a novel mutation, and K3326X (exon 27). It is of interest that frameshift mutation 8984delG was the most frequent, since it was detected in 5 patients from three different families. Among the 6 polymorphisms detected, polymorphism T77T is novel and similarly 4 of the 12 intronic variants were also novel, namely IVS1+8G>A, IVS1-96insA, IVS4+36A>G and IVS11-51G>T. These results show that deleterious BRCA2 mutations, occur at the same frequency, about 20%, in Cypriot families, as that recorded in other European populations. We conclude that the BRCA2 gene plays a significant role in the familial breast cancer phenotype in the Cypriot population.

Adult↗

PubMed2006

Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis.

The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified. The two SNPs in exon 3 were in linkage disequilibrium. No significant difference was observed in either genotypic or allelic frequencies of these SNPs between controls (n = 260) and MAP dependent/psychotic patients (n = 170). Global analyses using the three SNPs and subcategory analyses on clinical parameters also showed no significant differences. These results suggest that the OPRD1 gene variants may not be a factor in vulnerability to MAP dependence/psychosis.

Adult↗

PubMedDate not supplied

An adenine trimer precedes a C/G polymorphism in the 3'-amplimer region of the human platelet glycoprotein IIIa intron 6 CT repeat.

Restriction enzyme and short tandem repeat polymorphisms are often used to link a particular allele with an inheritable disease-related gene in the absence of the information regarding the DNA mutation or defect. Polymorphic markers within the gene in question are particularly useful and can provide sufficient information for genetic counselling to potential carriers of the disease. Using a published method for the CT repeat in intron 6 of the GP3A gene, it was found that a single nucleotide deletion in the published genomic GP3A sequence in the region of the antisense amplimer and a C/G nucleotide polymorphism (allele frequencies, G = 0.883, C = 0.117) immediately adjacent to the deletion were responsible for the lack of PCR amplification. The absence of amplification has important implications for the assignment of a particular CT repeat to a given allele and for the population frequencies of the various CT repeats.

Adenine↗

PubMedDate not supplied

[Molecular analysis of hemophilia A in families of Northeastern Mexico].

We analysed DNA through Southern blot and polymerase chain reaction using blood samples of northeastern Mexican families affected by hemophilia A. Our aim was to identify possible carriers of the mutated gene by indirect detection using the Bcl I polymorphism (RFLP) at intron 18 of the factor VIII gene. The sample studied consisted of 43 individuals within eight families with hereditary hemophilia A. Of 17 possible carrier women, three were positive, five were negative, and in the remaining nine, the lack of informativeness (heterozygosity for the polymorphism) of their mothers precluded reaching conclusions. The frequencies found for the Bcl I polymorphism were 63% for the 1.2 kb allelic fragment and 37% for the 0.9 kb allelic fragment. Heterozygote women were found in 48.2% of the families studied. Our results show that probably, the Bcl I RFLP is more useful for HA carrier diagnosis in our sample (northeastern Mexico).

Alleles↗

PubMed2001

[A new pentanucleotide STR-marker, located in the intron of the ING1 tumor suppressor gene and its allelic polymorphism].

DNA samples of unrelated subjects from the Volga-Ural region of Russia were examined to study allele polymorphism of the pentanucleotide repeat (TTGTG)8 localized to an intron of the tumor suppressor gene ING1. STR marker was registered in the EMBL database with the accession number AJ277387. In a sample of 119 individuals, three pentanucleotide alleles consisting of seven, eight, and nine repeated monomers were revealed. The allele frequencies were 0.24, 0.74, and 0.02, respectively. Heterozygosity was 0.45. On the basis of these data, the repeat can be regarded as a polymorphic STR marker for the ING1 gene and used in population and clinical studies.

Alleles↗

PubMed2003

Polymorphisms of human TAP2 detected by denaturing gradient gel electrophoresis.

