Genetic association between Notch4 polymorphisms and Japanese schizophrenics

The objective of this study was to investigate whether three single nucleotide polymorphisms of the Notch4 gene are associated with the onset of schizophrenia. To confirm the linkage disequilibrium among these three single nucleotide polymorphisms of the gene, the three single nucleotide polymorphisms were genotyped by a polymerase chain reaction-restriction-fragment length polymorphism method for all samples. The genotypic frequencies of each single nucleotide polymorphism in the schizophrenic were compared with respective controls using a chi method. To check linkage disequilibrium, the haplotype frequency program was utilized. No statistical association between the two single nucleotide polymorphisms of the Notch4 gene and schizophrenia was observed in our Japanese samples. Although one nonsynonymous single nucleotide polymorphism did show a weakly significant P-value, its allelic frequencies are not positive. Two of the single nucleotide polymorphisms showed strong linkage disequilibrium in our Japanese samples. The single nucleotide polymorphism between the other two single nucleotide polymorphisms showed a weaker linkage disequilibrium with the others. Our study suggests that the three single nucleotide polymorphisms are not associated with the onset of schizophrenia. The linkage disequilibrium of this locus indicates that there is genetic heterogeneity in the Notch4 gene. Linkage disequilibrium may differ among ethnic groups, and so a larger study should be performed in this region.     

Genetic association of the presenilin-1 regulatory region with early-onset Alzheimer's disease in a population-based sample

Genetic association has been reported between a di-allelic polymorphism in intron 8 of presenilin-1 (PSEN1) and Alzheimer's disease (AD) in some studies but not in others. In a population-based series of 102 patients with early onset AD and 118 community controls we examined whether polymorphisms in linkage disequilibrium with intron8 of PSEN1 may explain the association. In addition to the intron 8 polymorphism (P = 0.05), a promoter polymorphism (P = 0.03) and the simple tandem repeat (STR) polymorphism D14S1028 located upstream of PSEN1 (P = 0.04) were found to be marginally significantly associated to AD. When excluding PSEN1 mutation cases (n = 6), the intron 8 association was explained by linkage disequilibrium to the dominant PSEN1 mutations. In the non-mutation cases, the weak associations between the polymorphisms in the regulatory region remained. Our study suggests that a polymorphism/mutation in the promoter or regulatory region of PSEN1 rather than the polymorphism in intron 8 of PSEN1 is associated with early onset AD.     

维生素D受体基因多态性与乳腺癌的相关性

目的：研究维生素D受体基因的多态性与乳腺癌的关系。方法：收集86例乳腺癌患者及134名对照,用聚合酶链反应－限制性片段长度多态性方法,在维生素D受体基因的3’端分析了两个限制性酶切位点（ApaI及TaqI）的多态分布。结果：发现TaqI位点等位基因在两个群体间分布的差异有显著性（P＝0．0004）。进一步对基因型进行分析发现,Tt、tt基因型与乳腺癌相关。而ApaI位点两等位基因未发现在两群体中存在差异。对ApaI及TaqI两座位的单体型进行分析,发现tA间存在连锁不平衡。在两群体中分析单体型的分布发现tA在病例中的比例明显高于对照人群,提示tA单体型与乳腺癌相关。两个位点等位基因及单体型与临床指标的分析均未发现阳性结果。结论：维生素D受体基因的多态怀与乳腺癌有关,提示维生素D受体基因与乳腺癌有关。     

Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia.

