Microtubule-associated protein tau (MAPT) influences the risk of Parkinson's disease among Indians

Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system and its prevalence increases with age. Microtubule-associated protein tau (MAPT), a neuronal protein is involved in the pathogenesis of several neurodegenerative diseases including PD. To determine the broader significance of this association with PD, replicative studies in distinct ethnic populations are required. In this study, we investigated MAPT for its potential association with PD using five haplotype-tagging SNPs and the del-In9 polymorphism of MAPT in 301 PD patients and 243 healthy controls from eastern India. Our case–control analysis did not show a significant association with any of the markers and PD. However, a risk haplotype [GAC + G] for PD was identified (OR = 1.563; 95% CI = 1.045–2.337; p = 0.03). In addition, haplotype AAC + A (OR = 2.787; 95% CI = 1.372–5.655; p = 0.004) was strongly associated with early onset PD (age at onset ≤40 years) and AAC + G haplotype showed a weak association (OR = 2.233; 95% CI = 1.018–4.895; p = 0.045) with late onset PD (age at onset >40 years). This observation highlights the significance of rs7521 in modifying the age at onset of PD under a common haplotype background. We also identified AGC + A as a risk haplotype for sporadic cases (OR = 2.773, 95% CI = 1.198–6.407, p = 0.016). This is the first association study from India conducted on MAPT among PD patients and provides valuable information for comparison with other ethnic groups.     

Panic disorder and serotonergic genes (SLC6A4, HTR1A and HTR2A): Association and interaction with childhood trauma and parenting

Objective

The aim of this study is to evaluate the association between HTR1A, HTR2A and the 5-HTTLPR in panic disorder (PD) patients and controls. In addition, this study also aims to evaluate the interaction between these genes and two environmental factors previously associated with PD: childhood trauma and parental bonding.

Methods

This is a case–control candidate gene association study (107 PD patients and 125 controls). Genes were analyzed using a gene-based test in PLINK followed by single marker association tests and haplotype test only for genes that reached experiment-wide significance in the gene-based test in order to minimize multiple testing. Logistic regression was used to test the relationships between genotype in the additive model, trauma, optimal paternal parenting and optimal maternal parenting and their interactions.

Results

Only HTR1A was associated with PD in gene-based test after correction for multiple tests (p_corrected = 0.027) and one HTR1A haplotype comprising four SNPs was associated with PD (p_corrected = 0.032). In the interaction analysis, no significant gene–environment interaction was found with the genes evaluated.

Conclusion

This study reinforces the association between HTR1A and PD. No major evidence of gene–environment interaction in PD with parenting or trauma was found. Further studies are necessary in order to confirm these findings.     

Genetic variations of SOCS1 are associated with chronic hepatitis B virus infection

Suppressor of cytokine signaling (SOCS)-1 is involved in viral infection through regulation of both innate and adaptive immunity. The SOCS1 gene polymorphisms may affect the outcome of viral infection. The relationship between SOCS1 polymorphisms and hepatitis B virus (HBV) infection has not yet been explored. This study genotyped SOCS1 rs243327 and rs33932899 polymorphisms in 477 patients with chronic HBV infection, 93 HBV infection resolvers and 215 healthy controls. In statistical analysis, p-values less than 0.05 in multiple comparisons were corrected by Bonferroni method and presented as p_c. The results showed that the allele T-containing genotypes (CT + TT) of rs243327 were higher in HBV patients than resolvers and lower in resolvers than healthy controls although the difference was not significant. The allele T of rs243327 was significantly lower in resolvers than controls (p = 0.033). The genotype GC and allele C of rs33932899 were significantly less frequent in HBV patients than controls (p_c < 0.001 and p < 0.001, respectively). The haplotype T/G of rs243327/rs33932899 was significantly more frequent in HBV patients than resolvers (p_c < 0.001) or controls (p_c = 0.009). These data indicate that SOCS1 polymorphisms might affect the susceptibility and outcome of HBV infection.     

Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study

Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r² = 0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR = 0.7; 95% CI: 0.5-0.9 (CC vs. AC) and HR = 0.5; 95% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR = 1.0; 95% CI: 0.7-1.3 (CC vs. AC) and HR = 1.7; 95% CI: 0.8-3.6 (CC vs. AA) (P-trend = 0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.     