The human transporter associated with antigen processing (TAP1 and TAP2) genes are located in the human leukocyte antigen (HLA) class II region of the genome and encode proteins that form a heterodimer essential for the transport of endogenous peptides into the endoplasmic reticulum for assembly with HLA class I molecules. Type 1 diabetes is an autoimmune disease that is associated with the HLA region of the genome, with HLA class II genes conferring the greatest statistical risk. The presentation of self-peptides by HLA class I molecules is defective in individuals with this disease, and both TAP1 and TAP2 are potential contributors to this defect. Denaturing gradient gel electrophoresis (DGGE) was applied to screen all 11 exons and the 3' flanking region of TAP2 for polymorphisms in individuals with type 1 diabetes patients and controls. Seventy polymorphisms, including 51 in introns, 4 in the 3' flanking region, and 15 in exons, were identified. Sequencing of polymorphic DNA fragments revealed several new polymorphisms, including a Gln --> Arg substitution at codon 611 and a GT --> GC polymorphism affecting the donor splice site of intron 4, that might be of functional significance. None of the polymorphisms examined differed in frequency between individuals with type 1 diabetes and controls.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Monoamine oxidase B polymorphism, cigarette smoking and risk of Parkinson's disease: a study in an Asian population.

Cigarette smoking is associated with reduced monoamine oxidase B (MAO B) activity. Polymorphisms of the MAO B gene may modify the relationship between smoking and Parkinson's Disease (PD). We examined the association of MAO B intron 13 G/A polymorphism and risk of PD, and the modulation of the polymorphism on smoking and PD in an Asian study population in Singapore. Two hundred and thirty PD patients (mean age 66.0 +/- 9.4 years, 63% men) and 241 age, gender, and race matched controls (mean age 64 +/- 9.2 years, 58.9% males) were studied. The frequency of G and A alleles in PD and controls was; 66/315 (21.0%) vs. 73/340 (21.5%) and 249/315 (79.0%) vs. 267/340 (78.5%). For women, the genotype frequency in PD and controls was; GG: 7/85 (8.2%) vs. 8/99 (8.1%); GA: 25/85 (29.4%) vs. 27/99 (27.3%); AA: 53/85 (62.4%) vs. 64/99 (64.6%). For men, allele frequency in PD and controls was; A: 118/145 (81.4%) vs. 112/142 (78.9%) and G: 27/145 (18.6%) vs. 30/142 (21.1%). The allele and genotype frequencies were not significantly different between young and late onset PD. The frequency of "ever" smokers in PD and controls was 31/230 (13.5%) vs. 52/241 (21.6%), P = 0.02. A stepwise logistic regression analysis did not reveal any interaction of smoking and the G allele and risk of PD. The MAO B G/A genotype frequency in our Asian population was quite different from Caucasians suggesting that ethnicity specific effects need to be considered in evaluating gene-environmental interaction.

Aged↗

PubMed1998

Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A.

The voltage-gated sodium channel SCN8A is associated with inherited neurological disorders in the mouse that include ataxia, dystonia, severe muscle weakness, and paralysis. We report the complete coding sequence and exon organization of the human SCN8A gene. The predicted 1980 amino acid residues are distributed among 28 exons, including two pairs of alternatively spliced exons. The SCN8A protein is evolutionarily conserved, with 98.5% amino acid sequence identity between human and mouse. Consensus sites for phosphorylation of serine/threonine and tyrosine residues are present in cyoplasmic loop domains. The polymorphic (CA)n microsatellite marker D12S2211, with PIC = 0.68, was isolated from intron 10C of SCN8A. Single nucleotide polymorphisms in intron 19 and exon 22 were also identified. We localized SCN8A to chromosome band 12q13.1 by physical mapping on a YAC contig. The cDNA clone CSC-1 was reported by others to be a cardiac-specific sodium channel, but sequence comparison demonstrates that it is derived from exon 24 of human SCN8A. The genetic information described here will be useful in evaluating SCN8A as a candidate gene for human neurological disease.

Alternative Splicing↗