A survey of KIR2DL4 polymorphism revealed seven common sequences in the Australian population. The seven sequences encode three different amino acid sequences of the immunoglobulin domains. Two of the sequences encoding different amino acid sequences in the immunoglobulin domains also occur on some chromosomes with a single nucleotide deletion at the end of exon 6, which encodes the transmembrane domain (DeltaTM mutation), resulting in exon 6 skipping during mRNA production. Due to alternate splicing, a fraction of the mRNA produced by these alleles includes the transmembrane region but is missing the cytoplasmic region. The remaining two sequences differed only by synonymous substitutions. All of the exonic polymorphisms of KIR2DL4 could be detected by single-stranded conformational polymorphism of individually amplified exons. The DeltaTM mutation is in linkage disequilibrium with the killer cell immunoglobulin-like receptor (KIR) A haplotype, and the wild-type sequence is in linkage disequilibrium with the B haplotype. The frequencies of alleles with the DeltaTM mutation or Ig-domain polymorphisms did not differ between women who experienced pre-eclampsia and normotensive controls. Similarly there was no difference in the KIR gene repertoire in pre-eclampsia and normotensive controls.     

Novel polymorphisms in the promoter region of the neurotrophin-3 gene and their associations with schizophrenia

Based on the neurodevelopmental hypothesis in the etiology of schizophrenia, neurotrophic factors may be involved in the pathogenesis of the illness. We searched for polymorphisms in the promoter region of the neurotrophin-3 (NTF3) gene by using denaturing high performance liquid chromatography (DHPLC). Six single nucleotide polymorphisms (SNPs) were found. When these polymorphisms were examined for association with schizophrenia, a weakly significant difference was observed in the genotype distribution of the G/- 3004/A polymorphism between 184 schizophrenics and 185 controls (P < 0.05), although no statistically significant association was detected in a family-based sample of 50 trios (schizophrenics and their parents). With respect to the other polymorphisms, there was no significant association with schizophrenia. The G/- 3004/A polymorphism was in linkage disequilibrium with the CA repeat polymorphism in the first intron of the NTF3 gene. When haplotype-based analysis was performed, an increased frequency of the haplotype containing the G(- 3004) and the "A3" ([CA]23) alleles was observed for the schizophrenics compared to controls. Our results suggest that the G(- 3004)-A3 haplotype has a modest effect of giving susceptibility to schizophrenia.     

Regional European differences in allele and genotype frequencies of low density lipoprotein receptor-related protein 1 polymorphism in Alzheimer's disease.

The low density lipoprotein receptor-related protein 1 (LRP1 gene) is a candidate gene for Alzheimer's disease (AD), because it is a ligand for proteins involved in AD pathogenesis, such as apolipoprotein E (APOE), alpha2-macroglobulin (A2M), amyloid precursor protein (APP), and is located on chromosome 12, within a region linked with AD. An association between a silent polymorphism (C/T) in exon 3 and late onset AD has been reported, with an increased frequency of the C allele, although with conflicting results. We examined this polymorphism in a cohort of 166 sporadic AD patients and 225 sex- and age-matched nondemented controls from Southern Italy. No statistically significant differences were found in LRP1 genotype and allele frequencies between the whole AD sample and controls, nor in early- and late-onset subsets of AD patients. No statistically significant differences in frequencies between LRP1 alleles and AD among APOE allele, age, or gender strata were found. Finally, comparing our results with the findings from other European populations, the LRP1 C allele frequency showed a statistically significant decreasing trend from Northern to Southern regions of Europe, with a concomitant increase in LRP1 T allele frequency, but in AD patients only. Finally, in the AD sample, a decreasing geographical trend from North to South of Europe was found for LRP1 CC genotype, and an inverse trend for LRP1 CT genotype frequency. We suggest that these regional variations in LRP1 genotype and allele frequencies in AD could be related to the different patterns of association between this polymorphism and the disease in various European studies.     

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population

The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The alpha level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk.     

