Subgroup Of Carriers Research Articles

Cognition and gray and white matter characteristics of presymptomatic C9orf72 repeat expansion.

To investigate cognitive function, gray matter volume, and white matter integrity in the presymptomatic stage of chromosome 9 open reading frame 72 repeat expansion (C9orf72RE). Presymptomatic C9orf72RE carriers (n = 18) and first-degree family members without a pathogenic expansion (healthy controls [HC], n = 15) underwent a standardized protocol of neuropsychological tests, T1-weighted MRI, and diffusion tensor imaging within our cohort study of autosomal dominant frontotemporal dementia (FTD). We investigated group differences in cognitive function, gray matter volume through voxel-based morphometry, and white matter integrity by means of tract-based spatial statistics. We correlated cognitive change with underlying gray or white matter. Our data demonstrate lower scores on letter fluency, Stroop card I, and Stroop card III, accompanied by white matter integrity loss in tracts connecting the frontal lobe, the thalamic radiation, and tracts associated with motor functioning in presymptomatic C9orf72RE compared with HC. In a subgroup of C9orf72RE carriers above 40 years of age, we found gray matter volume loss in the thalamus, cerebellum, and parietal and temporal cortex. We found no significant relationship between subtle cognitive decline and underlying gray or white matter. This study demonstrates that a decline in cognitive functioning, white matter integrity, and gray matter volumes are present in presymptomatic C9orf72RE carriers. These findings suggest that neuropsychological assessment, T1-weighted MRI, and diffusion tensor imaging might be useful to identify early biomarkers in the presymptomatic stage of FTD or amyotrophic lateral sclerosis.

Long term verbal memory recall deficits in fragile X premutation females

Carriers of a FMR1 premutation allele (between 55 and 199 CGG repeats) are at risk of developing a wide range of medical, psychiatric and cognitive disorders, including executive dysfunction. These cognitive deficits are often less severe for female premutation carriers compared to male premutation carriers, albeit similar in nature. However, it remains unclear whether female premutation carriers who exhibit executive dysfunction also report verbal learning and memory deficits like those of their male counterparts. Here we employed the CVLT to assess verbal learning and memory function in 19 female premutation carriers, contrasting performance with 19 age- and IQ-matched controls. Group comparisons revealed similar performance during the learning and short delay recall phases of the CVLT. However, after a long delay period, female premutation carriers remembered fewer words for both free and cued recall trials, but not during recognition trials. These findings are consistent with reports for male premutation carriers, and suggest that aspects of long term memory may be adversely affect in a subgroup of premutation carriers with signs of executive dysfunction.

Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias – Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene

BackgroundAndersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. MethodsThis study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0±17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats>2000/24h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. ResultsIn KCNJ2 mutation carriers vs non-carriers (n=25 vs n=19) significant differences were observed in U-wave manifestations in V2–V4, Tpeak−Tend duration, QTUc duration (p<0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n=9), in those with arrhythmias and/or syncope and/or CA (n=16) micrognathia (p=0.004), periodic paralysis (p=0.019), palpitation (p=0.005), U-wave n V2–V4 (p=0.049) were more frequent; QTU (p=0.045) and Tpeak−Tend (p=0.014) were also longer (n=9). In the subgroup of carriers with syncope and/or cardiac arrest (n=10, 90% women), K897T-KCNH2 polymorphism (p=0.02), periodic paralysis (p=0.004), muscle weakness (p=0.04), palpitations (p=0.04), arrhythmias (biventricular VT, p=0.003; polymorphic VT, p=0.009) were observed more frequently. Tpeak−Tend duration was longer (p=0.007) and the percentage of patients with premature ventricular contraction >2000/24h was higher (p=0.005). ConclusionA higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged Tpeak−Tend time. Our findings suggest that K897T may contribute to the occurrence of syncope.

Handgun Carrying Among Youth in the United States

Despite a wealth of research finding that adolescents who carry handguns are involved in risky behaviors, there has been little exploration into the heterogeneity of this behavior. Using a pooled sample of 12- to 17-year-olds from the National Study on Drug Use and Health who report past-year handgun carrying ( N = 7,872), this study identified four subgroups of handgun carriers: low risk ( n = 3,831; 47.93%), alcohol and marijuana users ( n = 1,591; 20.16%), fighters ( n = 1,430; 19.40%), and severe externalizers ( n = 1,020, 12.51%). These subgroups differed on demographic, behavioral, and psychosocial characteristics. Findings are discussed in light of prevention and focused deterrence.

Increased peripheral inflammation in asymptomatic leucine-rich repeat kinase 2 mutation carriers.

