Lack of association between atopy and RsaI polymorphism within intron 2 of the PcεRI-β gene in a Spanish population sample

Background The B genotype of RasI polymorphism located within intron 2 of the Fc-lgE receptor I (Fc.Rl) gene was previously found to be increased in atopic patients from a Japanese population sample.
Methods We studied these A/B genotypes in 70 Spanish atopic patients, and the results were compared to those of 51 nonatopic controls. RasI polymorphisms were studied by specific digestion of polymerase chain reaction fragments followed by polyacrylamide gel electrophoresis. Results The polymorphism frequency (A/A: 25/70, A/B: 28/70, B/B: 17/70) found in patients did not differ from the frequency in nonatopic control subjects.
Conclusions We did not find RasI polymorphisms associated with atopic disease. The genetic findings in atopy and asthma may be very different according to ethnic and local characteristics, and they must be carefully verified in difFerent population samples.     

Lack of association between the functional c-kit rs6554199 polymorphism and achalasia in a Spanish population

A functional polymorphism (rs6554199) located in the c-kit gene was associated with achalasia in a Turkish cohort. Our aim was to replicate this result in a large cohort of Spanish patients and controls. A case-control study was performed with 282 Spanish white unrelated patients and 687 healthy controls. All were genotyped for SNP rs6554199 using a TaqMan Assay. No association was found in our study (T allele frequency in patients and controls: 47.3% vs. 49.4%; OR = 0.92, p = 0.41). The finding that the T allele of the c-kit rs6554199 polymorphism could be associated with achalasia as reported in a Turkish population could not be replicated in a Spanish cohort. Although ethnic differences might explain these data, the sample size that compromised the statistical power in the Turkish cohort and is higher in our study, led us to suggest that the reported association seems to be a false positive.     

Lack of association between eNOS gene polymorphisms and ischemic heart disease in the Spanish population

Bartsocas-Papas syndrome (BPS) is a severe autosomal recessive syndrome characterized by neonatal or intrauterine death in most cases, severe popliteal webbing, oligosyndactyly, genital abnormalities, and typical face with short palpebral fissures, ankyloblepharon, hypoplastic nose, orofacial clefts, and small mouth. Until now at least 23 cases with this syndrome in 11 families were described, mostly from Mediterranean origin. We report on two Dutch families with six affected children having BPS. One of the patients was prenatally diagnosed by ultrasound examination. Additional unreported findings were omphalocele and aplasia of the urethra. The intrafamilial resemblance in severity is of importance for the genetic counseling of families and prenatal detection by ultrasound. We discuss possible pathogenic mechanisms and review similar cases from the literature.     

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

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

Lack of association between cathepsin D genetic polymorphism and Alzheimer disease in a Spanish sample

Cathepsin D (catD) is an intracellular aspartyl protease that exhibits beta and gamma secretase-like activity to cleave amyloid precursor protein into beta amyloid peptide. The T-allele of a biallelic (alleles C and T) polymorphism in the exon 2 of the catD gene has been found to be associated with increased risk of Alzheimer disease (AD) in two independent German populations. Other groups have been unable to replicate this association in Caucasian American and Northern Ireland populations. Moreover, a small and no significant tendency for the T-allele to be protective for AD has been demonstrated in Caribbean Hispanics. A case control study utilizing a clinically well-defined group of 311 sporadic AD patients and 346 control subjects was performed to test this association in an ethnically homogeneous population from Spain. We did not observe any association between the T-allele of the catD gene and the disease. Furthermore, catD was not predictive of AD in an interactive fashion when considering apolipoprotein E, age, or gender.     

