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PubMed2006

The taqI DRD2 A1 allele is associated with alcohol-dependence although its effect size is small.

BACKGROUND: Numerous studies of the relationship between the TaqIA DRD2 A1 allele and alcohol-dependence have been performed and many of these have shown an association whereas others have not (Noble, 2003). This has consequently generated some controversy as to whether such an association actually exists (Noble, 2003). In the two recent meta-analyses by Noble (2003) and Young et al. (2004) some very important methodological issues have been discussed, which need to be addressed in forthcoming studies. Thus, the sample size is of great importance. In case-control studies it has been estimated that to detect the role of genes with small effect size of approximately 2, which is in the range of the DRD2 A1 allele-alcoholism relationship, case-control sets of 300-400 subjects are necessary (Noble, 2003). METHODS: In the present study, we have consequently recruited a large number of subjects, 375 alcohol-dependent individuals, who were treated as inpatients for alcohol withdrawal symptoms and out of these 357 could be evaluated. As controls, 578 individuals screened and 254 individuals unscreened for alcohol consumption were used. Thus, the total number of subjects was 1217. RESULTS: In the present study, in which the TaqI A1/A2 DRD2 polymorphism was in Hardy-Weinberg equilibrium in the patient group and the two control groups, we found that the TaqI DRD2 A1/A2 genotype frequency differed significantly between the alcohol-dependent group and both the total and screened control groups. Furthermore, the TaqI DRD2 A1 allele frequency was significantly overrepresented in the alcohol-dependent subjects as compared with both the total and screened control groups. The odds ratio for alcohol-dependency being associated with the A1 allele was 1.34. CONCLUSIONS: Consequently, the findings in this study lend further support to the notion of an association between the DRD2 A1 allele and alcohol-dependence, although the effect size of the DRD2 A1 allele is small.

Adult↗
PubMed1982

Estimates of inbreeding in a natural population: a comparison of sampling properties.

The average inbreeding coefficient f of a population can be estimated in several different ways based solely on the genotypic frequencies at a single locus. The means and variances of four different estimates have been compared. While the four estimates are equivalent when there are two alleles, the best estimates when there are three or more alleles are based upon total heterozygosity (Formula: see text) where x and y are the expected and observed number of heterozygotes) and the proportion of alleles that are homozygous (Formula: see text) where k = the number of alleles, aii = the number of AiAi homozygotes, and 2aij = the number of AiAj heterozygotes). Both are minimally based estimates of f and have identical sampling variances when all alleles are equally frequent. However, when alleles have different frequencies, the choice between these two estimates depends on the gene frequencies and the true inbreeding coefficient of a population; f2 is the best estimate when the true average inbreeding coefficient is suspected to be low or f = 0, while f1 is best in populations with large average inbreeding coefficients. Approximate sampling variances of these two estimates are given for any f and any number of alleles with arbitrary gene frequencies; these approximations are accurate for samples as small as n = 100. The chi-square and maximum likelihood estimates of f are not as good for realistic sample sizes.

Alleles↗
PubMed2001

The functionally important IL-10 promoter polymorphism (-1082G-->A) is not a major genetic regulator in recurrent spontaneous abortions.

Enhanced secretion of anti-inflammatory Th2 cytokines is a characteristic feature in normal physiological pregnancy. In recurrent spontaneous abortions (RSA), however, defective production of interleukin-10 (IL-10) and other Th2 cytokines has been shown in humans. Association studies have shown that a base exchange polymorphism (guanine-->adenine) at position -1082 of the IL-10 promoter is associated with differential IL-10 production. Since factors contributing to IL-10 production appear to be important in RSA, we studied the IL-10 genotypes of 38 Finnish women with a history of three or more consecutive abortions and 131 ethnically matched healthy controls. No significant differences in the -1082 allele or genotype frequencies were found between the controls and the RSA women. The present study suggests that the IL-10 -1082 (G-->A) polymorphism is not a major genetic regulator in RSA.