Novel polymorphisms in the promoter region of the neurotrophin‐3 gene and their associations with schizophrenia

Based on the neurodevelopmental hypothesis in the etiology of schizophrenia, neurotrophic factors may be involved in the pathogenesis of the illness. We searched for polymorphisms in the promoter region of the neurotrophin‐3 (NTF3) gene by using denaturing high performance liquid chromatography (DHPLC). Six single nucleotide polymorphisms (SNPs) were found. When these polymorphisms were examined for association with schizophrenia, a weakly significant difference was observed in the genotype distribution of the G/? 3004/A polymorphism between 184 schizophrenics and 185 controls (P < 0.05), although no statistically significant association was detected in a family‐based sample of 50 trios (schizophrenics and their parents). With respect to the other polymorphisms, there was no significant association with schizophrenia. The G/? 3004/A polymorphism was in linkage disequilibrium with the CA repeat polymorphism in the first intron of the NTF3 gene. When haplotype‐based analysis was performed, an increased frequency of the haplotype containing the G(? 3004) and the “A3” ([CA]₂₃) alleles was observed for the schizophrenics compared to controls. Our results suggest that the G(? 3004)‐A3 haplotype has a modest effect of giving susceptibility to schizophrenia. © 2002 Wiley‐Liss, Inc.     

Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin

Alpha-2-Macroglobulin (A2M) is a highly plausible candidate gene for Alzheimer's disease (AD) in a region of chromosome 12 that has numerous independent reports of genetic linkage. We previously reported that a 5 bp deletion in A2M was associated with AD in a subset of the National Institute of Health (NIMH) Genetics Initiative AD family sample. Efforts to replicate this association finding in case - control samples have been largely negative, while those in family samples have been more positive. We hypothesized that variable findings regarding this deletion, along with variable reports of association with V1000I, another polymorphism in the gene, result from linkage disequilibrium in the area as well as ascertainment differences between family-based and case-control studies. Thus, we resequenced the A2M locus to identify novel polymorphisms to test for genetic association with AD. We identified seven novel polymorphisms and tested them in the full NIMH sample of 1439 individuals in 437 families. We found significant genetic association of the 5 bp deletion and two novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remain significantly associated with AD even after correction for multiple testing. Taken together, these findings, and the positive reports in other family-based studies, continue to support a potential role for A2M or a nearby gene in AD. However, the negative case - control studies suggest that any underlying pathogenic polymorphisms have a modest effect, and may operate primarily among individuals with a family history of AD.     

新疆维吾尔族、汉族阿尔茨海默病LRP基因766C/T多态性关联分析

目的 探讨新疆地区维吾尔族、汉族低密度脂蛋白受体相关蛋白基因(low density lipoproteinreceptor-related protein gene,LRP)766C/T多态性与阿尔茨海默病(Alzheimer's disease AD)的关系.方法 对新疆地区维吾尔族、汉族≥50岁8284名人群进行AD流行病学调查,参照ADRDA-NINCDS的标准,选取AD患者209例与正常对照220名,应用聚合酶链反应-限制性片段长度多态技术检测LRP基因766C/T多态性,采用病例-对照的关联分析方法进行基因型和等位基因频率分析.结果 (1)新疆维吾尔族、汉族之间LRP基因的基因型和等位基因分布频率差异有统计学意义(P<0.05).(2)汉族病例组与对照组间基因型和等位基因频率分布差异有统计学意义(P<0.05).(3)在年龄≥65岁的病例组与对照组间基因型和等位基因频率分布差异有统计学意义(P<0.05),且此年龄组携带C等位基因的个体发生AD的危险性显著增加(OR=1.98,P<0.05).(4)在女性病例组中C/C基因型分布频率和C等位基因频率显著高于对照组(P<0.05),女性携带C等位基因的个体发生AD的危险性显著增加(OR=2.927,P<0.05).结论 新疆维吾尔族和汉族之间LRP,基因766C/T多态性存在差异,并发现在汉族、年龄≥65岁及女性人群中LRP基因766C/T多态性与AD的发病风险存在关联.     

Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.     

