Meta-analysis of the influence of Parkin p.Asp394Asn variant on the susceptibility of Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The Parkin p.Asp394Asn variant (c.1281G>A) has been investigated as a potential genetic hallmark of PD, but studies investigating the association between the variant and PD have reported conflicting results. Therefore, we conducted this meta-analysis to assess whether pooled results show the association. We performed structured literature searches in MEDLINE, EMBASE, Cochrane Library, and China Academic Journals databases for studies addressing the association between Parkin p.Asp394Asn variant and PD. The meta-analysis was conducted in five genetic models: additive, dominant, recessive, heterozygous, and homozygous, with the odds ratio (OR) as the measure of association. When all 7 studies involving 2425 subjects (1213 cases and 1212 controls) were pooled into the analysis, there was no evidence for significant association between Parkin p. Asp394Asn variant and PD risk in additive genetic model (OR=1.06, 95% confidence interval (CI)=0.66-1.70, P=0.825). The OR for the dominant model was 1.07 (95% CI=0.69-1.67) while the OR for the recessive model was 0.84 (95% CI=0.16-4.35). The OR for the heterozygote was 1.08 (95% CI=0.73-1.60) while the OR for the homozygote was 0.85 (95% CI=0.16-4.61). Concluding, our study does not support an association between the Parkin p.Asp394Asn variant and PD risk.     

Lack of association between interleukin-1 alpha,beta polymorphisms and Parkinson's disease

The associations between interleukin-1 alpha (IL-1α-889) and beta (IL-1β-511) single nucleotide polymorphisms (SNPs) and the risk for Parkinson's disease (PD) are still controversial and ambiguous. The aim of this study was to determine a more precise estimation of the relationship by meta-analysis. We searched databases through March 2010 for all publications on the association between these variations and PD. A total of 11 studies including 2803 PD patients and 2539 healthy controls were identified. The overall and geographic subgroups analysis was conducted, and odds ratios (OR) and 95% confidence intervals (95% CI) were calculated in the fixed- or random-effects model. We found that the overall OR (95% CI) for TT and CT genotypes versus CC genotype for IL-1α-889 was 1.01 (0.88–1.16), while the overall OR (95% CI) for TT and CT genotypes versus CC genotype for IL-1β-511 was 1.19 (0.87–1.62). The sensitivity analysis strengthened our confidence in the validity of these null associations. There was no publication bias observed in this study. To sum up, there were no associations found between the SNPs of IL-1α-889, IL-1β-511 and risk for PD.     

Lack of association between UBQLN1 and Alzheimer disease.

Alzheimer disease (AD) is heterogeneous and complex with a strong genetic diathesis. It is the most common cause of dementia affecting the elderly. Linkage studies [Kehoe et al., 1999; Hum Mol Genet 8: 237-245]; [Pericak-Vance et al., 2000; Exp Gerontol 35: 1343-1352]; [Myers et al., 2002; Am J Med Genet 114: 235-244]; [Blacker et al., 2003; Hum Mol Genet 12: 23-32] identified chromosome 9q as a region containing a possible AD candidate gene. Functional protein studies [Mah et al., 2000; J Cell Biol 151: 847-862]; [Ko et al., 2002; J Biol Chem 277: 35386-35392] identified the UBQLN1 gene on chromosome 9q that encodes ubiquilin as a likely candidate for a role in late-onset AD pathogenesis. A recent family-based study by [Bertram et al., 2005; N Engl J 352: 884-894] reported genetic association and expression evidence for a putative AD risk allele of an intronic single nucleotide polymorphism (SNP) within the UBQLN1 gene. In this study, we comprehensively assessed whether any of seven polymorphisms located across the UBQLN1 gene are associated with AD in another large family-based data set and an independent case-control data set. We found no significant association of AD risk with any of the seven SNPs genotyped (including those SNPs previously reported by Bertram et al.) in either the family-based or case-control data set. Age-specific analyses and analyses conditional on Apolipoprotein E (ApoE) genotype and sex also revealed no significant associations to AD risk in either data set. Using age at onset (AAO) as a quantitative trait revealed a modest age modifying association; however, the results were inconsistent between the data sets. Our results suggest that UBQLN1 variants do not increase risk for AD in these data.     