Abortion, Habitual↗
PubMed2000

NAT2 polymorphism associated with plasma glucose concentration in Canadian Oji-Cree.

The prevalence of type 2 diabetes in the Oji-Cree of Northern Ontario is among the highest of any population in the world. We previously demonstrated that markers D8S264 and D22S683 were both linked and associated with type 2 diabetes in the Oji-Cree. Among the possible candidate genes for type 2 diabetes and related traits on chromosomes 8p and 22q were NAT2 and CYP2D6, respectively. We thus explored the possible association of NAT2 and CYP2D6 alleles and diabetes-related traits in a sample of 112 Oji-Cree subjects with type 2 diabetes and 481 Oji-Cree subjects without type 2 diabetes. We found no difference in the allele and genotype frequencies of the NAT2 G191A, C282T, C481T, G590A, A803G and G857A, and the CYP2D6 G1934A polymorphisms between Oji-Cree subjects with and without type 2 diabetes. However, we found a significant association between the NAT2 C282T polymorphism and plasma fasting glucose concentration. Specifically, NAT2 282T/T homozygotes had significantly higher plasma fasting glucose than 282C/C homozygotes, and heterozygotes had intermediate levels of this trait. Thus, variation in NAT2 or CYP2D6 was not associated with the presence of type 2 diabetes, and would not be causative for this phenotype in Oji-Cree. However, NAT2 might be a 'modifier gene' affecting the level of glycaemia in non-diabetic subjects.

Adolescent↗
PubMed2001

A polymorphism in the promoter of the serotonin transporter gene is not associated with suicidal behavior.

A 44 base pair deletion/insertion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was examined in 124 German suicide attempters, who were consecutively hospitalized, and 185 German normal control subjects without a history of any DSM-IV axis I or II mental disorder. Both patients and control subjects were recruited from the same geographic area. There was no significant difference in allele or genotype frequency between patients and control subjects. There were also no differences when the patients were divided into several subgroups (suicide attempters with a violent method, and suicide attempters with a lifetime history of mood disorders, unipolar depression, personality disorders). These results suggest that the 5-HTTLPR polymorphism is unlikely to play a major role in the genetic susceptibility to suicide attempts. Conflicting results among the present and previous studies regarding an association between the polymorphism and suicidal behavior, however, suggest the possibility that there may be unidentified specific subtypes of suicidal behavior that are significantly associated with the polymorphism or, alternatively, simply reflect false-positive association results.

Carrier Proteins↗
PubMed2003

Case-control and linkage disequilibrium studies of the tryptophan hydroxylase gene polymorphisms and major depressive disorder.

OBJECTIVES: Alterations in the level of the serotonin, serotonin uptake and the number of binding sites have been linked to affective illness. We investigated the association of tryptophan hydroxylase gene polymorphisms and unipolar depression in a case-control study design. METHODS: Patients and ethnically matched controls were genotyped for three polymorphisms of the tryptophan hydroxylase gene. RESULTS Significant difference in genotype frequency between patient and control groups was observed for the IVS7+218A >C polymorphism but not for the two promoter polymorphisms -1067G >A and -347T >G. Strong linkage disequilibrium among the three polymorphisms was also observed. CONCLUSIONS: As the sample size was small, the positive association would need to be replicated by family-based association studies or in a larger set of samples. As our results did not indicate association with either of the two promoter polymorphisms, there is a need to continue the search for the causative variant directly involved in the susceptibility to unipolar depression in Chinese as this polymorphism within the intron might not be the true susceptibility variant.

Case-Control Studies↗
PubMed2005

Influence of the eNOS gene on development of blood pressure and left ventricular mass: longitudinal findings in multiethnic youth.

