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PubMed2004

Lack of association between IL-12B gene polymorphism and autoimmune thyroid disease in Japanese patients.

Interleukin (IL)-12 is a key factor in cell-mediated immunity that drives the development of Th1 cells and stimulates T lymphocytes and natural killer cells to produce interferon (INF)-gamma. The IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33 and a linkage finding for autoimmune thyroid disease (AITD) on 5q31-33 in a Japanese population has been reported. It is also reported that the A/C polymorphism in the 3' untranslated region (UTR) of the IL-12B gene (1188A/C) is associated with IL12B mRNA expression levels. We attempted to determine whether genetic polymorphisms of the IL-12B gene are associated with AITD. One hundred three patients with Hashimoto's thyroiditis, 90 patients with Graves' disease, and 123 healthy control subjects were recruited. We detected the 1188A/C polymorphism using a PCR-RFLP method and the A/T polymorphism in intron 4 of the IL-12B gene using a cycle sequencing method. These IL-12B gene polymorphisms showed strong linkage disequilibrium, and their genotype and allele frequencies in the patients did not differ from those in the control subjects. Our results suggest that IL-12B gene polymorphisms were unlikely to have an effect on the development of Hashimoto's thyroiditis or Graves' disease in Japanese patients.

3' Untranslated Regions↗

PubMed2005

Effects of the osteopontin gene variants on milk production traits in dairy cattle.

Osteopontin (OPN) is a highly phosphorylated glycoprotein whose gene has been cloned and sequenced in different species. Several whole genome scans have identified quantitative trait loci (QTL) affecting milk production traits on bovine chromosome 6 close to the osteopontin gene (OPN) location. The presence of OPN in milk and its elevated expression in mammary gland epithelial cells together with previous QTL studies have prompted us to investigate the effects of OPN variants on milk production traits in the Holstein dairy cattle population. A single nucleotide polymorphism in intron 4 (C/T) was detected and primers were designed to amplify genomic DNA from 1362 bulls obtained from Cooperative Dairy DNA Repository and from 214 cows from the University of Wisconsin herd. For the Repository population, the C allele was associated with an increase in milk protein percentage and milk fat percentage. Correlation between milk protein percentage and milk fat percentage was about 0.57. For the University of Wisconsin herd, the estimates of the effects of allele C were in the same direction as for the Repository population, although these estimates did not reach statistical significance. Our results are consistent with other studies that showed a significant association of the microsatellite markers in the region of OPN with milk protein percentage and other correlated traits.

Alleles↗

PubMed2000

MspI polymorphism at +83 bp in intron 1 of the human apolipoprotein A1 gene is associated with elevated levels of HDL cholesterol and apolipoprotein A1 in nondiabetic subjects but not in type 2 diabetic patients with coronary heart disease.

OBJECTIVE: Elevated HDL cholesterol and its principal carrier protein apolipoprotein a1 [apo(a1)] are associated with reduced risk of coronary heart disease (CHD). No studies are available on the impact of the -75-bp and/or +83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We determined the prevalence of the: -75-bp and +83-bp polymorphisms of the apo(a1) gene by restriction fragment length polymorphism analysis among 308 unrelated nondiabetic subjects with CHD and among 251 unrelated patients with type 2 diabetes with CHD and in randomly selected 82 healthy men (CHD-). RESULTS: The rare M1- and M2- allele frequencies of the apo(a1) gene were 23 and 1.8%, respectively, among control subjects; 20 and 1.5%, respectively, among nondiabetic subjects with CHD; and 22 and 2.6%, respectively, among patients with type 2 diabetes and CHD (NS). Nonsmoking nondiabetic subjects with CHD having the M2+- genotype had higher HDL cholesterol (1.48 +/- 0.19 vs. 1.23 +/- 0.02 mmol/l, P < 0.01) and apo(a1) (1.43 +/- 0.10 vs. 1.36 +/- 0.02 g/l, P < 0.05) levels than subjects with the M2++ genotype, even after adjustment for confounding factors. This association was not found among patients with type 2 diabetes and CHD. CONCLUSIONS: We conclude that the +83-bp polymorphism of the apo(a1) gene is associated with elevated HDL cholesterol and apo(a1) levels in Finnish nondiabetic subjects but not in patients with type 2 diabetes.

Apolipoprotein A-I↗

PubMed2001

Interleukin-1beta gene and receptor antagonist gene polymorphisms in patients with calcium oxalate stones.