Lack of association between methylenetetrahydrofolate reductase (MTHFR) C677T and ischaemic heart disease (IHD): family-based association study in a Spanish population

The effect of the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, traditionally associated with ischaemic heart disease (IHD), was assessed in a Spanish population. The transmission disequilibrium test (TDT) was used to determine a possible association in a sample of 101 trios of IHD patients. The distribution of MTHFR genotypes was similar in the IHD subjects and the parental group; the TT genotype was present in 14.9% of IHD patients, as compared to 15.2% in the parents. The frequency of the T allele was also similar in IHD cases and parents (39.6% vs. 42.4%; p = 0.649). The TDT confirmed that the observed transmission of the T allele did not deviate significantly from the expected one (chi2 = 0.743; p > 0.4). Our TDT analysis clearly demonstrates a lack of association between the T allele of the C677T mutation in MTHFR and cardiovascular artery disease, both for the general group and for different risk subgroups (smokers, hypertension, male sex, overweight and type A behaviour pattern) in the Spanish population.     

Lack of association between the CALM1 core promoter polymorphism (-16C/T) and susceptibility to knee osteoarthritis in a Chinese Han population

Background

Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations.

Methods

Full genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify APC gene mutations, which were correlated to the clinical presentations.

Results

10 novel APC gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC) both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA) developed colon cancer at age 72 as the first manifestation of attenuated FAP.

Conclusion

With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.     

Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals

Weight gain is a major side effect of treatment with clozapine and other antipsychotics. Recent studies suggest an important role of the serotonin type 2C receptor gene (5-HT2CR) in antipsychotic-induced weight gain. However, investigations pertaining to a possible association between a -759C/T polymorphism (C allele) of the 5-HT2CR and weight gain induced by clozapine and/or other antipsychotics have yielded inconsistent results. We investigated the -759C/T polymorphism of the 5-HT2CR in relation to clozapine-induced change in body mass index (BMI) (kg/m) in 97 German patients with schizophrenia and found no association between the -759C allele and weight gain after 12 weeks of clozapine treatment. In addition, confounding effects of initial BMI, age, sex and duration of illness on change in BMI could not be detected by multiple linear regression analysis. Our data do not support an involvement of the -759C/T polymorphism of the 5-HT2CR in clozapine-induced weight gain in German patients with schizophrenia. Further pharmacogenetic studies pertaining to antipsychotic-induced weight gain are warranted.     

Lack of association between DNA repair gene ERCC1 polymorphism and risk of lung cancer in a Chinese population

The ERCC1 (Excision Repair Cross Complementation Group 1) gene is involved in the nucleotide excision repair pathway. This study was designed to examine whether ERCC1 Asn118Asn (G19007A) polymorphism, which has been associated with risk of some cancers among Caucasians, may be associated with risk of lung cancer in a Chinese population. ERCC1 Asn118Asn (G19007A) genotypes were determined in DNA samples from 151 cases and 143 controls. The distribution of genotypes between cases and controls was not associated with an increased risk of lung cancer (AA versus GG: adjusted OR (odds ratio) = 1.41, 95% CI (confidence interval) = 0.76-2.59; AG versus GG: adjusted OR = 0.78, 95% CI = 0.47-1.29; and AA + AG versus GG: adjusted OR = 0.93, 95% CI = 0.73-1.19). The frequency A (0.20) of the A-allele was significantly lower among these Chinese controls than in the Caucasian control populations (A = 0.54-0.65) (All P < 0.001). No statistically significant effects of age, histological subtype or smoking were found. These findings suggest that ERCC1 Asn118Asn (G19007A) polymorphism may play a limited role for lung cancer in this Chinese population.     

