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PubMedDate not supplied

Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder.

Serotonin systems appear to play a key role in the pathogenesis of major depression and the therapeutic mechanisms of antidepressants. The firing rate of dorsal raphe serotonergic neurons is controlled by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors, and desensitization of these receptors is implicated in the antidepressant mechanism of selective serotonin reuptake inhibitors. We tested whether a functional polymorphism (C-1019G) in the promoter region of the HTR1A gene and serotonin-related genetic variants are related to fluoxetine antidepressant effect. We genotyped the HTR1A C-1019G polymorphism as well as polymorphisms in the serotonin transporter gene-linked polymorphic region (SERTPR), variable-number tandem-repeat polymorphisms in intron 2 (STin2) of the serotonin transporter gene, serotonin 2A receptor (T102C), tryptophan hydroxylase (A218C), and G-protein beta3 subunit (C825T) in 224 Chinese patients from southern Taiwan with major depression, who accepted 4-week fluoxetine treatment and therapeutic evaluation. Our results demonstrated that the HTR1A -1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response. The major limitation of this study is the lack of a placebo control. Future prospective study with placebo control may help to predict and individualize antidepressant treatment.

Adult↗

PubMed2003

Interleukin-1 cluster combined genotype and restenosis after balloon angioplasty.

The interleukin-1 system is fundamentally involved in the pathogenesis of restenosis after percutaneous transluminal angioplasty (PTA). In order to further define the clinical impact of genetic variation in this potent proinflammatory pathway we investigated the joint effects of two single nucleotide polymorphisms in the interleukin-1 beta gene [IL-1B(-511) and IL-1B(+3954)] and a variable number tandem repeat polymorphism in intron 2 of the interleukin 1 receptor antagonist gene (IL-1RN VNTR) on postintervention inflammation and occurrence of restenosis in 183 consecutive patients who underwent successful femoropopliteal PTA. C-reactive protein (CRP) and serum amyloid A (SAA) were determined pre- and 48 hours postintervention. Patients were followed up to 12 months for the occurrence of postangioplasty restenosis (> or = 50%). When analyzed separately, none of the polymorphisms was associated either with inflammation or restenosis. However, when the IL-1B (-511) and the IL-1RN VNTR genotypes were combined, a highly significant relationship was observed: Non-carriers of the two repeat allele of the IL-1RN VNTR (IL-1RN*2) who were heterozygous and homozygous for the IL-1B (-511)T allele exhibited a gradually increased inflammatory response and a higher restenosis risk. In contrast, carriers of the IL-1RN*2 and the IL-1B (-511)T allele showed a significantly better outcome. This remarkable gene dose-dependent association emphasizes the advantage of considering combinations of genetic markers rather that isolated polymorphisms in the analysis of multifactorial vascular disease.

Aged↗

PubMed1992

The origin of glucose-6-phosphate-dehydrogenase (G6PD) polymorphisms in African-Americans.

DNA samples from 54 male Afro-Americans were examined for glucose-6-phosphate dehydrogenase (G6PD) genotypes G6PD A(+)376G, G6PD A(-)202A/376G, and G6PD B and for polymorphisms in intron 5 (PvuII), at nucleotide 1311, and at nucleotide 1116 (PstI). In the G6PD B subjects, the nucleotide 1311 mutation and the PstI site appeared to be in linkage equilibrium. No PvuII+ G6PD men were encountered. The G6PD A(+) mutation was in disequilibrium with respect to both the nucleotide 1311 mutation and the PstI site. The G6PD A- nucleotide 202 mutation was in disequilibrium with all three polymorphic sites. No conclusion could be drawn with respect to the PvuII site, except that it preceded the nucleotide 202 (A-) mutation. We conclude from these and our previous studies that G6PD B is the most ancient genotype. The nucleotide 1311 mutation, with its worldwide distribution, probably occurred next. The PstI mutation, limited to Africans, probably arose next and is more ancient than the A(+) mutation, which occurred in a gene without either the PstI or the 1311 mutation. G6PD A-202A/376G is the most recent of these mutations and is still in linkage disequilibrium with all of the sites. Presumably it occurred in an individual with both the A(+) and PvuII mutations.