Interleukin-1 (IL-1) might play a role in the process of bone loss and hypercalciuria and is therefore considered to be involved in the formation of urinary stones. The aim of this study is to test whether the IL-1beta promoter region, exon 5 region and IL-1 receptor antagonist gene intron 2 polymorphisms could be genetic markers for the susceptibility to the formation of urinary stones. A control group of 152 healthy people and a group of 105 patients with recurrent calcium oxalate stone were examined in this study. Polymerase chain reaction (PCR) analyzed the variable number tandem repeats at intron 2 of the IL-1Ra gene for the polymorphisms. PCR-based restriction analysis was done for the IL-1beta gene polymorphisms of the promoter region and exon 5 by the endonucleases Ava I and Taq I, respectively. The polymorphisms studied in the IL-1beta genes did not reveal a strong association with calcium oxalate stone disease when compared with the control group (promoter region by chi-square test, P=0.627: exon 5 region by Fisher's exact test, P = 0.403). Only two frequent alleles of the IL-1Ra gene corresponding to one and two copies of an 86-bp sequence repeat were identified by PCR. The result revealed significant differences between control individuals and stone patients (P < 0.01. Fisher's exact test). In addition, the frequency of the type I allele in the stone group (99.0%) was higher than in the control group (94.0%). The odds ratio for the type I allele of the IL-1Ra gene in calcium oxalate stone disease is 6.041 (95% CI: 1.683 approximately 21.687). There is an association between urolithiasis and polymorphism in the IL-1Ra gene. No significant difference was found when dividing the stone patients into groups with normocalciuria and hypercalciuria in relation to these genetic polymorphisms. Further studies of the type I allele of the IL-IRa gene are worthwhile because of its correlation with stone disease. In our study, neither the IL-1beta promoter region nor the exon 5 polymorphisms were significantly different when comparing control subjects and calcium oxalate stone patients.

Adult↗

PubMed1996

Association between a polymorphism in the angiotensin-converting enzyme gene and microvascular complications in Japanese patients with NIDDM.

The relationship between diabetic nephropathy and an insertion (I)/deletion (D) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene is still under debate. The association of ACE gene polymorphism with nephropathy and retinopathy was therefore examined in 362 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) and 105 healthy control subjects. Distribution of the ACE genotype did not differ between healthy control subjects and diabetic patients without complications. However, the frequency of the D allele was significantly higher in the diabetic subjects with nephropathy than in those without (0.32 in normoalbuminuric patients vs 0.44 in albuminuria patients with albuminuria) (chi 2 = 7.7; p = 0.006). There was no significant association between ACE genotype and retinopathy. These observations thus demonstrate a significant association of the ACE gene polymorphism with nephropathy, but not with retinopathy, in Japanese patients with NIDDM.

Alleles↗

PubMed2005

Polymorphisms of the CHRNA4 gene encoding the alpha4 subunit of nicotinic acetylcholine receptor as related to the oxidative DNA damage and the level of apoptotic proteins in lymphocytes of the patients with Alzheimer's disease.

The study aimed at the analysis of polymorphisms in the gene coding for the nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) and the evaluation of the extent of the oxidative damage to DNA (8-oxo2dG), as well as the level of proteins participating in DNA repair (p53, PARP) and DNA degradation (Bax:Bcl-2, 85-kDa fragment) in the peripheral blood lymphocytes of the patients suffering from Alzheimer's disease (AD) and in the healthy individuals of the control group. In the AD patients the increased levels of oxidized guanine were demonstrated in DNA, accompanied by the elevated expression of p53, Bax, PARP, and of a 85-kDa protein subunit as well as an augmented ratio of Bax:Bcl-2. Also, the level of Bcl-2 protein was decreased. In the AD patients with the CHRNA4 polymorphisms the highest level of 8-oxo2dG and of proteins involved in DNA repair were documented in patients with polymorphisms in exon 5, in contrast to the patients with polymorphisms in intron 5. In the former patients, levels of pro- and antiapoptotic proteins remained at the same level. Both CHRNA4 polymorphisms and the extent of dementia seem to affect the levels of DNA oxidative damage as well as to activate factors that participate in the DNA degradation and its repair.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Association between achalasia and nitric oxide synthase gene polymorphisms.