OBJECTIVES: To evaluate the impact of the endothelial nitric oxide synthase (eNOS) gene on longitudinal development of blood pressure (BP) and left ventricular mass (LVM) from childhood into early adulthood. METHODS: Three polymorphisms including -922A>G, intron 4VNTR, and Glu298Asp of the eNOS gene were investigated. Individual growth-curve modeling and haplotype trend regression analyses were conducted for 579 white and black American youths with 12 assessments over a 15-year period. RESULTS: Significantly different allele and genotype frequencies were observed between blacks and whites for all three polymorphisms. Linkage disequilibrium (LD) patterns among these polymorphisms were also different between ethnic groups: strong LD between the -922A>G and intron 4 VNTR loci was observed in whites but not in blacks. Single locus analyses identified a significant interaction between the intron 4 VNTR and gender on diastolic BP (DBP) levels. The 4a allele carriers had significantly lower DBP levels in males (P=0.012), but higher DBP levels in females (P=0.045). Haplotype analyses confirmed the DBP lowering effect in males (P=0.049). DBP in males homozygous for haplotype G-4a-Glu was 2.58 mmHg lower than males homozygous for the most common haplotype (A-non4a-Glu). Additionally, individuals homozygous for haplotype G-non4a-Glu showed a 0.51 mmHg steeper increase in DBP per year with age as compared to the most common haplotype (P=0.007). No associations between single polymorphisms or haplotypes of the eNOS gene and systolic BP or LVM were found. CONCLUSIONS: our results suggest that eNOS gene may have gender-specific and age-dependent effects on DBP and the development of hypertension risk.

Age Factors↗
PubMed2003

Cytochrome P450 2D6 polymorphism and character traits.

OBJECTIVE: It has been suggested that cytochrome P450 2D6 (CYP2D6) is involved in dopamine metabolism within the brain. The dopamine system is suggested to play a role in determining normal character. The purpose of this study was to examine whether character traits are dependent on cytochrome P450 2D6 activity. METHODS: We investigated the association between temperament and CYP2D6 gene polymorphism. The subjects were all Japanese and the polymorphism genotyped in the present study was CYP2D6*10. Character traits were assessed using the Temperament and Character Inventory. RESULTS: There was no overall or specific association between personality traits and the CYP2D6*10 allele and genotype frequencies. CONCLUSIONS: The present results do not support the hypothesis that CYP2D6 activity affects temperament and character.

Character↗
PubMed2002

Assortative fertilization and selection at larval stage in the mussels Mytilus edulis and M. galloprovincialis.

Assortative mating (prezygotic isolation) and reduced hybrid fitness (postzygotic isolation) are typically invoked to explain the stability of hybrid zones. In the tension zone model, these factors work in opposition to migration, which promotes genetic homogeneity. Many marine animals migrate over long distances through a planktonic larval stage. Therefore, strong reproductive isolation is needed to maintain stable marine hybrid zones. However, surprisingly little is known about mating preferences and hybrid fitness in marine organisms. Smooth-shelled mussels (Mytilus spp.) form a well-known species complex, with hybridization over extensive areas such as the contact zone of M. edulis and M. galloprovincialis around European Atlantic coasts. This paper reports direct experimental evidence of assortative fertilization, hybrid larval inviability, and early heterosis for growth rate in M. edulis and M. galloprovincialis. Four crosses between pure M. edulis and M. galloprovincialis were analyzed with a new polymerase-chain-reaction-based diagnostic marker. Gamete competition between taxa was allowed in two out of the four crosses. Genotype frequencies observed at an early stage (36 h after fertilization) unambiguously revealed assortative fertilization when gamete competition was allowed. A significant reduction in hybrid viability was subsequently observed during the larval stage. At the same stage an antagonistic effect, heterosis, was observed on growth rate. However, even if heterosis is observed in the F1, it is expected to vanish in subsequent hybrid generations. Although specialization for different habitats and asynchronous spawning have been mentioned as factors contributing to the maintenance of the blue mussel hybrid zone in Europe, we argue that assortative fertilization and reduced hybrid fitness are important factors that also contribute to the stabilization of this zone. These results emphasize that multiple factors may act concomitantly in a barrier to gene flow, especially in complex life cycles. Furthermore, they show that assortative mating through gamete preference, as already demonstrated for sea urchins, may play a role in speciation processes taking place in the sea.

