Mitochondrial translation initiation factor 3 polymorphism and Parkinson's disease

Mitochondrial dysfunction has been proposed to play a role in the pathogenesis of Parkinson's disease (PD). Supportive of this hypothesis, several genetic variants that regulate mitochondrial function and homeostasis have been described to alter PD susceptibility. A recent report demonstrated association of a single nucleotide polymorphism in the mitochondrial translation initiation factor 3 (MTIF3) gene with PD risk. The protein encoded by this nuclear gene is essential for initiation complex formation on the mitochondrial 55S ribosome and regulates translation of proteins within the mitochondria. Changes in the function or expression of the MTIF3 protein may result in altered mitochondrial function, ATP production or formation of reactive oxygen species thereby affecting susceptibility to PD. We examined the association of rs7669 with sporadic PD in three Caucasian case control series (n=2434). A significant association was observed in the largest series (Norwegian; n=1650) when comparing CC vs. CT/TT genotypes, with the Irish and US series having a similar but non-significant trend. The combined series also revealed an association with risk of PD (P=0.01), supporting the possible involvement of this gene in PD etiology.     

Association study of SCARB2 rs6812193 polymorphism with Parkinson's disease in Han Chinese

Recently, a nucleotide polymorphism rs6812193 near SCARB2 was found to be significantly associated with Parkinson's disease (PD) in populations of European ancestry. Herein, we conducted a case-control study with attempt to further evaluate the association between SNP rs6812193 and PD in a Chinese population from mainland China. rs6812193 was genotyped by PCR-RFLP technique in 449 PD patients and 452 controls in a Chinese population. In our study, we did not detect statistically significant differences between cases and controls in terms of both allele and genotype distribution of the rs6812193 polymorphism (P=0.97 and P=0.77, respectively), even after stratification by age at onset. Our data do not support the association of SNP rs6812193 with PD in Han Chinese of mainland China.     

Genetic variants of the PITX3 gene are not associated with late-onset sporadic Parkinson's disease in a Chinese population

To investigate whether the xenon-induced inhibition of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in rat dorsal root ganglion (DRG) neurons reduces nociceptive processing, we examined the effect of xenon in reducing the release of calcitonin gene-related peptide (CGRP) from those neurons. We found that exposure to xenon failed to effect a reduction of capsaicin-evoked CGRP release from cultured primary sensory neurons when stimulated by capsaicin. This finding suggests that xenon acts on several molecular targets on nociceptive primary sensory neurons, and that xenon's action on one, or more, of those targets serves to offset the inhibitory, pro-analgesic, effect of xenon on TRPV1. It is concluded that xenon may not produce any analgesic effect through peripheral nociceptors.     

Lower serum UA levels in Parkinson's disease patients in the Chinese population

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, and oxidative stress plays an important role in its pathogenesis. Uric acid (UA) is a product of purine metabolism and is a natural antioxidant that can relieve the oxidative stress that occurs in PD. Recent studies have indicated that the serum UA level are associated with a risk of PD and PD progression of motor symptoms and have proposed UA as a possible biomarker of the underlying pathophysiology of PD. In our study, we investigated the association between serum UA level and PD in a Chinese population. We found that the serum UA levels in PD patients were lower than the levels in control patients and were correlated with PD progression and duration in the Chinese population. These associations were observed in both genders, but hyperuricemia is more strongly associated with lower rates of PD among men compared to women and older people compared to younger people. Our results indicate that UA could be an important biomarker of PD and that the serum UA level could be a useful biomarker of PD diagnosis and disease progression.     

SORL1 is genetically associated with Alzheimer disease in a Japanese population

A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-?4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.     

The transcription factor PITX3 is associated with sporadic Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease with typical motor symptoms due to the preferential loss of midbrain dopaminergic (mDA) neurons in the Substantia nigra pars compacta. Several proteins of the homeodomain family are crucial for the development of mDA neurons. These proteins remain expressed into adulthood with largely unknown functions, but potentially influence mDA neuronal survival. To determine whether genetic variation in these genes plays a role in sporadic PD, we performed a genetic association study in a screening sample of 340 PD patients and 680 controls and a large replication sample of 669 PD patients and 669 controls using 54 single nucleotide polymorphisms in and around the Engrailed 1/2, PITX3, LMX1B and OTX2 genes. We provide evidence for a novel, strong and reproducible association of the PITX3 promoter SNP rs3758549: C>T (p=0.004) with PD. The C-allele appears to be a recessive risk allele with an estimated population frequency of 83%. An allele-dependent dysregulation of PITX3 expression might contribute to the susceptibility to PD.     