BACKGROUND: Our group previously reported the absence of nitric oxide synthase (NOS) in the gastroesophageal junction of patients with achalasia. NOS exists in three distinct isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible isoform (iNOS). Some studies have shown that NO production is regulated by NOS polymorphisms. AIM: To assess whether some functional polymorphisms in the nNOS, iNOS, or eNOS genes are involved in susceptibility to suffer from achalasia. METHODS: Genomic DNA from 80 unrelated Spanish Caucasian patients with sporadic achalasia and 144 healthy subjects matched for age (+/-5 yr) and gender was typed by PCR and RFLP methods for the 27-bp variable number of tandem repeat (VNTR) polymorphism in intron 4 of the eNOS gene, a CA microsatellite repeat and a Nla III (C-->T) restriction fragment length polymorphism (RFLP) in exon 29 of the nNOS gene, and two nucleotide substitutions located in exon 16 (C-->T) and exon 22 (G-->A) of the iNOS gene. RESULTS: No significant differences in carriage, genotype, and allele frequencies of the nNOS, iNOS, or eNOS gene polymorphisms were found between patients with achalasia and controls. Individuals homozygous for genotype iNOS22*A/A tended to be more frequent in achalasia (20%vs 11%, odds ratio [OR] 1.79, 95% confidence interval [CI] 0.89-3.59, p= 0.09) as were those homozygous for the rare eNOS*4a allele (6.2%vs 1.4%, OR 4.5, 95% CI 0.89-22.67, p= 0.1) although the difference did not reach statistical significance. No differences in genotype and allele distribution were found with respect to epidemiological and clinical characteristics of patients with achalasia. CONCLUSION: Our data suggest that NOS gene polymorphisms are not involved in the susceptibility to and nature of the clinical course of sporadic achalasia. However, studies in a greater number of patients are required to analyze the tendency toward a higher prevalence of genotypes iNOS22*A/A and eNOS*4a4a.

Alleles↗

PubMed2005

No allelic variant associations of the IL-1 and TNF gene polymorphisms in the susceptibility to duodenal ulcer disease.

Recent studies have reported the association of a pro-inflammatory profile of genetic polymorphisms in IL-1B, IL-1RN, TNF-A, and IL-10 genes with an increased risk of non-cardia gastric cancer. Because gastric cancer and duodenal ulcer are mutually exclusive outcomes of Helicobacter pylori infection, we aimed to investigate possible allelic variant associations of several functional polymorphisms in the IL-1B, IL-1RN, TNFA, and LTA genes in the susceptibility to duodenal ulcer. Genomic DNA from 118 patients with duodenal ulcer and 97 healthy controls was typed for the IL-1B polymorphisms at positions -511, -31, and +3954, the VNTR polymorphism in intron 2 of the IL-1RN gene, the TNFA-308, TNFA -238, and the NcoI and BsI LTA polymorphisms by PCR, SSCP and TaqMan assays. H. pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs) use was investigated in patients and controls. Logistic regression analysis identified H. pylori infection (OR: 12.86; 95%CI: 3.85-43), NSAID use (OR: 11.95; 95%CI: 4.19-34.05), and family history-ulcer (OR: 3.79; 95%CI: 1.68-8.54) as independent risk factors for duodenal ulcer. When the effect of the combinations of IL-1 and TNF genotypes was studied we found that the distribution of all possible combinations of these eight polymorphisms was similar in duodenal ulcer patients and controls. The simultaneous carriage of alleles IL-1RN*2/IL-1B -31T/IL-1B -511C/IL-IB +3954C/TNF-HaplotypeE negative (termed in some studies as 'low-producing' alleles) was increased in H. pylori-positive duodenal ulcer patients compared to H. pylori-infected healthy controls (10.5% vs. 5.9%) although the difference did not reach statistical significance (OR: 1.85; 95%CI: 0.57-5.99, P = 0.41). Moreover, no differences were found with respect to H. pylori status, NSAID use, age, gender, smoking habit, type of complication, recurrence of the ulcer, and need for surgical treatment. Our data show no association between allelic variants of IL-1 and TNF gene polymorphisms in the susceptibility to and final outcome of duodenal ulcer.

Alleles↗

PubMed2004

A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism.

Current evidence suggests that estrogen plays a dominant role in determining bone mineral density (BMD) in men, and inactivating mutations in the aromatase CYP19 gene have been associated with low bone mass in young males. We previously reported an association between a TTTA repeat polymorphism in intron 4 of the CYP19 gene and osteoporotic risk in postmenopausal females. Here we explore the role of this polymorphism as a genetic determinant of BMD in a sample of elderly males who were recruited by direct mailing and followed longitudinally for 2 (n = 300) and 4 (n = 200) yr. Six different allelic variants, containing seven, eight, nine, 10, 11, and 12 TTTA repeats, were detected. There was a bimodal distribution of alleles, with two major peaks at seven and 11 repeats and a very low distribution of the nine-repeat allele. Men with a high-repeat genotype (>nine repeats) showed higher lumbar BMD values, lower bone turnover markers, higher estradiol levels, and a lower rate of BMD change than men with a low-repeat genotype ( 25), suggesting that the effect of CYP19 genotypes on bone may be masked by the increase in fat mass. Moreover, the high-repeat genotype was less represented, although not significantly, in the vertebral fracture group with respect to the nonvertebral fracture group. Functional in vitro analysis after incubation with [3H]-androstenedione showed a higher aromatase activity in fibroblasts from subjects with a high-repeat genotype than in fibroblasts from subjects with a low-repeat genotype. In conclusion, differences in estrogen levels due to polymorphism at the aromatase CYP19 gene may predispose men to increased age-related bone loss and fracture risk.

