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PubMed2004

Nonassociation of interleukin 4 intron 3 and 590 promoter polymorphisms with bronchopulmonary dysplasia for ventilated preterm infants.

Interleukin 4 (IL-4) stimulates and amplifies the inflammatory response, stimulates collagen synthesis in fibroblasts, promotes the progression to fibrosis and has been shown to inhibit the production of several inflammatory cytokines in the development of bronchopulmonary dysplasia (BPD) and airway hyperreactivity. We aimed to investigate whether IL-4 polymorphisms in ventilated preterm infants were associated with BPD. BPD was defined as infants who remained dependent on active respiratory support or oxygen supplementation at 36 weeks postconceptional age. A case-control study of 224 preterm infants (<30 weeks) who had respiratory distress syndrome and needed intermittent mandatory ventilation (IMV) were undertaken between January 1999 and December 2003. The typing of each genetic polymorphism was performed by polymerase-chain-reaction-based restriction analysis. Genotype distribution and allelic frequencies were compared between ventilated preterm infants who developed BPD and those who did not and the duration of IMV. The demography of these ventilated BPD and non-BPD preterm infants was not different. We observed no significant differences in genotype distribution or allelic frequency of the IL-4 intron 3 or IL-4 promoter polymorphisms between ventilated preterm infants who developed BPD and who did not. There was no significant association of the genotype or allelic frequency of IL-4 polymorphism with duration of IMV. We conclude that neither IL-4 intron 3 nor the 590 promoter polymorphism is a useful marker for predicting the susceptibility to BPD in ventilated Taiwanese preterm infants.

Bronchopulmonary Dysplasia↗
PubMed1999

The porcine hormone-sensitive lipase gene: sequence, structure, polymorphisms and linkage mapping.

The porcine hormone-sensitive lipase gene and its cDNA have been isolated and sequenced. Several putative regulatory sequences have been detected in the promotor region. The deduced amino acid sequence is 85% identical to the corresponding human, mouse and rat sequence. A search for polymorphisms revealed one intronic and one exonic polymorphism, the latter resulting in a conservative amino acid substitution. Linkage mapping located the LIPE gene close to the calcium release channel (CRC) locus on chromosome 6.

Amino Acid Sequence↗
PubMed2005

CYP19 (aromatase) haplotypes and endometrial cancer risk.

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)(n) repeat polymorphism in intron IV as well as a 3'UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case-control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989-1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning > 123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency > or = 5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13-2.48) to 2.07 (95% CI 1.33-3.23), comparing variant allele carriers to wild-type homozygotes. We observed significant interactions between menopausal status and 2 of the high-risk loci (p = 0.03 and p < 0.01), with > 2-fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high-frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women.

Adult↗
PubMed1999

The DD genotype of the angiotensin converting enzyme gene is negatively associated with right ventricular hypertrophy in male patients with chronic obstructive pulmonary disease.

The renin angiotensin system plays an important role in the development of pulmonary artery remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary hypertension as may occur in patients with COPD. Several polymorphisms of genes encoding for components of the renin angiotensin system such as the M235T polymorphism in the angiotensinogen gene, the 287-base-pair insertion (I)/deletion (D) polymorphism at intron 16 of the ACE gene, and the A1166C polymorphism in the angiotensin II type 1 receptor gene have been associated with an increased risk of cardiovascular diseases. With respect to the pulmonary circulation, only limited data exist on possible associations between polymorphisms of these genes and pulmonary hypertension and/or right ventricular hypertrophy. The objective of the present study was to investigate a possible relationship between polymorphisms of the renin angiotensin system and electrocardiographic evidence of right ventricular hypertrophy in patients with COPD. We therefore determined the angiotensinogen (M235T), angiotensin converting enzyme (I/D), and angiotensin II type 1 receptor (A1166C) genotypes in 87 patients with severe COPD and correlated these data with electrocardiographic parameters of right ventricular hypertrophy. Thirty-one patients (36%) of 87 patients with COPD showed electrocardiographic evidence of right ventricular hypertrophy. In the male, but not in the female, subgroup, the angiotensin-converting enzyme DD genotype was negatively associated with electrocardiographic evidence of right ventricular hypertrophy (male: chi2 = 3.8, p = 0.05; female: chi2 = 0.05, p = 0.82). We found no associations between the investigated polymorphisms in the angiotensinogen and angiotensin II type 1 receptor genes and electrocardiographic evidence of right ventricular hypertrophy.