Further tests of the association between schizophrenia and single nucleotide polymorphism markers at the catechol-O-methyltransferase locus in an Askenazi Jewish population using microsatellite markers

Association studies are now primarily being conducted with single nucleotide polymorphisms because they are present everywhere in the genome and can be genotyped in "high throughput" formats. Microsatellite markers have a higher degree of polymorphism than single nucleotide polymorphisms and have been widely used in both linkage and association studies of disease. Polymorphic microsatellite markers with several alleles can readily detect linkage disequilibrium but at any given locus there may be differences between single nucleotide polymorphisms and microsatellites in their power to detect linkage disequilibrium because of the evolutionary history of the locus, especially the rate at which both the single nucleotide polymorphisms and microsatellite polymorphisms have mutated and the number of disease mutations and their history. In the current study, we examined the efficiency of microsatellite markers in association analysis by looking at all existent microsatellite markers in the catechol-O-methyltransferase gene region and by genotyping these microsatellites in a large cohort of schizophrenia patients and healthy controls, a subset of a sample where catechol-O-methyltransferase and schizophrenia were found to be associated. We also estimated the levels of linkage disequilibrium between these microsatellites and the previously reported single nucleotide polymorphisms (within the catechol-O-methyltransferase gene) found to be associated with schizophrenia. A modest allelic association of P=0.041 was found between schizophrenia and the microsatellite marker D22S944, which was not significant, however, when corrected for all microsatellites tested. Nevertheless, significant linkage disequilibrium was found between this marker and the three single nucleotide polymorphisms within the catechol-O-methyltransferase gene that displayed association with the disease in the previously published research on this sample. Significant linkage disequilibrium was also observed between microsatellites up to approximately 300 kb distant from those single nucleotide polymorphisms. Although significant, the extent of linkage disequilibrium in terms of r2 was small (in the order of 0.01).     

MTHFR genetic polymorphism increases the risk of preterm delivery

Aims: This study aimed to investigate the association between the methylene tetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and premature delivery susceptibility. Methods: With matched age and gender, 108 premature delivery pregnant women as cases and 108 healthy pregnant women as controls were recruited in this case-control study. The cases and controls had same gestational weeks. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was adopted to analyze C677T and A1298C polymorphisms of the participants. Linkage disequilibrium (LD) and haplotype analysis were conducted by Haploview software. The differences for frequencies of gene type, allele and haplotypes in cases and controls were tested by chi-square test. The relevant risk of premature delivery was represented by odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: TT gene type frequency of C677T polymorphsim was higher in cases than the controls (P=0.004, OR=3.077, 95% CI=1.469-6.447), so was allele T (P=0.002, OR=1.853, 95% CI=1.265-2.716). Whereas, CC gene type of A1298C polymorphism had a lower distribution in cases than the controls (P=0.008, OR=0.095, 95% CI=0.012-0.775), so was allele C (P=0.047, OR=0.610, 95% CI=0.384-0.970). Haplotype analysis and linkage disequilibrium test conducted on the alleles of two polymorphisms in MTHFR gene, we discovered that haplotype T-A had a higher distribution in cases, which indicated that susceptible haplotype T-A was the candidate factor for premature delivery. Conclusions: Gene type TT of MTHFR C677T polymorphism might make premature delivery risk rise while gene type CC of A1298C polymorphism might have protective influence on premature delivery.     

Low density lipoprotein receptor-related protein gene polymorphisms and risk for late-onset Alzheimer's disease in a Japanese population

Low density lipoprotein (LDL) receptor-related protein (LRP) gene polymorphisms located in the 5' region and in exon 3, and the apolipoprotein E (APOE) genotype were determined in 100 Japanese patients affected by late-onset Alzheimer's disease (AD). We matched 246 controls for age and found no association between the polymorphism located in the 5' region of the LRP gene. The distribution of LRP exon 3 genotypes and alleles did not differ between AD and the control groups. However, the frequency of T allele in the Alzheimer's group having APOE-epsilon4 was lower than that in the control group having APOE-epsilon4, but it was only marginally significant (p = 0.022). Age of onset was significantly younger in the patients with CC genotype than those carrying the T allele (p = 0.03), and this trend was more evident among non-APOE-epsilon4 carriers (p = 0.008). These results support the possibility that ApoE and LRP may contribute to the development of AD.     