Aged↗

PubMed2003

A novel variable number of tandem repeat polymorphism of the renin gene and essential hypertension.

The aims of the present study were to find new genetic markers of essential hypertension (EH) and to investigate relationships between EH and polymorphisms of the renin gene. Using single strand conformation polymorphism, we discovered a new variable number of tandem repeat (VNTR) polymorphism in intron 7 that is 18 bp upstream from the boundary with exon 8. Nucleotide sequencing revealed that this VNTR polymorphism is a tandem repeat of the 4-nucleotide sequence TCTG. There were 6 alleles of this VNTR polymorphism, ranging from 7 repeats to 12 repeats. We analyzed the association between EH and this VNTR polymorphism. There was no significant difference in the overall distribution of this VNTR polymorphism between the EH and normotensive subjects. In summary, we discovered a novel VNTR polymorphism in the renin gene, and this polymorphism was not associated with EH.

Adult↗

PubMed2003

[Analysis of the mutations of BRCA1 in 9 familiar breast cancer patients].

OBJECTIVE: To analyze the mutations of BRCA1 in 9 Chinese familiar breast cancer patients. METHODS: Peripheral blood samples were obtained from 9 patients enrolled from 9 breast cancer families, one normal control, 32 sporadic breast cancer patients and 33 normal donors. DNA extracted from lymphocytes was amplified by polymerase chain reaction (PCR). The 22 exons and partial introns of BRCA1 were screened by PCR-denaturing high performance liquid chromatography (PCR-DHPLC) and confirmed by direct sequencing. RESULTS: Among these 9 familiar breast cancer patients, a deleterious mutation was detected in one case in exon 11 (3870delTGTC) which was a 4-base deletion and caused a frameshift in turn. One novel and unique amino acid substitution (E867R) was detected in one case. Eight patients were detected to have a known variation in intron 18 (IVS18 + 65G-->A), and the ratio of this variation detected was 88.9% (8/9). The ratio of this variation was 37.5% (12/32) in sporadic breast cancer patients or 33.3% (11/33) in normal control. This variation was found to be accompanied all the time with a known missense variation in exon 11 (P871L) and a polymorphism in intron 9 (IVS8-57delT). Those three variants were also detected in homozygous in one case, which implies the linkage of the 3 sites. The linkage had not been reported. Two patients had been found with a known polymorphism in exon 13 (S1436S). Another known polymorphism was found in one case (L771L). In addition, intronic variants (IVS2 + 48C-->T, IVS2 + 133C-->T, IVS12 + 112C-->A) were detected. CONCLUSION: The mutations of BRCA1 in Chinese familiar breast cancer patients are different from the hot spots reported in Caucasian and Jewish. It is important that further study be conducted to seek for specific mutations of this gene or other possible relevant genes in Chinese familiar breast cancer patients.

Asian People↗

PubMed1990

Prenatal diagnosis of haemophilia A by the polymerase chain reaction using the intragenic hind III polymorphism.

A method is described which uses the Hind III polymorphism in intron 19 of the factor VIII gene for genomic family analysis and prenatal diagnosis by the polymerase chain reaction. The primers derived from the exon 19 and 20 sequences allow amplification of the whole intron 19 resulting in a 730 bp fragment. Hind III restriction of this fragment provides fragments of 250 bp or 160 bp and 90 bp respectively, specific for the intragenic Hind III polymorphism. The constant 480 bp fragment can be used as an internal control to circumvent misdiagnosis due to incomplete or failure of restriction. Using this method a prenatal diagnosis of haemophilia A in the first trimester of pregnancy is demonstrated.

Base Sequence↗

PubMed1998

Cathepsin L gene organization in crustaceans.

The gene structure of a cathepsin L of the shrimp Penaeus vannamei has been determined by the polymerase chain reaction. It comprises six exons of various lengths spanning a total of 1792bp. This architecture is homologous to that of rat cathepsin L, three conserved sites of intron position have been effectively identified, with the exception of the third intron break-point located immediately after the cysteinyl active site. In contrast, no similarity is observed with Drosophila or Plasmodium cathepsin L-like gene organizations. This gene expresses a major cathepsin L enzyme in the hepatopancreas. The last intron is polymorphic, suggesting the presence of at least three different genes.