Cigarette smoking and Parkinson's disease: a meta-analysis

Many but not all studies have indicated that smoking is inversely associated with Parkinson's disease (PD). Meta-analysis of epidemiological studies on smoking and PD was performed to summarize data from published studies. Fifty-four epidemiological studies (48 case-control and 6 cohort studies, 53 publications) were identified for potential inclusion in meta-analysis. The summary risk estimates for current smokers, former smokers, and ever (current and former) smokers were 0.31 (95% confidence interval (CI) = 0.25-0.38), 0.72 (95% CI = 0.63-0.83) and 0.55 (95% CI = 0.51-0.59), respectively. In stratified analysis by study design, smoking had a somewhat greater impact on PD risk in cohort studies than in case-control studies. However, meta-regression indicated that the study design did not significantly contribute to heterogeneity. Additional analyses were restricted to case-control studies because of the sufficient number of studies. Stratified analysis by ethnicity indicated that the summary OR for ever-smokers was nonsignificantly smaller in Asian populations than in Caucasian populations. In stratified analysis by source of controls, former smoking was significantly associated with a decreased risk of PD in hospital-based case-control studies but was marginally associated with a decreased risk in population-based case-control studies. The source of controls did not contribute significantly to heterogeneity. PD risk associated with ever-smoking was significantly lower for a hospital-based approach than a population-based approach. Among current smokers, the association held true to the same extent for both approaches. This meta-analysis indicated that smokers have a lower risk of PD. As PD is a multifactorial disease, further investigation of the smoking-gene interaction on PD risk may lead to a better understanding of the pathogenesis of PD.     

Lack of association between ATP13A2 Ala746Thr variant and Parkinson's disease in Han population of mainland China

ATP13A2 (PARK9) mutations are related to Kufor-Rakeb syndrome (KRS). We performed genetic analysis of the Ala746Thr variant in an independent cohort of the patients with PD and healthy controls from mainland China. The Ala746Thr variant was present in 1/532 (0.19%) of PD compared with 1/480 (0.21%) of healthy controls (odds ratio = 0.90, 95% CI 0.06, 14.39, P = 1.00). The two subjects carried the heterozygous genotype. Subset analysis in the group ≤50 years of age revealed a prevalence of 0.7% in PD compared with 0% in healthy controls and in the group >50 years of age showed 0% in PD versus 0.3% in healthy controls. We did not observe a significant association between Ala746Thr and Parkinson's disease in Han Chinese population, even after stratification by age at onset. The results suggested that Ala746Thr variant was not a major susceptible factor for PD in Han Chinese people.     

Lack of association between G‐protein coupled receptor kinase 5 gene and Parkinson's disease

The major component of Lewy Bodies (LB), the pathological hallmark of Parkinson's disease (PD) is α‐synuclein, most prominently phosphorylated at serine 129. G‐protein coupled receptor kinase 5 (GRK5) has been reported to phosphorylate α‐synuclein in vitro, enhancing the α‐synuclein toxicity to dopaminergic neurons in Drosophila model. Moreover, GRK5 was found in LBs from brain of PD patients. A genetic association study performed in the Japanese population revealed haplotypic association of the GRK5 gene with susceptibility to sporadic PD. We aimed at investigating whether four polymorphisms within the GRK5 gene (rs871196, rs2420616, rs7069375, rs4752293) could represent a risk factor for sporadic PD in Southern Italy. We genotyped 446 patients with PD and 450 controls for these markers and did not find any significant association with the disease at allelic, genotypic and haplotypic level. Our results indicate that the GRK5 gene does not confer risk to sporadic PD in our sample from Southern Italy. © 2010 Wiley‐Liss, Inc.     

Complement receptor 1 coding variant p.Ser1610Thr in Alzheimer's disease and related endophenotypes

We previously described an intragenic functional copy number variation (CNV) in complement receptor 1 (CR1) that is associated with Alzheimer disease (AD) risk. A recent study, however, reported a rare CR1 coding variant p.Ser1610Thr (rs4844609) associated with AD susceptibility, explaining the effect of genome wide association (GWA) top single nucleotide polymorphism rs6656401. We assessed the role of the Ser1610Thr variant in AD pathogenesis and the effect on AD-related endophenotypes in a Flanders-Belgian cohort. We evaluated whether this rare variant rather than the CR1 CNV could explain the association of CR1 in our population. The Ser1610Thr variant was not associated with AD, memory impairment, total tau, amyloid β_1–42 or tau phosphorylated at threonine 181 levels. It did not explain (part of) the association of genome wide association top single-nucleotide polymorphisms rs3818361/rs6656401, nor of the CR1 CNV, with AD in our cohort, whereas the CR1 CNV and rs3818361/rs6656401 represented the same association signal. These findings question a role for the Ser1610Thr variant in AD risk and related endophenotypes, and reaffirm our previous observation that the CR1 CNV could be the true functional risk factor explaining the association between CR1 and AD.     