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland

Genetic variation in one of the major APOE receptors in the brain has been associated with increased risk for Alzheimer disease (AD). A C/T polymorphism in exon 3 and a tetranucleotide repeat polymorphism in the 5' region of the low-density lipoprotein receptor-related protein gene have been reported to increase risk in some studies but these reports have not been universally replicated. In addition, genetic variation in another ligand of LRP, alpha-2 macroglobulin (A2M), has also been associated with increased AD risk. However, these reports also remain controversial. We have genotyped both LRP polymorphisms and two polymorphisms in the A2M gene in a large group of clinically well-defined AD cases and controls from the relatively genetically homogeneous Northern Ireland population. Comparison of genotype and allele frequencies for polymorphisms in LRP revealed no significant differences between cases and controls. Multiple logistic regression analysis performed to assess any possible interaction between LRP and APOE revealed little evidence for genetic interaction despite the obvious biological interaction. Genotype and allele comparisons between the groups for the A2M polymorphisms also gave no evidence that either polymorphism increased risk for disease. The results from this study indicate that polymorphisms in LRP and A2M are not associated with increased risk for AD in Northern Ireland.     

CAT53 and HFE alleles in Alzheimer's disease: A putative protective role of the C282Y HFE mutation

Alzheimer's disease (AD) is a complex disorder, resulting from an interaction between environmental and genetic factors. Several studies addressed the association of AD with MHC class-I polymorphisms without definite conclusions. Considering the remarkable linkage disequilibrium at the MHC region, it is not possible to assume if the reported associations result from a direct effect of the respective genes or result from associations with other closely linked genes transmitted in an extended conserved haplotype. Recent evidence pointed to CAT53, a newly described gene located at the MHC class-I region in the vicinity of HLA-C, as a candidate modifier gene in AD. CAT53 encodes a phosphatase 1 nuclear inhibitor protein and is strongly expressed in brain regions involved in memory and AD. Here we tested the potential association of CAT53 with the risk of developing AD and searched for potential haplotypic associations of CAT53 with two common mutations (H63D, C282Y) in the HFE gene, also located at chromosome 6p21.3. The allele frequencies of these mutations in AD patients were compared to the expected frequencies previously established in the normal Portuguese population. We detected only one polymorphism (G>A) in CAT53, at position 8232, in intron 17. Screening of this polymorphism in 113 AD patients and 82 controls did not show any evidence of association, therefore excluding the hypothetical role of the CAT53 polymorphism as modifier in AD. In contrast, we found a significant negative association of the C282Y HFE mutation with AD, thus supporting a putative protective role of this protein variant in neurodegeneration.     

No association between polymorphisms in the FACL4 (fatty acid-CoA ligase 4) gene and nonspecific mental retardation in Qin-Ba mountain region of China

Mental retardation (MR) is a common form of cognitive impairment among children. The underlying causes of mental retardation are extremely heterogeneous and include significant genetic factors. Long chain fatty acid-CoA ligase 4 is the first gene shown to be involved in mental retardation and fatty-acid metabolism. FACL4 gene mutations in three Italian MR pedigrees have been reported as causing non-specific mental retardation. To investigate the possible genetic contribution of the FACL4 gene to non-specific mental retardation children of the Qin-Ba mountain region in China we performed an association study of 556 subjects (118 NSMR, 116 borderline NSMR, and 322 controls) from the Han children of northwestern China using five common SNPs (rs5943427, rs12856122, rs5943418, rs7886473, and rs10126612) in the gene. No significant differences of genotypes and alleles frequencies from each single SNP between NSMR and controls were observed. Pairwise linkage disequilibrium analysis showed that four SNPs rs5943427, rs12856122, rs5943418, and rs7886473 were in strong linkage disequilibrium; therefore, a haplotype analysis was performed. However, there were no any significant differences in haplotype distributions between cases and controls. In conclusion, we have found no evidence for the FACL4 gene conferring susceptibility on non-specific mental retardation children of the Qin-Ba mountain region in China.     