Amino Acid Sequence↗

PubMed2002

Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene.

We identified seven novel polymorphisms in the human low density lipoprotein receptor related protein 5 (LRP5) gene. Two of them are predicted to replace amino acid in LRP5 protein (c.314A>G: Q89R and c.4037T>C: V1330A), whereas three are silent mutations in the coding region (c.2268T>C: N740N, c.3405A>G: V1119V, and c.4137C>T: D1363D) and two are polymorphisms in introns (IVS10+6T>C and IVS17-30G>A). Since LRP5 recognizes apolipoprotein E and is genetically linked with type 1 diabetes, these novel polymorphisms will be useful in genetic studies of hyperlipoproteinemia and diabetes. To our knowledge, this is the first report in the literature of sequence variants in the human LRP5 gene.

DNA Mutational Analysis↗

PubMed2004

Exclusion of CYP46 and APOM as candidate genes for Alzheimer's disease in a French population.

Alzheimer's disease (AD) is a complex, multifactorial disorder, probably resulting from an interaction between environmental and genetic factors. Increasing evidence points to a link between cholesterol turnover and AD, suggesting that genes implicated in brain cholesterol homeostasis may be potential candidate genes for AD. With this background, we tested the potential association of the CYP46, APOM and APOF genes with the risk of developing AD. CYP46 encodes the enzyme cholesterol 24-hydrolase, which plays a key role in brain cholesterol turnover, and APOF and APOM encode apolipoproteins belonging to the large lipocalin family, which also includes ApoE. In contrast to two previous reports but in accordance with one other, we were unable to detect an association between an intron 2 polymorphism of CYP46 and AD. We also searched for polymorphisms within the APOM and APOF by dHPLC. We were unable to detect any polymorphisms in the coding and exon/intron sequences of the APOF. Finally, we excluded APOM as a genetic determinant of AD in our large French case control population.

Aged↗

PubMed1998

No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and non-suicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders.

Bipolar Disorder↗

PubMed2001

Lack of association between the tryptophan hydroxylase gene A218C polymorphism and attention-deficit hyperactivity disorder in Chinese Han population.

Previous studies have suggested that the serotonergic (5-HT) system might be involved in the development of Attention-deficit hyperactivity disorder (ADHD). ADHD is frequently characterized by aggressive and impulsive behavior, a major symptom associated with reduction in serotonergic function. The tryptophan hydroxylase (TPH) gene is a reasonable candidate for ADHD because it encodes the rate-limiting enzyme in the process of 5-HT biosynthesis. In this study, we examined the relationship between the A218C polymorphism in TPH gene and ADHD. Sixty-nine ADHD patients and their biological parents were investigated. The A218C polymorphism in intron 7 of TPH gene was detected by PCR-RFLP method. No allele or genotype concerned with this A218C polymorphism was found to be associated with ADHD when analyzed with the haplotype relative risk method. Therefore, our data indicate that the TPH gene A218C polymorphism may not be a susceptibility factor of ADHD in the Chinese Han population.

Alleles↗

PubMed1999

Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1).

LOH11A is a region of Chromosome (Chr) 11p15.5 where 75% of lung cancers show loss of heterozygosity (LOH). Clinical and cell biological studies suggest that LOH11A contains a tumor/metastasis suppressor gene. We have mapped this region (650 kb) using overlapping genomic P1/PAC/BAC clones, and one of the genes that we have identified is RRM1. This gene encodes the large subunit (M1) of ribonucleotide reductase, the heterodimeric enzyme that catalyzes the rate-limiting step in deoxyribonucleotide synthesis. By comparing our genomic sequences with the previously published cDNA, we have found that the human gene is composed of 19 exons. It is oriented telomere to centromere and is Alu rich. In order to verify that RRM1 maps within the boundaries of LOH11A, we assessed the frequency of LOH at a SacI polymorphism within intron IX of the gene. We observed LOH in 48% (15/31) of informative lung tumor specimens. To determine whether RRM1 was mutated in tumors, SSCP analysis of the 19 RRM1 exons was performed. No mutations were revealed in 12 pairs of normal and tumor DNA samples. Immunoblots on protein extracts from normal/tumor pairs indicated that a protein of the expected size was present in both. Our conclusion is that RRM1 lies within the LOH11A region, but that its exons are not mutated in tumors. The potential for RRM1 to act as a tumor suppressor is discussed.

Base Sequence↗