Tryptophan hydroxylase gene polymorphisms are not associated with suicide

Several lines of evidence suggest a serotonergic dysfunction involved in the biological susceptibility of suicide. Abnormalities of serotonergic markers such as 5-hydroxyindoleacetic acid and prolactin response to fenfluramine have been demonstrated in suicide subjects. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is one of the most important regulating factors in the serotonergic system. Recently, polymorphisms of the TPH gene have been identified and some of these polymorphisms have been suggested to be associated with suicide, but the results are still inconsistent. We examined whether the -6526A/G polymorphism in the promoter region and the 218A/C polymorphism in intron 7 of the TPH gene were associated with suicide using 132 Japanese suicide victims. No significant difference in genotype distribution and allele frequencies of these polymorphisms was found between the suicide victims and the controls. We concluded neither the -6526A/G polymorphism nor the 218A/C polymorphism of the TPH gene is likely to have a major effect on the susceptibility of suicide. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:861-863, 2000.     

PERB11 (MIC): a polymorphic MHC gene is expressed in skin and single nucleotide polymorphisms are associated with psoriasis

The susceptibility genes for psoriasis remain to be identified. At least one of these must be in the major histocompatibility complex (MHC) to explain associations with alleles at human leucocyte antigen (HLA)-A, -B, -C, -DR, -DQ and C4. In fact, most of these alleles are components of just two ancestral haplotypes (AHs) designated 13.1 and 57.1. Although relevant MHC gene(s) could be within a region of at least 4 Mb, most studies have favoured the area near HLA-B and -C. This region contains a large number of non-HLA genes, many of which are duplicated and polymorphic. Members of one such gene family, PERB11.1 and PERB11.2, are expressed in the skin and are encoded in the region between tumour necrosis factor and HLA-B. To investigate the relationship of PERB11.1 alleles to psoriasis, sequence based typing was performed on 97 patients classified according to age of onset and family history. The frequency of the PERB11.1*06 allele is 44% in type I psoriasis but only 7% in controls (Pc = 0.003 by Fisher's exact test, two-tailed). The major determinant of this association is a single nucleotide polymorphism (SNP) within intron 4. In normal and affected skin, expression of PERB11 is mainly in the basal layer of the epidermis including ducts and follicles. PERB11 is also present in the upper keratin layers but there is relative deficiency in the intermediate layers. These findings suggest a possible role for PERB11 and other MHC genes in the pathogenesis of psoriasis.     

Fas ligand gene polymorphisms are not associated with Hashimoto's thyroiditis and Graves' disease

Hashimoto's thyroiditis and Graves' disease represent the two most common autoimmune thyroid disorders. Whereas in Hashimoto's thyroiditis FasL expression causes thyrocytes to undergo apoptosis, additional anti-apoptotic molecules appear to protect these cells in Graves' disease. Mutations of the FasL gene were observed in systemic lupus erythematosus. Given its functional relevance for the pathogenesis of thyroid autoimmunity we wondered whether variants of the FasL gene play a role in Hashimoto's thyroiditis and Graves' disease. We genotyped families with at least one offspring affected by Hashimoto's thyroiditis (n = 86) and Graves' disease (n = 90) for two FasL gene polymorphisms (C -843 T in the promoter, A IVS2nt-124 G in intron 2). Extended transmission disequilibrium (ETDT) and chi(2) testing were performed. Neither polymorphism alone nor the promoter/intron 2 haplotypes (p = 0.91) were associated with Hashimoto's thyroiditis. No association with Graves' disease was observed for the promoter polymorphism (p = 0.91) and the intron 2 "A" allele (57.1%; p = 0.36) or the promoter/intron 2 haplotypes (p = 0.31). Moreover, intron 2 genotyping revealed no difference between an additional 251 patients with Graves' disease and 197 healthy controls (p = 0.37). Italian and German families did not differ for the studied polymorphisms. In conclusion, our data do not suggest common genetic FasL variants to significantly contribute to the pathogenesis of either Hashimoto's thyroiditis or Graves' disease.     

Mannose-binding lectin gene polymorphisms are not associated with susceptibility to severe early childhood caries

Our purpose was to investigate a possible relationship between severe early childhood caries (S-ECC) and polymorphism of the mannose binding lectin gene and investigate the role of allele variant as a possible factor in the susceptibility to S-ECC. Sixty-two Chinese children with S-ECC and 68 caries-free control children were included in this study. Genomic DNA was extracted from buccal epithelial cells of each individual. The identification of MBL B allele was performed by restriction fragment length polymorphism using Ban I restriction enzyme. The frequency of MBL mutant genotype (GGC/GAC and GAC/GAC) was more frequent among children with S-ECC compared with control groups, but did not significantly differ between two groups (x² = 2.82, p > 0.05). There was no significant difference in the allele frequency of codon54 wild type (allele A) between two groups (x² = 2.76, p > 0.05). The present study did not find evidence of MBL codon54 polymorphisms being associated with S-ECC in the population studied, but a larger sample size is necessary to confirm the present results.     