Lack of association between the interleukin-1 alpha (-889) polymorphism and early-onset Parkinson's disease

An increasing number of studies have shown that an inflammatory process is part of Parkinson's disease (PD) brain pathology. Interleukin-1 (IL-1) is a multifunctional cytokine and is considered to contribute to several inflammatory diseases. Recently, we detected an associated risk in a subgroup of PD patients with a disease onset < 50 years and a C to T transition in the IL-1alpha promoter (-889). One-hundred-seventy-six German PD patients (42.1 +/- 6.4 years; 42.4% male) and 170 unrelated age-matched control individuals (40.4 +/- 8.7 years; 57.6% male) were investigated for the presence of the IL-1alpha (-889C/T) polymorphism. No significant difference in the allelic distribution of the analyzed IL-1alpha polymorphism has been found between PD and controls. We conclude that the C/T polymorphism in the IL-1alpha promoter region at -889 does not increase the risk to develop PD.     

Lack of association of APOE and tau polymorphisms with dementia in Parkinson's disease

Some APOE or tau gene polymorphisms have been associated with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan-Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD.     

Lack of association between Alzheimer''s disease and histocompatibility antigens

The present report describes the distribution of histocompatibility antigens in 52 patients with Alzheimer's disease. No significant associations were observed between this illness and particular HLA types before or after statistical correction for multiple comparisons. These findings are discussed in terms of the difficulties inherent in the clinical diagnosis of Alzheimer's disease and with regard to the choice of suitable control populations.     

A meta‐analysis of the relationship of the Parkin p.Val380Leu polymorphism to Parkinson's disease

Parkinson's disease (PD) is one of the most common movement disorders. Parkin p.Val380Leu polymorphism (c.1239G > C) has been investigated as a potential genetic hallmark of PD, but studies examining the association between the polymorphism and PD have reported conflicting results. Therefore, we conducted a meta‐analysis to assess the influence of Parkin p.Val380Leu polymorphism on the susceptibility of PD. Computer and hand searches of the literature were conducted using the MEDLINE, EMBASE, Cochrane Library, and China Academic Journals databases to identify studies addressing the association between the Parkin p.Val380Leu polymorphism and PD risk. We performed analyses of study characteristics, heterogeneity, and funnel plot asymmetry in analyses analogous to additive, dominant, recessive, homozygous, and heterozygous genetic models with the odds ratio (OR) as the measure of association. A total of 11 case–control studies involving 2,073 PD cases and 2,131 controls were included. When all 11 studies were pooled into the analysis, the presence of the Leu allele at the Parkin p.Val389Leu polymorphism was associated with decreased risk for PD in three genetic comparison models: OR in additive model: 0.79, 95% confidence interval (CI) = 0.64–0.98, P = 0.029; OR in recessive model: 0.55, 95% CI = 0.35–0.89, P = 0.014; OR in homozygous model: 0.51, 95% CI = 0.32–0.82, P = 0.005. Begg's funnel plot and Egger's test provided visual and statistical evidences for funnel plot symmetry, without evidence presence of publication bias. We conclude that the presence of the Leu allele at the Parkin p.Val380Leu polymorphism is associated decreased risk for PD. © 2013 Wiley Periodicals, Inc.     

Lack of an association between Paraoxonase 1 gene polymorphisms (Q192R, L55M) and Alzheimer's disease: a meta-analysis

The association between Paraoxonase 1 (PON1) gene polymorphisms (Q192R, L55M) and Alzheimer's disease (AD) risk has been reported inconsistent results. To assess the association between PON1 polymorphisms and AD risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, a total of 10 studies including 3081 AD cases and 3054 controls were identified. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were performed. There was no significant association between PON1 Q192R polymorphism and AD risk in all comparison models (R vs. Q, OR=0.89, 95% CI=0.82-0.96; RR vs. QQ, OR=0.83, 95% CI=0.68-1.01; RR+RQ vs. QQ, OR=0.86, 95% CI=0.75-0.97; and RR vs. QR+QQ, OR=0.94, 95% CI=0.81-1.11). For the PON1 L55M polymorphism, lack of an association was also found (L vs. M, OR=0.95, 95% CI=0.86-1.05; LL vs. MM, OR=0.67, 95% CI=0.51-0.88; LL vs. ML+MM, OR=0.82, 95% CI=0.69-0.98; and LL+ML vs. MM, OR=0.75, 95% CI=0.58-0.96). On subgroup analysis by ethnicity, similar results were found. Conclusively, the present meta-analysis revealed that PON1 gene polymorphisms (Q192R, L55M) were unlikely to contribute to AD susceptibility.     

Obstacles and opportunities in meta-analysis of genetic association studies.