Association of PRKCH gene with lacunar infarction in a local Chinese Han population

Recent evidence indicated that the PRKCH gene was a susceptibility gene for lacunar infarction in a Japanese population. The aim of the present study was to explore the association of the gene with lacunar infarction in a population of Chinese Han ancestry. A total of 280 consecutive lacunar infarction patients and 306 unrelated population-based controls that had been matched for age and sex were examined using a case–control design. Two single nucleotide polymorphisms (SNPs) of PRKCH gene (rs3783799 and rs2230500) were genotyped with ligase detection reaction (LDR) and multiplex polymerase chain reaction (PCR). Linkage disequilibrium (LD) and haplotype analysis were also investigated between these two groups. Overall alleles and genotype frequencies were similar between cases and controls. No significant association was detected with the gene polymorphisms mentioned above and lacunar infarction; no significant difference was found with haplotype analysis between these two groups. None of the two SNPs showed significant association with lacunar infarction in the whole subjects before and after adjustment for conventional stroke risk factors (hypertension, diabetes mellitus, and hypercholesterolemia). The frequencies of PRKCH differed largely from those in the Japanese population. The present study suggests that variants in the PRKCH gene are not the risk factors for lacunar infarction in individuals from a small population of Chinese Han ancestry. Population differences in alleles and haplotype frequencies as well as LD structure may contribute to the observed differences between populations.     

Association between − 308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma

BACKGROUND: Tumour necrosis factor (TNF) is a pivotal cytokine in the inflammation underlying asthma. The TNF gene is located in the polymorphic HLA class 3 region on chromosome 6p. Several polymorphisms in this region have been described and associated with alteration of TNF secretion in vitro. OBJECTIVE: In this study we tested the hypothesis that two such polymorphisms, lymphotoxin alpha NcoI B*1 and -308 TNF2 may be components of the genetic predisposition to asthma. METHODS: Five hundred and fifty-six random individuals were studied, comprising approximately equal numbers of asthmatic subjects, with or without atopy, and a nonatopic nonasthmatic control group. In addition, 355 subjects (172 asthmatics) from 60 multiplex families were typed at the LTalpha NcoI locus. RESULTS: There was an association between allele two of the -308 TNF polymorphism and bronchial hyperreactivity (OR 2.12, 95% CI 1.04-4.32, P = 0.036). However, there was no association with LTalpha NcoI alleles. To determine whether this was influenced by linkage disequilibrium within the MHC, 91 subjects with bronchial hyperreactivity and 85 control subjects were typed for class 2 and 3 alleles. Following identification of the extended TNF2 haplotype, we found no independent association of these alleles with BHR. CONCLUSIONS: We conclude that the -308 TNF2 promoter polymorphism may form a component of the genetic predisposition to BHR in asthma.     

Linkage disequilibrium on the COMT gene in French schizophrenics and controls.

Catechol-O-methyltransferase (COMT) catalyzes the degradation of catecholamines and could therefore play a role in the etiology of schizophrenia. Moreover, microdeletions including the COMT locus have been found in schizophrenics presenting typical features of the velo-cardio-facial syndrome. In the present work, five single-strand conformation polymorphisms were detected in exons of the COMT gene. The linkage disequilibria between the polymorphisms were estimated, and the genotypic frequencies were calculated on a sample of 126 to 137 schizophrenics and 136 to 140 controls, depending on the marker. Patients and controls were matched for ethnicity and geographical origin. A trend toward association was found between schizophrenia and (i) genotype 11 of the Pml I polymorphism (p = 0.034; OR = 1.82); (ii) haplotype 1-2 for the Pml I and Bcl I polymorphisms (p = 0.022; OR = 1.75). The Pml I polymorphism is in complete linkage disequilibrium with the common Met-->Val(158) substitution, which affects the activity of the enzyme. This finding suggests a possible minor effect of COMT in a multifactorial threshold model of vulnerability to schizophrenia.