Functional polymorphisms in the FCN2 gene are not associated with invasive pneumococcal disease

L-ficolin is a pattern-recognition molecule which binds lipoteichoic acid and Gram-positive bacteria and activates the lectin pathway of complement. Five common functional polymorphisms have recently been identified in the FCN2 gene which encodes L-ficolin: three promoter polymorphisms (at positions -986, -602 and -4) which affect serum L-ficolin concentration, and two non-synonymous polymorphisms (Thr236Met and Ala258Ser) which influence carbohydrate binding. We studied the frequencies of these polymorphisms in individuals with invasive pneumococcal disease (IPD) and a control group. Although the five FCN2 polymorphisms were each present in the UK Caucasian population studied, no significant associations were observed between the FCN2 polymorphisms and susceptibility to IPD. This is in contrast to mannose-binding lectin deficiency, which we have previously shown to be associated with increased susceptibility to IPD. Although we are unable to exclude small effects of FCN2 genetic variation on susceptibility to IPD, the result suggests that L-ficolin may not be critical for host defence against pneumococcal infection.     

Dinucleotide repeat polymorphisms in the neprilysin gene are not associated with sporadic Alzheimer's disease

In the pathological process of Alzheimer's disease (AD), deposition of amyloid beta-peptide (A beta) in the brain parenchyma plays an important role. Neprilysin (NEP), a neutral endopeptidase, degrades A beta, and it is postulated that decreased NEP activity may contribute to the development of AD by promoting the accumulation of A beta. The human NEP gene possesses four dinucleotide repeat polymorphisms, and it is possible that these polymorphisms regulate the NEP expression levels and influence the pathological cascade of AD. Therefore, we investigated the association of these polymorphisms with AD. We performed genotyping of each polymorphism in 201 Japanese sporadic AD patients and 208 Japanese controls. There were no significant differences between the AD and control groups in allele frequencies of each polymorphism. We conclude that these polymorphisms in the NEP gene do not contribute to genetic risk factors for sporadic AD.     

Promoter polymorphisms of the CD14 gene are not associated with bronchial asthma in Caucasian children

Several studies have investigated the association of a promoter polymorphism in CD14 with atopic phenotypes. We screened this and another polymorphism in 182 asthmatic children and found no association with asthma. Furthermore, there was substantial linkage disequilibrium of the polymorphisms. Thus CD14 does not play a major role in the development of asthma in our population of Caucasian children.     

CCL5/RANTES chemokine gene promoter polymorphisms are not associated with atopic and nonatopic asthma in a Spanish population

CCL5/RANTES, a member of the C-C chemokine family, is a potent eosinophil, monocyte, basophile and lymphocyte chemo-attractant at the site of inflammation. Recent studies revealed that a functional mutation at the -403 position in the promoter may have significance for atopic dermatitis, bronchial asthma, sarcoidosis, rheumatoid arthritis and HIV infection, and others. Another polymorphism in the -28 position has been reported. Our objective was to investigate the possible influence of the CCL5/RANTES promoter polymorphisms in the different types of bronchial asthma. CCL5/RANTES genotyping was performed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) in 306 asthmatic patients with non-atopic (n = 145) and atopic (n = 161) asthma and 242 controls. The 81.9% of the atopic asthma patients for -403G/A had the G allele and the A allele frequency was 18%. Of the non-atopic asthma patients, the G allele frequency was 79.7% and the A allele was 20.3%. Concerning the -28C/G polymorphism, the frequency of the CCL5/RANTES -28G allele in our patients is 2.8%, which is similar to Spanish adult population. After comparing patients with asthma, atopic patients, non-atopic patients and control population, we found no significant deviation in the distribution of the alleles or genotypes of CCL5/RANTES promoter polymorphisms in any tested comparison. Therefore, human CCL5/RANTES gene promoter polymorphisms are not associated with the different types of bronchial asthma in Spanish population.     

Promoter polymorphisms of the CD14 gene are not associated with bronchial asthma in Caucasian children.