Aged↗
PubMed2004

A 212-kb region on chromosome 6q25 containing the TAB2 gene is associated with susceptibility to type 1 diabetes.

The IDDM5 gene, which is identified by whole-genome searches, is located on chromosome 6q25. TAB2 (MAP3K7IP2 [mitogen-activating protein kinase kinase kinase 7 interacting protein 2]) is a potential candidate gene for type 1 diabetes because it is located on chromosome 6q25 and is involved in nuclear factor (NF)-kappaB regulation. We have conducted familial association studies using 478 families and demonstrate that a type 1 diabetes susceptibility gene resides within a 212-kb region containing the TAB2 gene (Tsp = 1.0 x 10(-2) to 4.0 x 10(-4)). No amino acid polymorphisms were detected in TAB2; however, multiple single nucleotide polymorphisms (SNPs) found within 5' untranslated, 3' untranslated, and intron regions were associated with type 1 diabetes susceptibility. Two additional genes, LOC340152, a predicted gene with currently unknown function, and SMT3, which has homology to SUMO (small ubiquitin-related modifier) were found within the 212-kb region and were associated with type 1 diabetes susceptibility. Functional studies of the three genes will be required to determine their biological relevance to type 1 diabetes. However, both TAB2 and SUMO are involved in NF-kappaB activation and may thus be involved in type 1 diabetes through apoptosis in pancreatic beta-cells.

3' Untranslated Regions↗
PubMed2006

Serotonin transporter protein polymorphism and harm avoidance personality in migraine without aura.

OBJECTIVE: To investigate polymorphisms in the serotonin transporter protein gene and harm avoidance personality dimension in patients with migraine without aura (MWOA). BACKGROUND: The serotonin transporter protein is a key modulator of serotonergic synaptic neurotransmission. Two polymorphic regions of the gene for serotonin transporter protein have been found, and are associated with variations in the functional activity of serotonin caused by differing transcriptional efficiency. The harm avoidance (HA) personality trait may also be heritable and associated with altered serotonergic neurotransmitter activity. DESIGN: We amplified the polymorphism in the promoter of serotonin transporter protein (5-HTTLPR) and the variable number of tandem repeats polymorphism within intron 2 (VNTR) using the polymerase chain reaction and performed genotype polymorphism analyses in 97 patients with MWOA and 100 healthy controls. We investigated serotonin-related personality traits by evaluating the HA personality dimension using a tridimensional questionnaire. RESULTS: The genotype frequencies and allele distributions of 5-HTTLPR did not differ between patients with MWOA and controls. The VNTR genotype STin2.12/STin2.12 was significantly more common in patients with MWOA (90%) than in controls (77%; P= .017). Patients with MWOA also had HA scores (21.9 +/- 6.4) significantly higher than those of controls (16.3 +/- 6.1; P < .001). CONCLUSIONS: Serotonergic activity might be involved in the development of MWOA and VNTR of serotonin transporter gene might be one of the genetically contributing factors.

Adult↗
PubMed2002

X-linked recessive Menkes disease: carrier detection in the case of a partial gene deletion.

X-linked recessive Menkes disease is a lethal disorder of copper metabolism, caused by defects in the ATP7A gene. About 15% of the mutations causing Menkes disease are partial gene deletions. We have previously demonstrated carrier diagnosis of deletions in heterozygotes by Southern blot analysis. As this technique is very time-consuming alternative methods are obviously of high value. Multiplex polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR) and spanning the deletion on genomic DNA can all be used for detection of partial gene deletions in male patients, but only spanning of the deletion can be applied for carrier detection. Simple multiplex PCR is not applicable for carrier detection because the normal allele of ATP7A will be PCR amplified thus masking the deletion. Here, we demonstrate, in addition to spanning of the deletion on genomic DNA, carrier detection based on the use of a previously unrecognized polymorphism in intron 13 of ATP7A in combination with previously identified intragenic polymorphic markers. We show that these intragenic markers can be used for carrier detection, not only indirectly by determining segregation of the disease related allele but also directly if located within the deleted region. We demonstrate determination of the carrier status of 21 at-risk carriers.

Exons↗
PubMed1995

Microsatellite polymorphisms reveal phylogenetic relationships in primates.