Association of Ala589Ser polymorphism of <Emphasis Type="Italic">WNK4</Emphasis> gene with essential hypertension in a high-risk Chinese population

Recent studies on the association between particular single nucleotide polymorphisms of serine–threonine kinase with no lysine (K) 4 gene (WNK4) and essential hypertension have yielded controversial results. Here, frequencies of Ala589Ser polymorphism within exon 8 of the WNK4 gene were assessed among 259 unrelated ethnic Chinese patients with essential hypertension and 235 strictly matched normotensive controls. All subjects were derived from a relatively isolated population identified in the Kerqin desert region in Zhangwu county of Liaoning, northeastern China, which features a dry climate and the people having a high dietary salt intake, in addition to a significantly higher prevalence (~35%) of essential hypertension. Genotypes were verified with polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. Expression pattern and regulatory mechanisms of the WNK4 gene were also explored using Northern blotting and in vitro hormone stimulation assays. Strong associations between the Ala589Ser polymorphism and both raised systolic and diastolic blood pressures were identified. In addition to the kidneys, WNK4 gene expression was also found in many other organs. Several cis-acting elements had been discovered in the promoter region of the gene. As revealed by preliminary experiment, various hormones can down-regulate the expression of WNK4, among which glucocorticoid hormone seems to act in a dose-dependent manner. The WNK4 gene probably plays an important role in the pathogenesis of essential hypertension. As a missense mutation, the Ala589Ser polymorphism may bring changes to the enzyme’s function(s), resulting in increased susceptibility to the disease.     

Clusterin variants are not associated with southern Chinese patients with Alzheimer's disease

Recent genome-wide association studies identified clusterin (CLU) to be associated with sporadic Alzheimer's disease. To help clarify the relevance of CLU as genetic determinant of AD, we analyzed its association in southern Chinese Han population. This study comprised 499 sporadic Alzheimer's disease patients and 592 unrelated age- and sex-matched healthy controls. Four single-nucleotide polymorphisms (rs2279590, rs9331888, rs11136000, and rs1532278) within CLU were selected for genotyping. No positive association was found between the CLU variants and AD. Our study suggests that CLU variants may not be an AD susceptibility factor in southern Chinese Han population.     

Association of ADAM33 polymorphisms with childhood asthma in a northern Chinese population

Background

Genetic factors contribute to the increasing incidence of childhood asthma. The ADAM33 (a disintegrin and metalloprotease domain-containing protein 33) gene, discovered through positional cloning, is the first to be associated with asthma and bronchial hyperresponsiveness. This case–control study conducted in a Han Chinese population in northern China compared the genotypes of child asthmatic patients to healthy controls for the presence of 6 single nucleotide polymorphisms (SNPs) in the ADAM33 gene.

Methods

The study population was composed of 412 children with asthma and 397 healthy controls. We genotyped 6 SNPs (F + 1, T + 1, T2, T1, V4, and Q-1) of ADAM33 with the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Data were statistically analyzed to determine if an association existed between these genotypes and childhood asthma morbidity.

Results

Three SNPs (T + 1, T1, and V4) and 4 haplotypes (H1, H3, H5, and H8) were strongly associated with childhood asthma in children of northern China compared to healthy controls (P < 0.05), whereas the other tested SNPs and haplotypes demonstrated no significant relationship.

Conclusion

The ADAM33 gene plays an important role in facilitating susceptibility to childhood asthma in this Han Chinese population.     

Histamine N-methyltransferase Thr105Ile polymorphism is associated with Parkinson's disease

Histamine is a central neurotransmitter degraded by histamine-N-methyltransferase (HNMT). Several abnormalities in the histaminergic system were found in patients with Parkinson's disease (PD), thus we tested the possible association of a Thr105Ile functional polymorphism in HNMT with PD. A total of 913 patients with PD and 958 controls were genotyped using a TaqMan RT-PCR Genotyping Assay (Foster City, California, USA). Lower frequency of HNMT Ile105 allele that is associated with decreased enzymatic activity was found in patients compared with controls (χ(2) = 11.65; p = 0.0006). We performed meta-analysis to confirm the association of Thr105Ile functional polymorphism with PD. Our results indicate that lower HNMT activity plays a role in the pathogenesis of PD.     

Effect of SOX10 gene polymorphism on early onset schizophrenia in Chinese Han population

Schizophrenia is one of highly heritable psychiatric disorders. Patients with early onset schizophrenia tend to have a greater genetic loading and may be an attractive subpopulation for genetics studies. A single nucleotide polymorphism (SNP) rs139887 in sex-determining region Y-box 10 (SOX10), a candidate gene for schizophrenia, was suggested to be associated with schizophrenia although inconsistent results had been reported. The aim of this study was to evaluate the association between SOX10 rs139887 polymorphism and schizophrenia using an early onset sample in the Chinese Han population. A total of 321 schizophrenic patients with onset before age 18 and 400 healthy controls were recruited for association study. In addition, two populations involved in three studies were selected for meta-analysis to determine the effect of rs139887 on schizophrenia. Our association study results showed that the allele and genotype frequencies were significantly different between schizophrenic patients and controls (P=0.013 and P=0.034, respectively). Interestingly, a significant association in allele and genotype frequencies were found in male patients (P=0.017 and P=0.045, respectively), but not female patients. Moreover, the C/C genotype had a significant association with an earlier age of onset in male schizophrenic patients (Kaplan-Meier log-rank test P=0.029), but not in female patients (Kaplan-Meier log-rank test P=0.876). The meta-analysis result showed the same C allele was significantly associated with schizophrenia (P=0.007). In conclusion, the SOX10 rs139887 polymorphism was related to the development of schizophrenia in a gender-specific manner, and may be a significant genetic marker for managing subgroups and etiological clues in schizophrenia.     