We aimed to determine if peripheral or central inflammatory cytokines are altered in healthy subjects carrying a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation, and thus genetically at risk of Parkinson's disease (PD). We also aimed to identify differences in inflammatory cytokines between LRRK2 G2019S-associated and idiopathic PD once the disease manifests. Participants were genetically screened and phenotyped, and biological samples were collected and stored by the Michael J. Fox Foundation LRRK2 Cohort Consortium. Serum samples and matching clinical data were obtained from 71 asymptomatic LRRK2 G2019S mutation carriers (CSF n=25), 75 neurologically normal controls (CSF n=22), 75 idiopathic PD patients (CSF n=29), and 76 PD patients with a LRRK2 G2019S mutation (CSF n=20). Inflammatory cytokines were measured using multiplex enzyme-linked immunosorbent assays. Serum levels of interleukin 1 beta could discriminate asymptomatic LRRK2 G2019S mutation carriers from controls, with a high inflammatory subgroup of carriers identified. This subgroup was significantly higher in a number of PD-implicated pro-inflammatory cytokines. Once PD had manifest, LRRK2 G2019S patients were discriminated from idiopathic PD by higher serum platelet-derived growth factor, and higher CSF vascular endothelial growth factor and interleukin 8. The results suggest that peripheral inflammation is higher in a percentage of subjects carrying the LRRK2 G2019S mutation. Replication and longitudinal follow-up is required to determine whether the increased peripheral cytokines can predict clinical PD. Importantly, these biological changes were observed prior to the clinical manifestations thought to herald PD. © 2016 International Parkinson and Movement Disorder Society.

Association between DCHS2 gene and mild cognitive impairment and Alzheimer's disease in an elderly Brazilian sample.

In 2012, Kamboh and colleagues published a genome-wide association study that identified the DCHS2 gene (rs1466662 T/A) influencing the age at onset of Alzheimer's disease (AD). We aimed to investigate if there is association between the DCHS2 gene and amnestic mild cognitive impairment (aMCI) and AD in a sample of the Brazilian population. 143 controls, 79 aMCI and 299 AD patients were selected and submitted to the same protocol of tests. Genotyping was performed using the Real Time PCR RESULTS: Amnestic MCI patients showed a higher prevalence of AA than controls and a lower frequency of TT when compared with controls. We also stratified the sample according to the APOE ε4 status. No difference in DCHS2 genotype or allelic frequency occurred in the APOE ε4 allele carrier subgroup. Amnestic MCI patients showed a higher frequency of AA genotype and a lower frequency of TA and TT when compared with controls in APOE ε4 allele non-carrier subgroup. The allelic distribution followed the same pattern. In AD group, we observed a significant difference with a higher A allelic frequency in AD in this subgroup. A multiple logistic regression demonstrated that in APOE ε4 non-carriers, allele rs1466662 was associated to aMCI group. Different variables were associated with aMCI and AD according to APOE ε4 status in our sample. Low level of education was associated with AD, while diabetes mellitus type 2 was associated with aMCI. Copyright © 2016 John Wiley & Sons, Ltd. Our findings suggest a possible role for DCHS2 gene in aMCI and AD.

Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3.

The aim of the present study is to describe the serum concentrations of a broad spectrum of cytokines in symptomatic and asymptomatic carriers of Machado Joseph disease (SCA3/MJD) CAG expansions. Molecularly confirmed carriers and controls were studied. Age at onset, disease duration, and clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), SCA Functional Index (SCAFI), and Composite Cerebellar Functional Score (CCFS) were obtained from the symptomatic carriers. Serum was obtained from all individuals and a cytokine panel "consisted of" eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, interferon gamma-induced protein (IP)-10, monocyte chemoattractantprotein (MCP)-1, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-a, MIP-b,regulated on activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α was analyzed. In a subgroup of symptomatic carriers, the cytokine panel was repeated after 360days. Cytokine distribution among groups was studied by discriminant analysis; changes in serum levels after 360days were studied by generalized estimation equation. Sixty-six symptomatic carriers, 13 asymptomatic carriers, and 43 controls were studied. No differences in cytokine patterns were found between controls and carriers of the CAG expansions or between controls and symptomatic carriers only. In contrast, eotaxin concentrations were significantly higher in asymptomatic than in symptomatic carriers or in controls (p = 0.001, ANCOVA). Eotaxin did not correlate with age, disease duration, CAG expansion, NESSCA score, and SARA score. Among symptomatic carriers, eotaxin dropped after 360days (p = 0.039, GEE). SCA3/MJD patients presented a benign pattern of serum cytokines. In contrast, levels of eotaxin, a peptide secreted by astrocytes, were elevated in the asymptomatic carriers, suggesting that a specific response of these cells can be related to symptom progression, in SCA3/MJD.