Several studies have investigated the association of a promoter polymorphism in CD14 with atopic phenotypes. We screened this and another polymorphism in 182 asthmatic children and found no association with asthma. Furthermore, there was substantial linkage disequilibrium of the polymorphisms. Thus CD14 does not play a major role in the development of asthma in our population of Caucasian children.     

Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder with possible involvement of several genetic and environmental factors. For late-onset AD (LOAD), the epsilon4 allele of apolipoprotein E (APOE) has been identified as a major susceptible gene. However, the observation that APOE epsilon4 accounted for approximately one half of the genetic variance of LOAD prompted many researchers to undertake genome surveys to identify other susceptible genes. Recently, several candidate genes such as alpha-1 antichymotrypsin (ACT) and alpha-2 macroglobulin (A2M) were reported to be associated with LOAD. To evaluate the possible association between these genes and LOAD in Korean population, we genotyped ACT A/T and A2M 5-bp deletion (exon 18) polymorphisms in 89 LOAD cases and 50 age-matched healthy controls. The frequencies of ACT A and A2M 5-bp deletion alleles in LOAD and controls were 0.39 vs. 0.37, and 0.05 vs. 0.05, respectively. Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status. Our results do not support previously reported association of ACT and A2M with LOAD, at least in Korean population.     

Fragile X gene expansions are not associated with dementia

The purpose of this study was to determine the frequency of fragile X mental retardation 1 (FMR1) premutation size expansions in individuals with Alzheimer's disease (AD) and other cognitive disorders compared with control subjects. FMR1 genetic screening was completed in patients being seen in a neurobehavioral or AD clinics. Appropriate controls were also collected. A second cohort was a community based, autopsy confirmed, sample of individuals with normal cognitive function, mild cognitive impairment, or AD. There was not an increased frequency of FMR1 expansions in individuals with cognitive disorders, including AD, compared with control subjects.     

ATG16L1 gene polymorphisms are associated with palmoplantar pustulosis

Genes in autophagy pathway play an important role in innate and adaptive immunity. The aim of the study was to assess the impact of ATG16L1 gene on susceptibility of palmoplantar pustulosis. Four single nucleotide polymorphisms (SNPs) within the ATG16L1 region (rs2241880, rs2241879, rs7587633, and rs13005285) were genotyped in 241 control subjects and 38 palmoplantar pustulosis (PPP) patients of Estonian descent. The data analysis revealed a significantly higher frequency distribution of the rs2241880 G (odds ratio [OR] = 1.88, p = 0.0073) and rs2241879 A (OR = 1.87, p = 0.0079) allele in the PPP group when compared with the control group. The frequency distribution of the GACG haplotype was significantly higher (OR = 1.82, p = 0.016) in the PPP group when compared with the control group. The current study provides evidence of an association of the ATG16L1 gene in susceptibility to palmoplantar pustulosis, and supports the notion that the ATG16L1 gene as a member of the autophagy pathway most likely plays an important role in immune response.     

Genetic polymorphisms in the cell growth regulated gene, SC1 telomeric of the HLA-C gene and lack of association of psoriasis vulgaris

Psoriasis vulgaris is associated with the HLA-Cw6 and Cw7 antigens. We have previously narrowed down the critical region most likely to contain the psoriasis vulgaris gene to 111 kb spanning 89 kb to 200 kb telomeric of the HLA-C locus by microsatellite mapping. This segment includes three known genes (POU5F1, SC1 and S) and four new expressed genes. Among them, SC1 (TCF19) is the cell growth regulated gene possibly with trans-activator activity. Since psoriasis vulgaris is a common skin disorder characterized by hyperproliferation of epidermal cells, it is tempting to speculate that the SCI gene is one of the strong candidate genes responsible for the development of psoriasis vulgaris. Here, we investigated genetic polymorphisms in the SC1 gene by direct DNA sequencing and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) techniques. Three single nucleotide polymorphisms in exon 2, two of which are accompanied by amino-acid substitutions, were identified. Further, one 4-bp deletion polymorphism was detected around the acceptor site of the lariat-shaped structure necessary for RNA splicing in intron 2. No significant difference in the dimorphic or haplotypic distribution at these four polymorphic sites was observed between the patients with psoriasis vulgaris and healthy controls. This suggests that the susceptible gene for psoriasis vulgaris is not the SC1 gene itself, although a unique homozygous haplotype was identified in the patients.     