Animals↗
PubMed1998

Rapid genotyping of transforming growth factor beta1 gene polymorphisms in a UK Caucasoid control population using the polymerase chain reaction and sequence-specific primers.

Transforming growth factor (TGF) beta1 is a growth factor which has multiple functions including the promotion of matrix deposition during wound healing and scar formation. Gene polymorphisms within or close to the 5' region of TGFbeta1 have been identified; three in the upstream region, one in the non-translated region, two in the signal peptide sequence and one in a region of the gene coding for the precursor protein. We have developed a method using 14 polymerase chain reaction-sequence-specific primer reactions to characterise six of these polymorphisms. In the upstream region, both forward and reverse allele-specific primers were used to demonstrate the cis/trans orientation of alleles at adjacent polymorphisms (haplotypes). We report the allele and genotype frequencies of TGFbeta1 genes in two sets of UK Caucasoid control subjects.

DNA Primers↗
PubMed2005

The C46T polymorphism of the coagulation factor XII gene and idiopathic recurrent miscarriage.

Thrombophilia has been described to be involved in the pathogenesis of idiopathic recurrent miscarriage (IRM). We investigated the association between IRM and a C-->T polymorphism at nucleotide 46 in the 5'-untranslated region of the coagulation factor XII (FXII) gene. Two hundred and twelve women with a history of IRM and 149 healthy controls were tested by a mutagenically separated polymerase chain reaction assay (MS PCR). Allele and genotype frequencies were not significantly different between the study and the control groups. Our data suggest that the FXII gene is not a candidate gene for this condition.

Abortion, Habitual↗
PubMed2004

G protein beta3 subunit C825T polymorphism in primary IgA nephropathy.

BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism has been associated with increased signal transduction, increased activity of the kidney Na+/H+ exchanger, and also with late-onset essential hypertension. Hypertension is a strong independent risk factor for progression in IgA nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989 to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to 303 local Caucasian controls matched for the male predominance (214 males). The technique used was a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers, followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2% in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015). The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97; P= 0.05). This data indicated that this polymorphism had a significant but mild influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In contrast, we could not demonstrate any significant and sustained difference in the clinical presentation and evolution of the homozygous TT patients compared to non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The progression to arterial hypertension or to chronic renal failure or to end-stage renal failure (ESRF) was not significantly different. In addition, multivariate Cox regression analysis excluded a significant independent role of C825T polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgAN, but played no significant role in the progression of the disease.

Adult↗
PubMed2004

A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease.

In meningococcal sepsis, disseminated intravascular coagulation with deposition of fibrin and formation of microthrombi occurs in various organs and enhanced inhibition of fibrinolysis is associated with adverse outcome. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between coagulation and fibrinolysis, as TAFI can be activated by thrombin and once activated potently attenuates fibrinolysis. On the basis of this one would predict that DNA polymorphisms that increase TAFI activity would deteriorate the outcome in meningococcal sepsis. Therefore, we studied the prevalence of the Thr325Ile dimorphism in the TAFI gene, which is associated with increased TAFIa stability and activity in 50 patients who survived meningococcal disease, in 176 first-degree relatives of a consecutive patient series with meningococcal disease and 212 controls from the same geographic region. The TAFI 325 Ile/Ile genotype was slightly more common among parents of patients with meningococcal disease than in controls (11% vs. 7.1%, P= 0.24). This difference was pronounced among the subgroup of parents of non-surviving patients (19.2%, P= 0.03). Patients whose parents were carriers of the TAFI 325 Ile/Ile genotype had a 1.6-fold (95% CI 0.7-3.7) higher risk to contract meningococcal disease and a 3.1-fold (95% CI 1.0-9.5) increased risk to die from the infection compared with all other genotypes. Survivors had a genotype frequency (4.0%) that was lower than in the general population. TAFI 325 variants affect the outcome of meningococcal disease.