Black People↗

PubMed2002

Identification of the PPARA locus on chromosome 22q13.3 as a modifier gene in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder that is present in 10% of patients with premature coronary artery disease (CAD). It was the objective of the present study to evaluate the possible involvement of the PPARA locus in the pathophysiology of FCHL. Mutation detection analyses of the six coding PPARA exons resulted in the identification of four novel variants, [C/T] intron 3, S234G, [G/A] intron 5, and [C/A] 3(') UTR in three FCHL probands, whereas no novel variants were identified in spouses. In a case-control study, markers D22S275 and D22S928 were shown not to be associated with FCHL. However, D22S928, mapped within 1Mb of the PPARA gene, was shown to have a modifying effect on plasma apoCIII concentrations (P=0.011) and the combined hyperlipidemic FCHL phenotype (P=0.038). In addition two PPARA polymorphisms in intron 2 and 7 were studied, but these were not associated with FCHL. The frequency of the L162V variant was less in FCHL probands (1.98%) compared to that in spouses (4.84%). These results clearly demonstrate the genetically complex nature of FCHL and identify the PPARA gene as a modifier of the FCHL phenotype.

Case-Control Studies↗

PubMed1999

Association of an extended haplotype in the tau gene with progressive supranuclear palsy.

We describe two extended haplotypes that cover the human tau gene. In a total of approximately 200 unrelated caucasian individuals there is complete disequilibrium between polymorphisms which span the gene (which covers approximately 100 kb of DNA). This suggests that the establishment of the two haplotypes was an ancient event and either that recombination is suppressed in this region, or that recombinant genes are selected against. Furthermore, we show that the more common haplotype (H1) is significantly over-represented in patients with progressive supranuclear palsy (PSP), extending earlier reports of an association between an intronic dinucleotide polymorphism and PSP.

Aged↗

PubMed2001

The polymorphic IL-1B and IL-1RN genes in the aetiopathogenesis of peptic ulcer.

Besides environmental factors, the genetic background of an individual may contribute to the development and final outcome of peptic ulcer disease. Interleukin-1beta (IL-1beta) and the interleukin-1 receptor antagonist (IL-1ra) are cytokines that play a key role in modulating the inflammatory response in the gastrointestinal mucosa. This study aimed to investigate whether polymorphisms in the IL-1B and IL-RN genes are involved in the susceptibility to and final outcome of peptic ulcer disease. DNA from 179 unrelated Spanish Caucasian patients with peptic ulcer diseases and 99 ethnically matched healthy controls was typed for the TaqI polymorphism at position + 3954 in the IL-1B gene and the variable number of tandem repeats polymorphism in intron 2 of the IL-1RN gene. The determination of Helicobacter pylori status and non-steroidal anti-inflammatory drug (NSAIDs) use was studied in all patients and in controls. H. pylori infection and NSAID use were more frequent in ulcer patients than in controls. There were no significant differences in carriage rate, genotype and allele frequencies of the IL-1RN and the IL-1B(+3954) gene polymorphisms between peptic ulcer patients and controls. However, a strong allelic association between IL-1B and IL-1RN genes was found in duodenal ulcer patients (P < 0.0006). Logistic regression identified H. pylori infection and NSAIDs use as independent risk factors for peptic ulcer diseases whereas the simultaneous carriage of IL-1B(+3954) allele 2 and IL-1RN allele 2 was associated with reduced risk for duodenal ulcer disease (OR: 0.37, 95% CI = 0.14-0.9). Our data suggest that IL-1B and IL-1RN genes in addition to bacterial and environmental factors play a key role in determining the final outcome of peptic ulcer disease.

Adult↗

PubMed1999

Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease.

Gaucher disease, an inherited glycolipid storage disorder, is caused by a deficiency of the catabolic enzyme glucocerebrosidase (EC 3.2.1.45). The gene for human glucocerebrosidase is located on chromosome 1q21 and has a highly homologous pseudogene situated 16 kb downstream. We report two novel polymorphic sequences in the glucocerebrosidase gene region: the first consists of a variable number of dinucleotide (CT) repeats located 3.2 kb upstream from the glucocerebrosidase gene, and the second is a tetranucleotide (AAAT) repeat found between the glucocerebrosidase gene and its pseudogene, 9.8 kb downstream from the functional gene. These polymorphic sequences, along with a previously reported PvuII polymorphism in intron 6 of the glucocerebrosidase gene, were analyzed in patients with Gaucher disease (n=106) and in two normal control populations, one of Ashkenazi Jewish ancestry (n=72) and the second comprising non-Jewish individuals (n=46). In these samples, strong linkage disequilibrium was found between mutations N370S, c.84-85insG, and R463C and specific haplotypes; no significant linkage disequilibrium was found when examining haplotypes of patients with the L444P mutation. Studies of these polymorphic sites in several instances also led to the recognition of genotyping errors and the identification of unusual recombinant alleles. These new polymorphic sites provide additional tools for mutational screening and founder effect studies of Gaucher disease.