Fibulin-5 (FBLN5) gene polymorphism is associated with pelvic organ prolapse

Objective

FBLN5 encodes a key protein of elastic fiber matrix assembly and function that contributes to maintaining pelvic support and plays the important role in the pathophysiology of pelvic organ prolapse (POP). The aim of the study was to investigate whether there is an association between common single-nucleotide polymorphisms (SNPs) of the FBLN5 gene and POP.

Study design

A total of eleven tag SNPs of the FBLN5 gene were genotyped using the polymerase chain reaction with confronting two-pair primers (PCR-CTPP) in 210 patients with POP (stages III–IV) and 292 controls with no even minimal POP.

Results

We revealed significant associations of tag SNPs rs2018736 and rs12589592 with POP. The top association signal was found for SNP rs2018736 (protective effect for the minor allele A) in the entire set: p = 0.0026, OR = 0.42, 95% CI: 0.24–0.75; in the stratum with pelvic floor trauma: p = 0.0018, OR = 0.27, 95% CI: 0.11–0.64; and in the stratum with fetal macrosomia: p = 0.013, OR = 0.14, 95% CI: 0.03–0.71. The results of the haplotype analyses were consistent with the single SNP analysis. In the strata without perineal trauma and fetal macrosomia effects were non-significant, possibly, due to the smaller effect sizes.

Conclusions

Current data provide, for the first time, strong evidence that common SNPs of the FBLN5 gene are associated with POP especially after pelvic floor injury.     

Association study on the NAPG gene and bipolar disorder in the Chinese Han population

Background: Bipolar disorder is a mental health problem throughout the world. Chromosome 18p11 has been identified by several studies as a susceptiblilty region for bipolar disorder and NAPG, located on 18p11, has been suggested as being associated with bipolar disorder in European population. Methods: Our study employed five SNPs (rs2290279, rs495484, rs510110, rs617040 and rs473938) to investigate the role of NAPG in the Chinese Han population based on a sample of 465 controls vs. 499 bipolar patients. Results: Rs617040 was excluded from further analysis because of deviation from Hardy–Weinberg equilibrium. Rs473938 and rs2290279 showed significant association in both allele and genotype frequencies (rs473938: allele p = 0.0028 after 100,000 permutations, genotype p = 0.0018; rs2290279: allele p = 0.0042 after 100,000 permutations, genotype p = 0.0028). Several combinations of haplotype were found to be associated with bipolar disorder. Haplotype T–A–T of rs473938–rs2290279–rs495484 was defined by confidence intervals algorithm and had a p value of 0.0038 after 100,000 permutations. Conclusions: Our study supports NAPG as a candidate for susceptibility to bipolar disorder.     

Association analysis of GRIN1 and GRIN2B polymorphisms and Parkinson's disease in a hospital-based case–control study

Hyperactivation of N-methyl-d-aspartate receptors (NMDARs) leads to neuronal excitotoxicity and is suggested to play a role in many brain disorders, including Alzheimer's disease and schizophrenia. However, the association between polymorphisms in the genes that code for NMDAR subunits, N-methyl-d-aspartate 1 and 2B (GRIN1 and GRIN2B) and Parkinson's disease (PD) remains unclear. In a hospital-based case–control study of PD, DNA samples were collected from 101 PD patients and 205 healthy controls. Genotyping assays were used to screen for polymorphisms in the GRIN1 (rs2301364 T > C, rs28489906 T > C, and rs4880213 T > C) and GRIN2B (C366G, C2664T, and rs1805476 T > G) genes, and logistic regression analysis was then used to assess the association between these single nucleotide polymorphisms (SNPs) and PD susceptibility. None of the 6 SNPs were significantly associated with PD risk on their own. However, in conjunction with putative low-risk genotypes for the GRIN1 gene, the GRIN2BC366G variant was significantly associated with reduced PD risk compared with the homozygous genotype 366CC (OR = 0.38, 95%CI = 0.17–0.93, P = 0.033). A synergistic effect on risk reduction was observed in subjects who carried multiple polymorphisms of GRIN1 and the GRIN2BC366G polymorphism (OR = 0.78, 95%CI = 0.59–1.02, P_trend = 0.073). Our results suggest that polymorphisms in the GRIN1 and GRIN2B genes may serve as potential biomarkers for a reduced risk of PD among the Chinese population in Taiwan.     

Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African–American and Isreali–Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of β amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45–70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR = 0.26, 95% CI: 0.08–0.86; and HR = 0.40, 95% CI: 0.16–0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.     