Association between bleeding tendency and health‐related quality of life in carriers of moderate and severe haemophilia

Carriers of severe and moderate haemophilia A and B are expected to have approximately 50% of the normal level of factors VIII and IX. However, due to X chromosome inactivation in early embryonic life, factor levels can vary considerably. This can lead to increased bleeding tendency, which may in turn impact on health-related quality of life (HRQOL). The aim of this study was to assess HRQOL in carriers of severe and moderate haemophilia with and without increased bleeding tendency. One hundred and twenty-four adult carriers and 90 controls were recruited. Bleeding tendency was evaluated using a structured bleeding assessment tool. HRQOL was measured by the short form 36 (SF-36) questionnaire. The SF-36 scores were compared with Swedish normative age-matched data and reported as Z scores. There was no significant difference between the whole groups of carriers and controls in the Z scores of the eight SF-36 domains. The mental component summary (MCS) was lower in carriers, compared with controls (P=0.048). The subgroup of carriers with an increased bleeding tendency had significantly lower Z scores compared to controls regarding the General Health (P=0.008), the Social Functioning (P=0.040) and the Mental Health (P=0.048) domains. The MCS was significantly lower in this carrier subgroup than in controls (P=0.033). We conclude that the subgroup of carriers of haemophilia with increased bleeding tendency have impaired HRQOL. The SF-36 results indicate that this condition affects mental rather than physical health.

A “reduced function” PTPN22 variant modulates the Toll-like receptor-driven type 1 interferon response in systemic lupus erythematosus (HUM2P.329)

Abstract Most systemic lupus erythematosus (SLE patients) exhibit whole-blood increased expression of type I interferon (IFN)-inducible transcripts, known as the "IFN signature". A variant allele of the PTPN22 gene is associated with increased risk of SLE. We recently demonstrated that PTPN22-encoded lymphoid tyrosine phosphatase (Lyp) promotes Toll-like receptor (TLR)-driven type 1 IFN production and type I IFN-dependent host defense and immunoregulation. Further, the disease-associated variant LypR620W (“LypW”) shows reduced function in promoting TLR-driven type 1 IFN-dependent immunity. Here we report that PBMC from LypW carrier SLE patients exhibit reduced type 1 IFN and type 1 IFN-inducible gene expression upon TLR7 activation. The percentages of plasmacytoid dendritic cells (pDC) producing IFNα, as well as the per-cell production of IFNα, are decreased LypW carrier SLE patients. Notably, we found that similar numbers of LypW carriers and non-carriers in SLE patients exhibit elevated IFN gene signatures in whole blood. Together, these data indicate that LypW SLE patient display reduced mononuclear cell capacity for TLR-induced type 1 IFN, despite exhibiting increased systemic type 1 IFN signaling. The findings raise the possibility that autoimmune phenomena in LypW SLE patients may reflect defective type 1 IFN-dependent host defense. Further, they suggest that therapeutic strategies to boost type 1 IFN-driven processes may benefit the LypW carrier subgroup of SLE patients.

Progressive hepatic mitochondrial dysfunction in premanifest Huntington's disease

A subclinical, hepatic involvement in manifest and premanifest Huntington's disease (HD) was recently demonstrated by using the (1) (3) C-methionine breath test (MeBT). In this longitudinal pilot study, we investigated whether there is evidence for progressive hepatic mitochondrial dysfunction in premanifest HD. The MeBT was performed within a group of 25 well-characterized premanifest HD mutation carriers at baseline and in a 14.5-month follow-up. The total group of mutation carriers (P = 0.033; Cohen's d = 0.6) and the subgroup of mutation carriers from our PreHD-B subgroup (nearer to disease onset; P = 0.030; Cohen's d = 1.12) revealed a lower amount of exhaled (13) CO2 in the follow-up. This study demonstrates in vivo progressive, subclinical, hepatic involvement in premanifest HD. Limitations of the study, such as high variance in breath test results, are discussed.

Efficacy of standard antiviral therapy retreatment following interferon treatment failure in chronic hepatitis C patients