Amino Acid Substitution↗

PubMed2002

A T2517C polymorphism in the GSTM4 gene is associated with risk of developing lung cancer.

The human Mu class Glutathione S-Transferases is a family of genes encoding phase II detoxifying enzymes thus playing a significant role in the detoxification of potential carcinogens. While there are many contradicting reports on the association of GSTM1 polymorphisms and cancer development, no studies exist to date describing polymorphisms in GSTM4. We have identified a new C-T polymorphism in intron 6 of the GSTM4 gene (T2517C, Genebank sequence accession number X68677) and termed the allele carrying T at this position allele *A and the allele carrying C, allele *B. Screening a population sample in Merseyside, England, revealed 23 carriers of the *B allele out of 156 healthy control individuals but only 12 carriers of the *B allele out of 163 individuals with lung cancer (O.R.=2.23, Fisher's test P=0.026). The polymorphism did not demonstrate any associations with tumour type, gender, and age at presentation. This is the first report on the implication of a polymorphism in the GSTM4 gene in lung cancer risk. Further studies are required to investigate the relation of this polymorphism to cancer risk to substantiate these findings.

Adult↗

PubMedDate not supplied

No association between common variations in the human alpha 2 subunit gene (ATP1A2) of the sodium-potassium-transporting ATPase and idiopathic generalized epilepsy.

Quantitative trait loci studies in inbred mice have identified a locus on chromosome 1 (Szs1) of fundamental importance to seizure susceptibility. High-ranking candidate genes in this susceptibility region include KCNJ9, KCNJ10 and ATP1A2. We performed a systematic mutation scan of the coding region of the human ATP1A2 gene and performed a case-control association study with seven common markers. Genotypes were assessed in 152 idiopathic generalized epilepsy (IGE) patients of German ancestry and 111 healthy German controls for all seven polymorphisms. No significant differences were found in genotype or allele frequencies for any of the variations between the IGE patients and controls. No haplotypes were associated with IGE when compared to controls. Linkage disequilibrium was demonstrated throughout the gene. Results suggest that the polymorphisms we studied in the ATP1A2 gene do not represent major susceptibility factors for common forms of IGE.

DNA↗

PubMedDate not supplied

The PROGINS progesterone receptor gene polymorphism and idiopathic recurrent miscarriage.

OBJECTIVE: Progesterone inhibits lymphocyte cytotoxicity, natural killer cell degranulation, and release of proinflammatory cytokines and has been shown to protect against spontaneous miscarriage. We investigated the association between idiopathic recurrent miscarriage (IRM) and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor gene, which is known to segregate with progesterone-dependent neoplasms. METHODS: In a case-control study we investigated 125 women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 79 healthy controls with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction, and polymerase chain reaction were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: Allele frequencies among women with IRM and controls were 85.2% and 89.2%, respectively, for allele T1 (wild type) and 14.8% and 10.8%, respectively, for allele T2 (mutant). No association between allele T2 and the occurrence of IRM was found (P =.3; odds ratio [OR] 0.69; confidence interval [CI] 0.34, 1.40). Genotype frequencies were not significantly different between the study group (T1/T1 73.6%, T1/T2 23.2%, T2/T2 3.2%) and the control group (T1/T1 79.7%, T1/T2 19%, T2/T2 1.3%) (P =.4). Between women with primary and secondary IRM, there were no statistically significant differences with respect to allele frequencies (82% versus 87%, P =.4 for allele T1 and 12% versus 13%, P =.6 for allele T2). CONCLUSIONS: We found that the PROGINS polymorphism in the progesterone receptor gene was not associated with IRM in white women.

Abortion, Habitual↗

PubMed2001

A new polymorphism in the proteolipid protein (PLP1) gene and its use for carrier detection of PLP1 gene duplication in Pelizaeus-Merzbacher disease.