Genetic association studies have the potential to advance our understanding of genotype-phenotype relationships, especially for common, complex diseases where other approaches, such as linkage, are less powerful. Unfortunately, many reported studies are not replicated or corroborated. This lack of reproducibility has many potential causes, relating to study design, sample size, and power issues, and from sources of true variability among populations. Genetic association studies can be considered as more similar to randomized trials than other types of observational epidemiological studies because of "Mendelian randomization" (Mendel's second law). The rationale and methodology for synthesizing randomized trials is highly relevant to the meta-analysis of genetic association studies. Nevertheless, there are a number of obstacles to overcome when performing such meta-analyses. In this review, the impacts of Type I error, lack of power, and publication and reporting biases are explored, and the role of multiple testing is discussed. A number of special features of association studies are especially pertinent, because they may lead to true variability among study results. These include population dynamics and structure, linkage disequilibrium, conformity to Hardy-Weinberg Equilibrium, bias, population stratification, statistical heterogeneity, epistatic and environmental interactions, and the choice of statistical models used in the analysis. Approaches to dealing with these issues are outlined. The supreme importance of complete and consistent study reporting and of making data readily available is also highlighted as a prerequisite for sound meta-analysis. We believe that systematic review and meta-analysis has an important role to play in understanding genetic association studies and should help us to separate the wheat from the chaff.     

Correlations between TLR polymorphisms and inflammatory bowel disease: a meta-analysis of 49 case-control studies

Immunologic Research - Recently, the roles of toll-like receptor (TLR) polymorphisms in inflammatory bowel disease (IBD) were intensively explored, with conflicting results. Therefore, we performed...     

Three patients of transthyretin amyloidosis in a Japanese family with amyloidogenic transthyretin Thr49Ser (p.Thr69Ser) variant

Transthyretin (TTR)-related hereditary amyloidosis (ATTRv) is a rare autosomal dominant disorder that is caused by pathogenic missense mutation of the TTR gene. As of today, more than 150 TTR gene variants have been reported to occur as causal mutations. Herein, we present three familial patients of ATTRv caused by the Thr49Ser (p.Thr69Ser) variant, including their phenotypes and penetrance.The first patient was a 68-year-old woman with a history of carpal tunnel syndrome, who was referred to our department with heart failure symptoms. Echocardiography, ^99mTechnetium (Tc)-pyrophosphate scintigraphy, and myocardial biopsy confirmed her diagnosis as TTR-related amyloidosis. Genetic testing for the TTR gene was performed, which confirmed the presence of a Thr49Ser (p.Thr69Ser) variant. The second patient, a 45-year-old woman, who was the niece of the first patient, presented with dyspnea on exertion. Her clinical manifestations included cardiac symptoms in addition to polyneuropathy. Similarly, myocardial biopsy showed TTR amyloid deposition within cardiac tissues, and TTR gene sequencing detected the presence of a Thr49Ser (p.Thr69Ser) variant. The final patient was a 42-year-old man, who was the nephew of the first patient, presented with numbness in his hands. Abdominal wall fat pad biopsy showed TTR amyloid deposition, and TTR gene sequencing was performed considering the familial history to confirm the presence of Thr49Ser (p.Thr69Ser) variant. No cardiac symptoms or dysfunctions have been observed yet, but imaging has detected TTR amyloid deposition in the heart.The present three patients with Thr49Ser (p.Thr69Ser) variant showed variation in phenotypes including cardiac and neurological manifestations at a fairly young age. In addition, the familial relationship in this report suggested that this variant is highly penetrant. Early genetic diagnosis due to collecting the genetic information from family medical history may be beneficial to improve patient prognosis via early therapeutic intervention.     

Genetic variation in LINGO-1 (rs9652490) and risk of Parkinson's disease: twelve studies and a meta-analysis

Mutations of the voltage gated sodium channel gene (SCN4A) are responsible for non-dystrophic myotonia including hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia, as well as congenital myasthenic syndrome. In vitro functional analyses have demonstrated the non-dystrophic mutants to show a gain-of-function defect of the channel; a disruption of fast inactivation, an enhancement of activation, or both, while the myasthenic mutation presents a loss-of function defect. This report presents a case of non-dystrophic myotonia that is incidentally accompanied with acquired myasthenia. The patient presented a marked warm-up phenomenon of myotonia but the repeated short exercise test suggested mutations of the sodium channel. The genetic analysis identified a novel mutation, G1292D, of SCN4A. A functional study of the mutant channel revealed marked enhancement of activation and slight impairment of fast inactivation, which should induce muscle hyperexcitability. The effects of the alteration of channel function to the myasthenic symptoms were explored by using stimulation of repetitive depolarization pulses. A use-dependent channel inactivation was reduced in the mutant in comparison to normal channel, thus suggesting an opposing effect to myasthenia.