Preliminary evidence of association between EFHC2, a gene implicated in fear recognition,and harm avoidance

Genetic variation at the EF-hand domain containing 2 gene (EFHC2) locus has been associated with fear recognition in Turner syndrome. The aim of this study was to examine whether EFHC2 variants are associated with non-syndromic anxiety-related traits [harm avoidance (HA) and behavioral inhibition (BI)] and with panic disorder (PD). Our sample comprised 127 PD patients and 132 controls without psychiatric disorder. We genotyped nine SNPs within the EFHC2 locus and used PLINK to perform association analyses. An intronic SNP (rs1562875) was associated with HA (permuted p = 0.031) accounting alone for over 3% of variance in this trait. This same SNP was nominally, but not empirically, associated with BI (r² = 0.022; nominal p = 0.022) and PD (OR = 2.64; nominal p = 0.009). The same association was found in a subsample of only females. In sum, we observed evidence of association between a variant in EFHC2, a gene previously associated with the processing of fear and social threat, and HA. Larger studies are warranted to confirm this association.     

PINK1 polymorphism IVS1−7 A → G,exposure to environmental risk factors and anticipation of disease onset in Brazilian patients with early-onset Parkinson's Disease

Parkinson's disease (PD) etiology has been attributed both to genetic and environmental factors, although the exact mechanisms of its pathogenesis remains elusive. We investigated Brazilian early-onset PD (EOPD) patients with PINK1 polymorphisms (SNPs) in order to find possible correlations between SNPs, environmental exposure, and disease age of onset. We enrolled 48 patients and 61 controls. PINK1 SNPs and environmental exposure (living in rural areas, well-water drinking, exposure to pesticides, herbicides and organic solvents and smoking) were investigated in both groups. We divided our group of patients into four subgroups, according to the presence/absence of PINK1 SNP IVS1−7 A → G and the presence/absence of environmental factors exposure. We found a significant decrease (ANOVA test: p = 0.02) of age at disease onset in those patients that had the IVS1−7 A → G SNP and were exposed to environmental risk factors. Our data suggest that the interaction of PINK1 SNP IVS1−7 A → G and environmental risk factors together have an important role in EOPD: each of them individually has a minor influence, whereas their interaction is associated with a significant effect in anticipating the disease clinical onset.     

Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes (P = 0.016) and allele frequency (P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ?4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ?4 allele in the risk of developing AD.     

Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort

Neurofibrillary tangles, one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains, are composed of abnormally hyperphosphorylated tau protein. Tau-tubulin kinase-1 (TTBK1) is a brain-specific protein kinase involved in tau phosphorylation at AD-related sites. We examined genetic variations of TTBK1 by genotyping nine haplotype tagging SNPs (htSNPs) (rs2104142, rs2651206, rs10807287, rs7764257, rs3800294, rs1995300, rs2756173, rs6936397, and rs6458330) in a group of 645 Spanish late-onset AD patients and 738 healthy controls. Using a recessive genetic model, minor allele homozygotes for rs2651206 in intron 1 (OR = 0.50, p = 0.0003), rs10807287 in intron 5 (OR = 0.49, p = 0.0002), and rs7764257 in intron 9 (OR = 0.57, p = 0.023), which are in strong linkage disequilibrium, had a lower risk of developing AD than subjects homozygotes and heterozygotes for the major allele. TTBK1 is a promising new candidate tau phosphorylation-related gene for AD risk.     

Ubc9 gene polymorphisms and late-onset Alzheimer's disease in the Korean population: A genetic association study

Ubiquitin-conjugating enzyme E2I (Ubc9) ligates small ubiquitin-related modifier (SUMO) to target proteins, resulting in changes of their localization, activity, or stability. Sumoylation of amyloid precursor protein (APP) was reported to be associated with decreased levels of beta amyloid (Aβ) aggregates, suggesting that sumoylation may play a role in the pathogenesis of Alzheimer's disease (AD). We investigated the association between genetic variations of Ubc9 gene (UBE2I) and late-onset Alzheimer's disease (AD). Five single nucleotide polymorphisms (SNPs) in UBE2I were genotyped in the DNA samples of 312 AD patients, 347 subjects with mild cognitive impairment (MCI), and 489 cognitively healthy controls. The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p = 0.046, 95% CI: 1.01–2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p = 0.04, OR = 1.43. 95% CI; 1.01–2.01). Stratification by the ApoE-?4 allele gave no significant difference between the groups. When the samples were stratified by gender, the genotypes of two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. Our investigation suggests that UBE2I polymorphisms might be associated with a risk of AD and MCI.     

HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ² = 6.446, p = 0.040 for genotypic distribution; χ² = 5.762, p = 0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population.     

Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease

In the last decade, several genes have been linked to Parkinson's disease (PD), including GIGYF2, ATP13A2 and GBA. To explore whether mutations in these genes contribute to development of PD in the Brazilian population, we screened 110 patients with early-onset PD. No clearly pathogenic mutations were identified in ATP13A2 and GIGYF2. In contrast, we identified a significantly higher frequency of known pathogenic mutations in GBA gene among the PD cases (6/110 = 5.4%) when compared to the control group (0/155) (P = 0.0047). Our results strongly support an association between GBA gene mutations and an increased risk of PD. Mutations in GIGYF2 and ATP13A2 do not seem to represent a risk factor to the development of PD in the Brazilian population. Considering the scarcity of studies on GIGYF2, ATP13A2 and GBA mutation frequency in Latin American countries, we present significant data about the contribution of these genes to PD susceptibility.     

LRRK2 variant associated with Alzheimer's disease

Overlapping neurodegenerative pathologies (including Alzheimer's disease, AD) have been described in Parkinson's disease (PD) patients with leucine-rich repeat kinase-2 (LRRK2) mutations. We analyzed a LRRK2 PD (R1628P) risk variant in a group of 885 subjects comprising of AD and controls. The frequency of the R1628P allele was higher in AD compared to controls (3.5% vs. 1.6%, OR 2.3, 95 CI 1.2-4.4, p = 0.018). In vitro, the mean percentage of apoptosis and cell death observed for the R1628P transfected human cell lines was higher compared to wild type 21.8 ± 1.9, vs. 17.1 ± 1.3, p < 0.05, 30.2 ± 2.2 vs. 25.7 ± 1.3, p < 0.05). The LRRK2 R1628P variant increases the risk of AD in our population and our in vitro findings suggest that it is a functional variant and predisposes to apoptosis.     

Insulin-like growth factor 1 (IGF1) polymorphism is associated with Alzheimer's disease in Han Chinese

A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.006, allele P = 0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) ?4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE ?4 allele carriers (genotype P = 0.002, allele P = 0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE ?4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.     

SNP/haplotype associations of CCR2 and CCR5 genes with severity of chagasic cardiomyopathy

Background

Chronic inflammation plays a major role in the tissue injury seen in the chronic chagasic cardiomyopathy. The CCR2 and CCR5 chemokine receptors are involved with the type of cellular infiltrate present in cardiac tissue and CCR5-gene variants were previously associated with this pathology.

Methods and results

This is a replication study in an independent cohort with larger sample size. Nine SNPs of CCR5 and CCR2 were typified to confirm the association previously found with Chagas disease. Evidence of association with severity was found for the A allele of rs1799864 of CCR2 (p_ad = 0.02; OR = 1.91, 95% CI = 1.10–3.30), the T allele of the rs1800024 of CCR5 (p_ad = 0.01; OR = 1.95, 95% CI = 1.13–3.38), and the HHF^∗2 haplotype (p = 0.03, OR = 1.65, 95% CI = 1.03–2.65). These results were replicated in the study combined with previous data. In this analysis it was replicated the allele T of rs2734648 (p_ad = 0.009, OR = 0.52, 95% CI = 0.32–0.85) with protection. In addition, the allele G of rs1800023 (p_ad = 0.043, OR = 0.61, 95% CI = 0.38–0.98), and the HHC haplotype (p = 0.004, OR = 0.62, 95% CI = 0.44–0.86) were also associated with protection. In contrast, the allele A of rs1799864 of CCR2 (p_ad = 0.009; OR = 1.90, 95% CI = 1.17–3.08); and the allele T of rs1800024 of CCR5 (p_ad = 0.005, OR = 1.98, 95% CI = 1.22–3.23) were associated with greater severity. No evidence of association between symptomatic and asymptomatic patients was observed.

Conclusions

These results confirm that variants of CCR5 and CCR2 genes and their haplotypes are associated with the severity but not with susceptibility to develop chagasic cardiomyopathy.