Lack of association between hepatitis B virus infection and polymorphism of mannose-binding lectin gene in Korean population

Mannose-binding lectin (MBL) plays an important role in immune defense. This study was undertaken to investigate the association between hepatitis B virus infection and polymorphisms of MBL gene. We assessed the single nucleotide polymorphism at codon 54 in exon 1 of MBL in patients with hepatitis B virus infection and HBsAg negative controls in Korean population. A total of 498 enrolled subjects was classified into four groups. Group 1; Clearance, Group 2; Inactive healthy carrier, Group 3; Chronic hepatitis, Group 4; Liver cirrhosis. MBL gene polymorphisms at codon 54 led to three genotypes (G/G, G/A, A/A). When we divided subjects into clearance group (group 1) and persistence group (group 2-4), G/G genotype and A-allele carrier were observed in 55.6% and 44.4% in clearance group, 64.8% and 35.2% in persistence group (p=0.081), respectively. When hepatitis B virus persistent cases were divided into inactive healthy carrier (group 2) and disease progression group (group 3 and 4), MBL gene polymorphisms at codon 54 were not related to disease progression (p=0.166). MBL gene polymorphism at codon 54 was not associated with the clearance of hepatitis B virus infection nor progression of disease in chronic hepatitis B virus infection.     

Lack of association between ADAM33 gene and asthma in a Chinese population

Asthma is a complex polygenic disease with gene-environment interactions being important. It has been previously suggested that ADAM33, which is a member of a gene family that encodes membrane-anchored proteins with a disintegrin and a metalloprotease domain, is primarily expressed in lung fibroblasts and bronchial smooth muscle cells and has been associated with airway remodelling and bronchial hyperresponsiveness. A significant association has previously been demonstrated between single nucleotide polymorphisms (SNPs) and haplotypes of the ADAM33 and asthma in ethnically diverse populations. To assess whether SNPs or haplotypes of ADAM33 are related to asthma in a Chinese Han population, we genotyped three SNPs of ADAM33 (7575G/A in intron 6, 11188A/T in intron 19, and 12433T/C in exon 20) in a case-control study involving 296 patients with asthma and 270 healthy controls. No significant association was detected between these three SNPs and asthma susceptibility in the Chinese population.     

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

Previous studies have suggested that the serotonergic (5‐HT) system might be involved in the development of Attention‐deficit hyperactivity disorder (ADHD). ADHD is frequently characterized by aggressive and impulsive behavior, a major symptom associated with reduction in serotonergic function. The tryptophan hydroxylase (TPH) gene is a reasonable candidate for ADHD because it encodes the rate‐limiting enzyme in the process of 5‐HT biosynthesis. In this study, we examined the relationship between the A218C polymorphism in TPH gene and ADHD. Sixty‐nine ADHD patients and their biological parents were investigated. The A218C polymorphism in intron 7 of TPH gene was detected by PCR‐RFLP method. No allele or genotype concerned with this A218C polymorphism was found to be associated with ADHD when analyzed with the haplotype relative risk method. Therefore, our data indicate that the TPH gene A218C polymorphism may not be a susceptibility factor of ADHD in the Chinese Han population. © 2001 Wiley‐Liss, Inc.     

Lack of a genetic association between the frizzled-3 gene and schizophrenia in a British population

In recent studies, the frizzled-3 (FZD3) locus was found to be associated with schizophrenia in both Japanese and Chinese populations. To validate the initial finding, we detected three single nucleotide polymorphisms (SNPs) present in a 10-kb segment of DNA at the FZD3 locus, as described in a previous study with a Chinese population. We totally recruited 120 British family trios consisting of fathers, mothers and affected offspring with schizophrenia. The transmission disequilibrium test (TDT) did not show allelic association between these three SNPs and schizophrenia. The 3-SNP haplotype system was composed of only 3 individual haplotypes among the 120 family trios and these 3 SNPs were mainly carried by two distinct haplotypes, suggesting that these 3 SNPs may result from a single founding event in history. No association was shown between the 3-SNP haplotypes and schizophrenia. The present results imply that the FZD3 gene is less evolutionary in the British population than in the Chinese population. This may be a possible reason for the failure to replicate the FZD3 finding with the British sample.     