Pelizaeus Merzbacher Disease (PMD) is an X-linked recessive dysmyelinating disorder of the central nervous system. Most patients have point mutations in exons of the proteolipid protein (PLP1) gene or duplication of a genomic region that includes the PLP1 gene. We identified a common MspI polymorphism in intron 1 of the PLP1 gene and used it to determine carrier status for PLP1 gene duplication in PMD by using a quantitative PCR approach.

DNA↗

PubMed2002

Rapid scanning of myotubularin (MTM1) gene by denaturing high-performance liquid chromatography (DHPLC).

X-linked myotubular myopathy (XLMTM; OMIM# 310400) is a severe congenital muscle disease caused by mutations in the myotubularin (MTM1) gene. This gene encodes for a lipid phosphatase belonging to a large gene family involved in the regulation of phosphatidylinositide-3-kinase (PI 3-kinase) pathway and membrane trafficking. To date, more than 130 different mutations, distributed in all exons, have been identified in a large number of families. The majority of MTM1 mutations are private and rare, generating high allelic diversity, with a restricted number of recurrent mutations. We set up and formatted a denaturing high performance liquid chromatography (DHPLC) method to allow high throughput, greater accuracy and high resolution in detecting myotubularin mutations. The entire coding sequence of the gene was screened in 10 XLMTM patients using this technique. We identified seven mutated alleles [R37X, (137-11) A, (592-593) insA, T197I, R253X, G378R, G402R] previously characterised by SSCP and DNA sequencing, plus two novel mutations which are reported here [P199S, (1644+2) insG]. In addition we detected a common polymorphism within intron 11 (1314+3A/G). Our results suggest that denaturing high-performance liquid chromatography provides an accurate method for the rapid identification of MTM1 mutations.

Chromatography, High Pressure Liquid↗

PubMed2001

DAZLA: an important candidate gene in male subfertility?

PURPOSE: To study the role of the autosomal candidate gene DAZLA (Deleted in AZoospermia Like Autosome) in male subfertility. METHODS: We reviewed clinical data of subfertile men with oligozoospermia or azoospermia, mostly candidates for intracytoplasmic sperm injection (ICSI). Mutation detection was performed using polymerase chain reaction followed by single strand conformation polymorphism analysis. All shifted bands were analyzed by sequencing. RESULTS: We searched for mutations in 44 subfertile men. Nine subfertile men were included, because family history showed that their brothers also faced fertility problems. In these men a possible autosomal gene defect may contribute to their fertility problem. No mutations were found, except for two polymorphisms in intron 4 and 5. CONCLUSION: At this moment it does not seem relevant to search for possible mutations in the DAZLA gene in clinical practice.

DNA Mutational Analysis↗

PubMed1996

Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy.

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.

Alleles↗

PubMed1998

Natural selection at major histocompatibility complex loci of vertebrates.

The loci of the vertebrate major histocompatibility complex encode cell-surface glycoproteins that present peptides to T cells. Certain of these loci are highly polymorphic, and the mechanisms responsible for this polymorphism have been intensely debated. Four independent lines of evidence support the hypothesis that MHC polymorphisms are selectively maintained: (a) The distribution of allelic frequencies does not fit the neutral expectation. (b) The rate of nonsynonymous nucleotide substitution significantly exceeds the rate of synonymous substitution in the codons encoding the peptide-binding region of the molecule. (c) Polymorphisms have been maintained for long periods of time ("trans-species polymorphism"). (d) Introns have been homogenized relative to exons over evolutionary time, suggesting that balancing selection acts to maintain diversity in the latter, in contrast to the former.

Animals↗

PubMed1998

Molecular analysis of P16(Ink4)/CDKN2 and P15(INK4B)/MTS2 genes in primary human testicular germ cell tumors.