We amplified, via PCR, DNA segments from intron 1 of the tyrosine hydroxylase gene (TH01) and intron 40 of the von Willebrand factor gene (VWA) in ten nonhuman primate genera. In humans both introns contain polymorphic microsatellites with tetrameric repeats. Compared to the allelic ranges in human populations relatively short repeat arrays could be detected for the nonhuman primates typed, presumably reflecting an ancient precursor state at both microsatellite loci. Furthermore, our results provide evidence for an association of the average number of repeats present in different primate genera and their divergence time from man. DNA sequencing of VWA orthologues revealed a relatively high variability in the arrangement of repeats in the 5'-repeat arrays, the generation of which could probably be explained by polar mutational events.

Animals↗
PubMed2002

Infrequent somatic deletion of the 5' region of the COL1A2 gene in oesophageal squamous cell cancer patients.

Oesophageal squamous cell cancer is the leading cause of cancer death amongst African males in South Africa. DNA was isolated from normal and tumour biopsies of the oesophagi of 33 African patients with squamous cell carcinoma of the oesophagus and was analysed with two dinucleotide repeat polymorphisms, a GT repeat sequence in the first intron, and a CA repeat in the promoter of the human alpha2(I) procollagen gene (COL1A2), using the polymerase chain reaction (PCR). Normal and tumour DNAs from each individual were compared to identify changes present in the tumour DNA, but absent in normal DNA. Twenty two cases were informative (heterozygous) for the promoter polymorphism and 24 cases were informative for the intronic polymorphism. Loss of heterozygosity (LOH) was seen in 2/22 (9.1%) for the promoter and 3/24 (12.5%) for the intronic polymorphism. These changes involved a total of three patients: two patients displayed the lost allele incorporating both the CA repeat and GT repeat loci; the third patient revealed LOH at the intronic polymorphism, but was non-informative (homozygous) for the promoter polymorphism. Deletions within the procollagen genes may represent an as yet unrecognised but rare event in the multistep process of carcinogenesis.

5' Untranslated Regions↗
PubMed2006

Von Willebrand factor short sequence repeat locus 2 (intron 40) consists of three polymorphic subloci.

Currently, identification of alleles within the short sequence repeat locus (SSR locus) of intron 40 of the von Willebrand factor gene (previously known as VNTR II) is based on the size of PCR products that only predicts a certain number of repeats. Through cloning and sequencing, we demonstrated the complexity of nucleotide sequence structure of this region by describing three polymorphic tetranucleotide repeat subloci SSR 'a', SSR 'b' and SSR 'c' within the same originally described locus: the original TCTA (9-14 repeats), a small TCTA repeat locus (2 or 3 repeats) located at the 5' end and 30 nucleotides upstream from the original locus and a TGTA repeat locus (5 or 6 repeats), adjacent to the 2/3 repeat locus. Sequencing of 54 VWF alleles has revealed 14 different sequence combinations in this region while the size variability in the region only amounts to a 7-allele system. While the determination of VNTR alleles by PCR remains a practical methodology in linkage analysis, this may not be applicable in forensic medicine since not all alleles of identical length based on PCR are the same. Our study reveals the important implication of the identification of SSR 2 subloci and concludes that at least in some situations, there may be a necessity to take into consideration these polymorphic subloci.

Alleles↗
PubMed2006

Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review.

This review examines the association of a subset of endothelial nitric oxide synthase gene (NOS3) polymorphisms (Glu298Asp, intron 4, and -786T>C) with cardiovascular disease. The Glu298Asp polymorphism within exon 7 is the only common nonsynonymous variant. The variants have been associated with low plasma nitric oxide concentrations and reduced vascular reactivity; difficulties in measuring those phenotypes means that their functional role remains unclear. A large meta-analysis of NOS3 polymorphisms in coronary heart disease revealed per-allele odds ratios of 1.17 (95% confidence interval: 1.07, 1.28) for Glu298Asp, 1.17 (95% confidence interval: 1.07, 1.28) for -786T>C, and 1.12 (95% confidence interval: 1.01, 1.24) for intron 4. However, there was evidence that small studies with more striking results could affect the associations of the Glu298Asp and -786T>C polymorphisms with coronary heart disease. Associations of NOS3 polymorphisms with hypertension, preeclampsia, stroke, and diabetes remain uncertain. To date, no reliable gene-gene or gene-environmental interactions have been described. Use of these variants in predictive testing is unlikely to be useful, although the population attributable fraction could be substantial if the modest associations are causal. The need for large-scale genetic association studies using tagging polymorphisms is warranted to confirm or refute a role of the NOS3 gene in coronary heart disease.