Alleles↗
PubMed2007

Increased plasma levels of asymmetric dimethylarginine in patients with carotid stenosis: no evidence for the role of the common FABP2 A54T gene polymorphism.

OBJECTIVE: Both asymmetric dimethylarginine (ADMA), which is an inhibitor of endothelial nitric oxide synthase and the fatty acid-binding protein 2 (FABP2) A54T gene polymorphism have been associated with cerebrovascular disease. The objective of the present study was to investigate the role of ADMA and the FABP2 A54T polymorphism in carotid atherosclerosis. MATERIAL AND METHODS: 54 patients with severe carotid stenosis and 54 matched controls without significant carotid stenosis were compared. ADMA was analysed with an ELISA method. The FABP2 A54T polymorphism was determined with a polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Patients with carotid stenosis had higher ADMA levels (0.76 +/- 0.16 micromol/l) than the controls (0.70 +/- 0.14 micromol/l, P < 0,01). Allele and genotype frequencies of the FABP2 polymorphism did not differ between patients and controls. CONCLUSIONS: ADMA levels in subjects with carotid stenosis are increased which emphasize the role of ADMA as a novel risk factor for atherosclerosis and future cardiovascular risk. The FABP2 A54T polymorphism is not associated with severe carotid stenosis.

Aged↗
PubMed1993

Lack of association between schizophrenia and alleles in the dopamine D3 receptor gene.

Dopamine receptor dysfunction has been implicated in the pathophysiology of schizophrenia. Schizophrenic patients (n = 76) and control subjects (n = 53) were examined for allele frequencies in a 2-allele BalI polymorphism, causing a serine-->glycine amino acid substitution in the coding sequence of the dopamine D3 receptor gene. No statistical significant differences of allele frequencies or genotype frequencies could be found between the two groups. Neither were there any significant relationships between allele frequencies and a number of clinical variables within the schizophrenic subsample. However, if not corrected for multiple testing, an association was found between homozygosity and positive response to neuroleptic drugs. The present study does not provide evidence that the BalI polymorphism in the dopamine D3 receptor gene is involved in the pathophysiology of schizophrenia. Further investigations with an increased number and variety of patients concerning response to neuroleptic drugs and expression of the receptor in human brain should be performed to definitively exclude this hypothesis.

Adult↗
PubMed2004

Fas gene promoter polymorphisms in primary Sjögren's syndrome.

BACKGROUND: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS). OBJECTIVE: To examine genetic variation in the promoter region of the Fas gene in pSS. METHODS: Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls. RESULTS: No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). CONCLUSION: This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.

Antibodies, Antinuclear↗
PubMed2001

Genetic association of an LBP-1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease.

OBJECTIVES: The only locus unequivocally associated with late onset Alzheimer's disease (AD) risk is APOE. However, this locus accounts for less than half the genetic variance. A recent study suggested that the A allele of the 3'UTR biallelic polymorphism in the LBP-1c/CP2/LSF gene was associated with reduced AD risk. Samples were diagnosed predominantly by clinical rather than pathological criteria. We have sought to replicate this finding in a series of necropsy confirmed, late onset AD cases and non-demented controls. METHODS: The 3'UTR polymorphism in the LBP-1c/CP2/LSF gene was typed in 216 necropsy confirmed AD cases and 301 non-demented controls aged >73 years. RESULTS: We found different LBP-1c/CP2/LSF allele distributions in our AD cases and controls (p=0.048); the A allele was associated with reduced AD risk. The allele and genotype frequencies observed in our cases and controls were similar to those previously reported. No significant effects emerged when the data were adjusted for age, sex, or apoE epsilon4 carrier status. CONCLUSIONS: Our data support LBP-1c/CP2/LSF as a candidate gene/risk factor for AD and provide justification for future studies to investigate the role of this gene in Alzheimer's disease.

Age of Onset↗
PubMed2006

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype.

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.

Aged↗