PURPOSE: p16 (MTS 1) and p15 (MTS 2) are negative regulators of cell cycle progression at the G1 cell cycle checkpoint and function as tumor suppressor genes (TSG). Both p15 and p16 are located on chromosome 9p21 and alterations have been demonstrated in a variety of human malignancies and human cancer cell lines. In testicular germ cell tumors (TGCT) loss of heterozygosity of 9p21 to 23 has been observed in 41% to 72% of informative cases. The aim of our study was to examine TGCT and testicular cancer cell lines for deletions and mutations of the p15 and p16 genes. MATERIALS AND METHODS: 24 testicular germ cell tumors, 4 testicular cancer cell lines (TERA I, TERA II, HTE, HTH), 8 benign testicular tumors and 9 samples of normal testicular parenchyma were examined. Examinations for loss of heterozygosity (LOH) on 9p21 were performed for IFNA, D9S171, D9S126, D9S161, D9S1748 and PKY9 locus using Southern Blot analysis. Southern Blot analysis of the p16 gene to examine gross alterations was done using random primer labeled p16 cDNA. In addition all samples were examined for mutations of exons 1 to 3 of p16 and exons 1 to 2 of p15 by polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) analysis on MDE-gels. All observed band shifts on SSCP were further evaluated by direct DNA sequencing techniques. RESULTS: No major deletions were detected for p16 and p15. 42% of all TGCT demonstrated LOH of the IFNA locus, 16% of the D9S161 locus and 5.5% of the D9S171 locus. No LOH was seen for the D9S126 locus. 5/24 TGCT (21%) and 1 testicular cancer cell line (TERA II) demonstrated band shifts for exon 2, 8/24 TGCT (33%) and 1 testicular cancer cell line (TERA I) showed band shifts for exon 3; 4 TGCT had an allelic loss for exon 3 on SSCP. DNA sequencing analysis for exon 2 demonstrated a single base substitution (G-->A) in codon 140 resulting in an amino acid exchange (ala-->thre) in 4 cases and a single base deletion with frame shift mutation in codon 142 in 2 cases. DNA sequencing analysis for exon 3 demonstrated a polymorphism in intron 2 in all cases. For p15 no band shifts were observed for exons 1 to 2 in TGCT or testicular cancer cell lines; none of benign testicular tumors or normal control tissues demonstrated any band shifts for p15 or p16. DISCUSSION: We demonstrated a high frequency of mutations for exon 2 in specimens of primary testicular germ cell tumors, but not in benign tumors or normal controls. We therefore believe that p16 might be involved in the pathogenesis of human TGCT. The polymorphisms described for exon 3 might be utilized for further LOH studies. The absence of mutations in p15 gene in TGCT specimens suggests that p15 might not play an important role in the pathogenesis of testicular germ cell tumors.

Blotting, Southern↗

PubMed2002

Serotonin transporter genetic polymorphisms and harm avoidance in the Chinese.

The association for the harm avoidance (HA) dimension, as assessed by the Tridimensional Personality Questionnaire (TPQ), and the serotonin-transporter genetic polymorphisms has been investigated with controversial results. The aim of the present study was to replicate this investigation and to establish the association for a Chinese population. Two polymorphisms of the serotonin transporter (5HTT-LPR, serotonin transporter-linked polymorphism region; 5HTT-VNTR, variable number tandem repeat polymorphism in intron 2 of the serotonin transporter gene) were determined for 192 healthy Han Chinese who had completed the TPQ. No significant differences were demonstrated for TPQ HA scores, including the sub-scales, for subjects with different 5HTT-LPR genotypes. A significantly higher HA2 sub-score was demonstrated for subjects carrying the 10-12 5HTT-VNTR genotype, however, compared with those from the 12-12 genotype group, for the male population (P = 0.007). Our findings suggest that the 5HTT genetic polymorphism may be associated with HA scores; however, the effect is influenced by ethnicity and gender.

Asian People↗

PubMed2000

No association between the angiotensin-converting enzyme ID polymorphism and elite endurance athlete status.

Several studies have reported that the insertion (I) allele of the angiotensin-converting enzyme (ACE) I/deletion (D) polymorphism is associated with enhanced responsiveness to endurance training and is more common in endurance athletes than in sedentary controls. We tested the latter hypothesis in a cohort of 192 male endurance athletes with maximal oxygen uptake >/=75 ml. kg(-1). min(-1) and 189 sedentary male controls. The ACE ID polymorphism in intron 16 was typed with the three-primer polymerase chain reaction method. Both the genotype (P = 0.214) and allele (P = 0.095) frequencies were similar in the athletes and the controls. Further analyses in the athletes revealed no excess of the I allele among the athletes within the highest quartile (> 80 ml. kg(-1). min(-1)) or decile (>83 ml. kg(-1). min(-1)) of maximal oxygen uptake. These data from the GENATHLETE cohort do not support the hypothesis that the ACE ID polymorphism is associated with a higher cardiorespiratory endurance performance level.

Alleles↗