Cardiovascular Diseases↗
PubMed1998

Linkage analysis in haemophilia A: simultaneous genotyping of two polymorphisms of the human factor VIII gene using induced heteroduplex formation.

Linkage analysis is currently the most widely used approach to genetic testing in families affected by haemophilia A. Among the polymorphisms of the factor VIII gene which can be used in such studies, a T/A polymorphism affecting a Bc/I restriction site in intron 18 and a G/A polymorphism in intron 7 are potentially useful. Both may be analysed by polymerase chain reaction (PCR) amplification followed by restriction endonuclease digestion and gel electrophoresis (the intron 7 polymorphism does not directly affect a restriction site but a minor sequence change in one PCR primer introduces an AlwNI site if the 'G' allele is present). We have developed a novel approach for the analysis of these two polymorphisms which uses induced heteroduplex formation to distinguish their allelic forms. Heteroduplex analysis eliminates the restriction endonuclease step and reduces the analysis for both loci to PCR followed directly by gel electrophoresis. Additionally, the new test has been designed to permit both loci to be analysed in the same PCR (multiplex heteroduplex analysis). Multiplex analysis was used to determine the allele frequencies of these polymorphisms in 105 factor VIII genes in the local (South Wales) population: BclI 'T'/BclI 'A' = 0.80/0.20 +/- 0.08 (95% confidence interval), intron 7 'G'/intron 7 'A' = 0.88/0.12 +/- 0.06 (95% confidence interval). The polymorphisms were found to be in strong linkage disequilibrium. The utility of multiplex heteroduplex analysis for linkage studies in haemophilia A was demonstrated by its application to carrier status investigation for an at risk female in a haemophilia A family.

Alleles↗
PubMed2001

Association of IFN-gamma and IFN regulatory factor 1 polymorphisms with childhood atopic asthma.

BACKGROUND: IFN-gamma and related molecules play important roles in the differentiation and function of TH2 cells. OBJECTIVE: We sought to determine whether IFNG and related genes contribute to any susceptibility to atopic asthma, a representative TH2-dominant disorder. METHODS: We investigated the association of IFNG (CA repeat polymorphism within the first intron), IRF1 (GT repeat polymorphism within the intron 7), IFNGR1 (Val 14 Met), and IFNGR2 (Gln 64 Arg) gene polymorphisms with atopic asthma in the Japanese child population. RESULTS: A significant association (P =.0018) was observed between IFNG gene polymorphism and atopic asthma. The tendency was more prominent in patients with age of onset of 3 years or younger (P =.0004) or patients with a family history of allergic diseases (P =.0038). Furthermore, there was a significant association between IRF1 gene whole-allele distribution and atopic asthma (P =.044). The tendency was more prominent in patients with onset at 3 years of age or less (P =.0058). On the other hand, IFNGR1 and IFNGR2 gene polymorphisms showed no association with atopic asthma. CONCLUSION: These results suggested that among IFNG and related genes, IFNG and IRF1 genes confer genetic susceptibility to atopic asthma in Japanese children.

Adolescent↗
PubMed2000

Mutations in the hepatocyte nuclear factor-4alpha gene in Japanese with non-insulin-dependent diabetes: a nucleotide substitution in the polypyrimidine tract of intron 1b.

Mutations of the hepatocyte nuclear factor 4 alpha (HNF-4alpha) gene have been demonstrated in maturity-onset diabetes of the young (MODY) 1 families. To investigate the possibility that the HNF-4alpha gene contributes to the onset of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese patients, we screened all exons and flanking introns of this gene for mutations in 100 patients with NIDDM diagnosed after 25 years of age. We identified two missense mutations: M49V in exon 1c and T1301 in exon 4; and two nucleotide substitutions in introns: cytosine to thymidine at -5 nt in intron 1b and adenine to thymidine at -21 nt in intron 5. We screened an additional 220 diabetic subjects for the polymorphism in intron 1b. The c/t substitution in intron 1b was associated with NIDDM. This substitution in the polypyrimidine tract, an important cis-acting element directing intron removal, is likely to influence pre-mRNA splicing of this gene. T1301 in exon 4 was observed in only two diabetic subjects. This mutation could influence the conformation of this peptide, resulting in changes in ligand binding domain function. M49V in exon 1c was found in both diabetic and non-diabetic subjects; isoforms HNF-4alpha 4, 5, and 6 with this mutation may impair glucose metabolism in tissue. In contrast to the primary cause of nonsense and missense mutations of the HNF-4alpha gene in MODY1, the nucleotide substitution in intron 1b may partially contribute to development of NIDDM in combination with other genetic and environmental factors.