Single nucleotide polymorphisms in thymic stromal lymphopoietin gene are not associated with allergic rhinitis susceptibility in Chinese subjects

ABSTRACT: BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine, implicated in the development and progression of allergic diseases. Recent studies have demonstrated significantly increased expression and synthesis of TSLPin nasal mucosa of patients with allergic rhinitis (AR), compared with nonallergic control subjects. Also, there is significant correlation between the level of TSLP mRNA and symptom severity in AR patients. In this study, we investigated whether polymorphisms in the TSLP gene were associated with increased risk of AR in the Chinese population. METHODS: In a candidate gene association study, we tested 11 single nucleotide polymorphisms (SNPs) in the TSLP gene in 368 AR and 325 control adult Han Chinese subjects from Beijing. The 11 SNPs were selected from the Chinese HapMap genotyping dataset to ensure complete genetic coverage. AR was established by questionnaire and clinical examination, and blood was drawn from all subjects for DNA extraction. The PLINK software package was used to perform statistical testing. RESULTS: In the single-locus analysis of AR risk, no significant differences in allele and genotype frequencies were found between AR and control subjects. Further logistic regression analyses adjusted for age and gender also failed to reveal significant associations between AR and the selected SNPs. Similarly, analysis stratified by gender, and haplotype or diplotype did not reveal any association with AR risk. CONCLUSION: Although TSLP presents itself as a good candidate for contributing to allergy, this study failed to find an association between specific SNPs in the TSLP gene and AR susceptibility in the Han Chinese population.     

Paternal thrombophilic gene mutations are not associated with recurrent miscarriage

Problem Recurrent miscarriage (RM) affects 1–3% of couples. So far, diagnostic procedures are performed only in female patients. However, the main part of the placentary perfusion is encoded by both the maternal and the paternal genome. Method of study In this case–control study, German couples with two (n = 49) or three and more RM (n = 102) and 157 German control couples were analyzed for the factor V‐Leiden 1691G>A mutation (FVL), the prothrombin (PT) 20210G>A substitution, and the 677C>T replacement in the 5,10‐methylenetetrahydrofolate reductase (MTHFR) gene. Results No significant differences in the prevalence of the FVL, PT or MTHFR mutation were observed in male partners of RM patients and in control men [RM/control: FVL heterozygous 13/151 (8.6%): 14/157 (8.9%) (P = 0.9); PT heterozygous 2/151 (1.3%): 7/157 (4.5%) (P = 0.097); PT homozygous 0/151: 2/157 (1.3%); MTHFR homozygous 19/151 (12.6%): 18/157 (11.5%) (P = 0.12)]. This was also true for female RM patients. However, miscarriage during the embryonal period (5–10 weeks of gestation) was significantly associated with a maternal heterozygous FVL mutation (P = 0.014). Conclusion Recurrent miscarriage was not associated with paternal thrombophilia. Men of the control group showed an even higher incidence of the PT and MTHFR mutations. Abortions in the embryonic phase of fetal development were associated with a significantly higher incidence of maternal heterozygosity for FVL.     

SIRT1 gene polymorphisms are associated with nondiabetic type 1 cardiorenal syndrome

Type 1 cardiorenal syndrome (CRS1) is characterized by acute cardiac disease (e.g., acute heart failure [AHF]), leading to acute kidney injury. Sirtuin 1 (SIRT1), an NAD⁺‐dependent deacylase, has been found to be associated with CRS1. To confirm whether a correlation exists between SIRT1 variants and the risk of CRS1, the association between the prevalence of CRS1 and single‐nucleotide polymorphisms (SNPs) within the SIRT1 gene was investigated in AHF patients. A total of 316 Chinese AHF participants (158 patients with CRS1 and 158 age‐ and sex‐matched controls) were recruited for the present observational study to investigate the association between nine common SIRT1 SNPs (i.e., rs7895833 G > A, rs10509291 T > A, rs3740051 A > G, rs932658 A > C, rs33957861 C > T, rs7069102 C > G, rs2273773 T > C, rs3818292 A > G, and rs1467568 A > G) and the susceptibility to CRS1. Significant differences in genotype distribution between the control and CRS1 groups were found for rs7895833 and rs1467568. After applying a Bonferroni adjustment, the A allele of rs7895833 was still found to be protective (p = 0.001; odds ratio [OR] = 0.77) against CRS1 in this study population. The AA genotype of rs7895833 and the GA genotype of rs1467568 were associated with a significantly reduced risk of CRS1 (OR = 0.23 and 0.49, respectively). rs7895833 and rs1467568 were further analyzed as a haplotype, and the GA haplotype (rs7895833‐rs1467568) exhibited a significant association with CRS1 (p = 0.008), while the AA haplotype showed a significant protective effect (p = 0.022). Our study showed that SIRT1 rs7895833 and rs1467568 polymorphisms had a significant effect on the risk of developing CRS1 in a population in China.