A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was implicated to be associated with hypertension due to its role in catalyzing the formation of 5-methylenetetrahydrofolate, a co-substrate for the conversion of homocysteine to methionine. Association studies were reported in different populations; however, a great number of subsequent studies have produced contrary results, possibly reflecting inadequate statistical power. With the cumulative data in recent years in both Caucasian and Asian populations, it was necessary to carry out a comprehensive analysis of previous findings. In this meta-analysis, we combined 26 English and Chinese studies in Caucasian and Asian populations published up to November 2006 to give a new picture of the role of the C677T polymorphism in the MTHFR gene. Evidence of significant association was detected between C677T polymorphism and hypertension in both populations. Additionally, the significant association between C677T polymorphism and hypertension/hypertension-in-pregnancy suggested that this polymorphism was one independent risk factor of hypertension.     

Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia

Genetic anticipation, a phenomenon characterized by increased severity of symptoms and earlier age at onset of a disease in successive generations, is believed to be present in schizophrenia. In several neurodegenerative diseases showing anticipation, the mutation causing the disease is an expanded trinucleotide repeat. Therefore, genes containing trinucleotide repeats prone to expansion have become a suitable family of candidate genes in schizophrenia. A human calcium-activated potassium channel gene (hSKCa3), possibly mapping to chromosome 22q11-13, a region previously linked to schizophrenia, was recently described. This gene contains two contiguous expressed CAG repeat stretches. Recently, long allelic variants of one of these CAG repeats were found to be overrepresented in schizophrenic patients compared to normal controls. In this study we attempted to replicate this result and to study the relationship between the length of this CAG repeat on the one hand and the severity and age at onset of the disease on the other hand. No association with the disease or correlation with the severity of schizophrenia was identified. In addition, hSKCa3 was mapped to chromosome 1. Our results do not support the involvement of this particular CAG repeat-containing gene in schizophrenia.     

Lack of association between the unique LMP2 gene polymorphism and the outcome of lung cancer in a population of Chinese Han nationality

Lung cancer is characterized by a widely ranging incidence variation; it is the most common cancer in China. In this study we will assess the association of low-molecular-mass protease 2 (LMP2) gene codon 60 polymorphism with the risk of lung cancer. Genomic DNA of peripheral blood mononuclear cells was isolated from 207 patients with lung cancer and 264 healthy controls. DNA direct sequencing and polymerase chain reaction-restriction fragment length polymorphism were performed to scrutinize LMP2 gene codon 60 polymorphism. The risk of LMP2 gene polymorphism in lung cancer was assessed using an unconditional logistic regression model adjusted by the confounding factors. As a result of DNA direct sequencing, the LMP2 codon 60 polymorphic substitution of the nucleotide was CGC → TGC in Chinese individuals, not CGC → CAC as reported in other ethnic populations. In histology-specific analysis and TNM stages, there was no apparent association between this LMP2 gene polymorphism and any of the histologic types or TNM stages of lung cancer using the Arg/Arg genotypes as the reference group (all p values > 0.05). These results suggest that the polymorphic site is unique in the Chinese population of Han nationality at the LMP2 codon 60 loci (Arg60Cys), but a lack of association with lung cancer exists.     

Lack of association between CTLA-4 gene polymorphism and IDDM in Japanese subjects

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is determined by both environmental and genetic factors. The main gene associated with predisposition to IDDM is HLA. Recent studies have described linkage and association of IDDM to the CTLA-4 gene (IDDM12) in Caucasians. CTLA-4 is a candidate gene for T-cell-mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. We investigated the distribution of a CTLA-4 gene polymorphism in 110 Japanese patients with IDDM and 200 control subjects. In 84 patients, we also investigated associations between this CTLA-4 gene polymorphism and GAD65 antibody positivity. An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction-restriction fragment length polymorphism method. GAD65 antibody was detected using a radioligand binding assay. There was no significant difference in the distribution of CTLA-4 alleles in patients and controls and no difference was observed in prevalence of CTLA-4 alleles when GAD65 antibody-positive and -negative individuals in the IDDM groups were compared. The present study did not support an association between the CTLA-4 gene and IDDM in the Japanese population.     