Aged↗
PubMed1998

A tryptophan hydroxylase gene marker for suicidality and alcoholism.

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Low turnover rate of this monoamine neurotransmitter is associated with impaired impulse control. We previously reported that, in Finns, TPH genotype was associated with suicidality, a pathophysiological mechanism that may involve impaired impulse control. METHODS: Association and sib-pair linkage analyses of a polymorphism in intron 7 of the TPH gene with suicidality, alcoholism, and the Karolinska Scales of Personality were conducted in 804 Finnish alcoholic offenders, controls, and their relatives, in a sample that included 369 sib pairs. RESULTS: The association of the TPH 17 779C (L) allele to suicidality in impulsive offenders reported previously was replicated in a new group of Finnish offenders (P=.001, n=122). The intron 7 variant in the TPH gene showed significant evidence for linkage to suicidality (P=.006 in unaffected sib pairs), severe suicide attempts (P=.006 in unaffected sib pairs; regression: P=.01), alcoholism (P=.003 in unaffected sib-pairs; regression: P=.02), and Karolinska Scales of Personality socialization score (regression: P=.002). CONCLUSIONS: The status of the TPH A779C allele as a marker for suicidality was replicated and linkage with alcoholism and Karolinska Scales of Personality socialization score was also observed. A functional variant(s) in or close to the TPH gene may predispose individuals to suicidality and other behaviors thought to be influenced by serotonin.

Adult↗
PubMed2006

Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa.

Previous investigations have suggested that ghrelin, an endogenous orexigenic peptide, is involved in the pathology of eating disorders. We conducted a study to determine whether any preproghrelin gene polymorphisms are associated with eating disorders. Three hundred thirty-six eating disorder patients, including 131 anorexia nervosa (AN)-restricting types (AN-R), 97 AN-binge eating/purging types (AN-BP) and 108 bulimia nervosa (BN)-purging types (BN-P), and 300 healthy control subjects participated in the study. Genotyping was performed to determine the polymorphisms present, and with this information, linkage disequilibrium (LD) between the markers was analyzed and the distributions of the genotypes, the allele frequencies, and the haplotype frequencies were compared between the groups. The Leu72Met (408 C > A) (rs696217) polymorphism in exon 2 and the 3056 T > C (rs2075356) polymorphism in intron 2 were in LD (D' = 0.902, r2 = 0.454). Both polymorphisms were significantly associated with BN-P (allele-wise: P = 0.0410, odds ratio (OR) = 1.48; P = 0.0035, OR = 1.63, for Leu72Met and 3056 T > C, respectively). In addition, we observed a significant increase in the frequency of the haplotype Met72-3056C in BN-P patients (P = 0.0059, OR = 1.71). Our findings suggest that the Leu72Met (408 C > A) and the 3056 T > C polymorphisms of the preproghrelin gene are associated with susceptibility to BN-P.

Adult↗
PubMed2001

Absence of mutations in human ubiquitin fusion-degradation protein gene in tetralogy of Fallot.

Congenital defects in human chromosome 22q11 deletion syndromes are associated with the 3rd and 4th pharyngeal pouch during fetal development. In the cardiovascular system, these disorders are usually apparent as conotruncal heart defects and aortic arch anomalies. UFD1L, a gene that is downregulated in dHAND-deficient mice, expressed in the mouse embryo at the branchial arch and mapped to human chromosome 22q11, has recently been strongly suspected to be responsible for the phenotypes expressed in 22q11 deletion syndromes. Its putative causal role in relevant congenital cardiovascular malformations was studied by gene dosage analysis, mutation screening and sequence analyses. Sixty cases of tetralogy of Fallot with no detectable chromosome deletion at 22q11 or 10p13 were examined, including 51 cases of simple tetralogy of Fallot, and 9 cases of tetralogy of Fallot with pulmonary atresia. None of these patients revealed deletion limited to a portion of the UFD1L gene. Although mobility shift was found by heteroduplex analysis in 24 cases at exon 4 and flanking sequences, further sequence analysis demonstrated only two silent nucleotide variations and a single nucleotide polymorphism in intron 4. Our data suggest that, although the UFD1L gene is mapped to 22q11 and is expressed during early murine development at both cardiac and cranial neural crests, it is not responsible for the majority of tetralogy of Fallot cases in humans.

Adaptor Proteins, Vesicular Transport↗