TREM2 is associated with the risk of Alzheimer's disease in Spanish population

Two recent studies have reported the association of rs75932628-T in the TREM2 gene with the risk for Alzheimer's disease (AD). Rs75932628-T is a rare nonsynonymous variant (p.R47H) that confers a high risk of AD with an effect size similar to that of the APOE ?4 allele. However, this association has not been replicated in any independent studies to date. The allelic frequency of rs75932628 varies according to the population from 0.02% to 0.63% among healthy controls. In an attempt to replicate the association between rs75932628-T and AD risk, we genotyped rs75932628 in a cohort of 504 AD subjects and 550 healthy controls from a Spanish population. Rs75932628-T showed a minor allele frequency of 0.3% among this cohort. Interestingly, in our study, rs75932628-T was found exclusively in 1.4% of AD cases (7/504), including 4 early-onset AD cases, and in none of the controls (n = 0/550). Here, we report the first positive replication study in a Spanish population and confirm that TREM2 rs75932628-T is associated with the risk for AD.     

GAB2 is not associated with late-onset Alzheimer's disease in Japanese

The varepsilon4 allele of the apolipoprotein E gene (APOE) is unequivocally recognized as a genetic risk factor for late-onset Alzheimer's disease (LOAD). Recently, single-nucleotide polymorphisms (SNPs) of the GRB2-associated binding protein 2 gene (GAB2) were shown to be associated with LOAD in Caucasians carrying the APOE-varepsilon4 allele through a genome-wide association study. Here, we attempted to replicate the finding by genotyping these SNPs in a large clinical cohort of Japanese. We observed no association of any of the SNPs with LOAD. GAB2 may not be a disease susceptibility gene for LOAD in Japanese.     

The hOGG1 Ser326Cys polymorphism is not associated with sporadic Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative disorders characterized by progressive and profound loss of dopaminergic neurons in the substantia nigra (SN) resulting in resting tremor, rigidity, bradykinesia, and postural instability. The primary cause of the disease is still unknown, but mitochondrial dysfunction and oxidative stress have been implicated in the neurodegenerative process. Oxoguanine DNA glycosylase (OGG1) removes oxidized guanine (8-oxo-G) from the DNA, thus reducing the mutagenic potential of this modified base. Increased 8-oxo-G levels and up-regulation of OGG1 have been detected in the SN of PD brains. Moreover, studies performed in OGG1 knockout mice revealed the importance of this enzyme in protecting dopaminergic neurons against the accumulation of oxidative DNA damage. A common Ser326Cys polymorphism is known in the human gene encoding OGG1 (hOGG1), and the mutant Cys326 variant has been associated with reduced glycosylase activity. In the present study we screened 139 sporadic PD patients and 211 healthy matched controls for the presence of the hOGG1 Ser326Cys polymorphism. The Cys326 allele frequency was similar between the groups (0.20 in PD patients and 0.19 in controls; p = 0.817), and no difference in genotype frequencies was observed. Moreover, the hOGG1 Ser326Cys polymorphism was not associated with disease age at onset (p = 0.791). Overall, present results suggest that the hOGG1 Ser326Cys polymorphism is not associated with sporadic PD.     

A non-synonymous variant in SLC30A8 is not associated with type 1 diabetes in the Danish population

Genome-wide association scans in type 2 diabetes (T2D) have identified a risk variant, rs13266634 (Arg325Trp), in SLC30A8 on chromosome 8. SLC30A8 encodes a β-cell specific zinc-ion transporter and rs13266634 has been shown to affect insulin secretion. Recently, autoantibodies for Slc30A8 with high predictive value were demonstrated in individuals with type 1 diabetes (T1D), making this gene an interesting T1D candidate gene. We genotyped rs13266634 in 3008 cases and controls and 246 families from Denmark. Association to T1D could not be demonstrated.     

The functional Pro129Thr variant of the <Emphasis Type="Italic">FAAH</Emphasis> gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5,801 whites

Food intake and weight gain are influenced by endocannabinoids whose actions are regulated by the fatty acid amide hydrolase (FAAH) enzyme. The homozygous Thr/Thr genotype of the functional Pro129Thr variant (rs324420) in the gene encoding FAAH was recently reported to associate with overweight and obesity in white and black populations. We investigated the Pro129Thr variant in relation to overweight and obesity in a relatively large population-based study sample of Danish whites (n=5,801). In case-control studies of obesity, a borderline association with the major Pro allele was identified; however, after correction for multiple testing, no association was found. Furthermore, a possible association between the major Pro allele and obesity was not supported by studies of obesity-related quantitative traits. In conclusion, in a large study sample, we were unable to find robust evidence of an association of the Pro129Thr FAAH variant with overweight, obesity, and any related quantitative traits among the examined whites.