No association of PTGDR -441C/T polymorphism with asthma in a North Indian population

Background: Asthma is the most prevalent disease in India according to the national survey conducted by NFHS 2 in 1998–399. Prostaglandin D2 (PGD2) is a bronchoconstriction inducing metabolite of arachidonic acid in the mast cells, which is produced on exposure to allergens and acts as a ligand for the Prostaglandin D2 Receptor (PTGDR). Polymorphisms in the PTGDR gene have been suggested to be involved in the mechanism of asthma. Objective: This is the first study conducted in India, investigating the role of PTGDR −441C/T promoter polymorphism in asthma pathogenesis. Methods: A case-control study was performed with a total of 992 subjects, including 410 adult asthmatics and 582 healthy controls from regions of North India. The PTGDR−441C/T polymorphism was genotyped by Tetra-Primer Amplification Refractory Mutation System Polymerase Chain Reaction (Tetra-Primer ARMS PCR). Results: Statistical analysis of the results between asthma cases and controls for the PTGDR −441C/T polymorphism showed Chi² (χ²) = 0.29, OR = 0.95, 95% CI (0.70–1.15) and p = 0.599. Neither the genotypic nor the allelic frequencies observed for the PTGDR −441C/T polymorphism, were significantly associated with asthma or asthma phenotypes. Conclusions: The PTGDR −441C/T polymorphism is not associated with asthma or its phenotypes in the studied North Indian population.     

Lack of association between polymorphisms in C4b‐binding protein and atypical haemolytic uraemic syndrome in the Spanish population

Dysregulation of the alternative pathway of complement activation, caused by mutations or polymorphisms in the genes encoding factor H, membrane co‐factor protein, factor I or factor B, is associated strongly with predisposition to atypical haemolytic uraemic syndrome (aHUS). C4b‐binding protein (C4BP), a major regulator of the classical pathway of complement activation, also has capacity to regulate the alternative pathway. Interestingly, the C4BP polymorphism p.Arg240His has been associated recently with predisposition to aHUS and the risk allele His240 showed decreased capacity to regulate the alternative pathway. Identification of novel aHUS predisposition factors has important implications for diagnosis and treatment in a significant number of aHUS patients; thus, we sought to replicate these association studies in an independent cohort of aHUS patients. In this study we show that the C4BP His240 allele corresponds to the C4BP*2 allele identified previously by isoelectric focusing in heterozygosis in 1·9–3·7% of unrelated Caucasians. Crucially, we found no differences between 102 unrelated Spanish aHUS patients and 128 healthy age‐matched Spanish controls for the frequency of carriers of the His240 C4BP allele. This did not support an association between the p.Arg240His C4BP polymorphism and predisposition to aHUS in the Spanish population. In a similar study, we also failed to sustain an association between C4BP polymorphisms and predisposition to age‐related macular degeneration, another disorder which is associated strongly with polymorphisms in factor H, and is thought to involve alternative pathway dysregulation.     

A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population

Previous studies have reported genetic linkage evidence for a candidate gene of schizophrenia on chromosome 22q11 but no genes in this region have been really confirmed to be involved in the etiology of schizophrenia so far. Very recently, the proline dehydrogenase gene (PRODH), located in the most centromeric part of the 22q11 microdeletion region, has been reported to be strongly associated with schizophrenia from three sets of independent samples and the most significant evidence for association was derived from a single nucleotide polymorphism-PRODH*1945(T/C). We genotyped this polymorphism in 166 Chinese family trios with schizophrenia from East China. No evidence for preferential transmission of the PRODH*1945 alleles from parents to affected offsprings was found using either Transmission Disequilibrium Test (P=0.4) or Haplotype-based Haplotype Relative Risk analysis (P=0.35). Our results suggest that the 1945(T/C) polymorphism of the proline dehydrogenase gene is unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.