To investigate the therapeutic efficacy of standard antiviral therapy applied after interferon (IFN) treatment failure in patients with chronic hepatitis C (CHC). CHC patients who completed a 48-week course of IFN therapy (pegylated (Peg)-IFNa-2a at 180 mug, qw, ih with or without ribavirin (RBV) at 15 mg/kg/w) in our hospital between January 2009 and June 2012 but who showed no response (at week 48) or who relapsed (at week 72) were enrolled in the study. Prior to initiating the 48-week course of retreatment therapy (Peg-IFNa-2a plus RBV as above), the hepatitis C virus (HCV) genotype was detected and the viral load measured (baseline) by PCR of HCV RNA. Each patient's response to therapy was classified as follows: baseline vs. week 4 (rapid virological response, RVR), vs. weeks 12 and 24 (early virological response, EVR), vs. week 48 (end of treatment virological response, ETVR) and vs. week 72 (sustained virological response, SVR). Of the total 235 cases administered retreatment therapy, 60.0% (n = 140) achieved RVR, 77.4% (n = 182) achieved EVR, 83.8% (n = 197) achieved ETVR, 68.0% (n = 68%) achieved SVR, and 15.7% (n = 37) relapsed. Stratification analysis of recurrence (n = 158) and non-responsive (n = 77) sub-groups showed that the recurrence group experienced significantly higher rates of RVR, EVR, ETVR and SVR, but a significantly lower rate of relapse. Stratification analysis of genotype 1b carrier (n = 206) and non-1b carrier (n = 29) sub-groups showed that the 1b carriers had significantly lower rates of RVR, EVR, ETVR and SVR, but a significantly higher rate of relapse. Finally, the patients who achieved RVR (vs. non RVR, n = 95) and EVR (vs. non-EVR, n = 53) showed higher rates of SVR and ETVR. CHC patients who fail to respond to the initial course of standard IFN-based therapy may achieve SVR upon retreatment, especially those infected with the HCV genotype 1b.

COMT Val158Met Polymorphism and Executive Functions in Obsessive-Compulsive Disorder

This study investigated the association between the catechol-O-methyl transferase (COMT) Val158Met polymorphism and executive functions in 101 patients with obsessive-compulsive disorder (OCD) and 100 healthy-control subjects (HS). Results showed that there was no significant difference for the genotype distributions between the OCD and HS groups. OCD-Met carrier subgroup's TMT B-A difference and lexical fluency scores were found to be significantly poorer than both HS subgroups. These findings suggest that lower activity of COMT associated with the Met allele, leading to higher levels of dopamine in the prefrontal cortex, lead to poorer executive function in OCD.

Human genetic variants of homologous recombination repair genes first found to be associated with Epstein–Barr virus antibody titers in healthy Cantonese

Epstein-Barr virus (EBV) infection is a major risk factor for nasopharyngeal carcinoma (NPC). Despite high prevalence of infection among the general population worldwide, only a small proportion of infected individuals presents with seropositivity for EBV-specific IgA antibodies. This seropositive subgroup of EBV carriers has an elevated cumulative risk for NPC during their lifetime. Previous studies reported that the host homologous recombination repair (HRR) system participates in EBV lytic replication, suggesting a potential mechanism to influence EBV reactivation status and thus seropositivity. To investigate whether genetic variants of HRR genes are associated with the serostatus in a healthy population, we investigated the association between seropositivity for anti-VCA-IgA and 156 tagging SNPs in 35 genes connected with HRR in an observational study among 755 healthy Cantonese speakers in southern China. Six variant alleles of MDC1, RAD54L, TP53BP1, RPA1, LIG3 and RFC1 exhibited associations with seropositivity (p(trend) from 0.0085 to 0.00027). Our study provides evidence that genetic variation within the HRR might affect an individual's propensity for EBV seropositive status of anti-VCA IgA antibody.

Victimization and Health Risk Factors Among Weapon-carrying Youth

To compare health risks of 2 subgroups of weapon carriers: victimized and nonvictimized youth. 2003-2007 NYC Youth Risk Behavior Surveys were analyzed using bivariate analyses and multinomial logistic regression. Among NYC teens, 7.5% reported weapon carrying without victimization; 6.9% reported it with victimization. Both subgroups were more likely than non-weapon carriers to binge drink, use marijuana, smoke, fight, and have multiple sex partners; weapon carriers with victimization also experienced persistent sadness and attempted suicide. Subgroups of weapon carriers have distinct profiles. Optimal response should pair disciplinary action with screening for behavioral and mental health concerns and victimization.

Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

Hemochromatosis (HFE) genotype and atherosclerosis: Increased susceptibility to iron-induced vascular damage in C282Y carriers?

Background The C282Y mutation of the hemochromatosis (HFE)-gene increases body iron status. Among Caucasians, the carrier frequency of this mutation is 8–9%. C282Y carriers may be more susceptible to iron-induced atherosclerosis due to higher iron levels. It has also been postulated that the C282Y mutation could alter aspects of iron metabolism. We examined the relationship between the C282Y mutation, iron status, and carotid intima-media thickness (IMT) as a marker of atherosclerosis. Methods and results The present study comprised 764 Dutch men and post-menopausal women aged 50–70 years. Mean and maximum carotid IMT were assessed by B-mode ultrasonography. Blood was sampled for assessment of the C282Y mutation and body iron status. Parameters of iron status (e.g. ferritin and non-transferrin bound iron) were significantly higher in C282Y carriers ( n = 80; 10%) compared to non-carriers ( P-values <0.001), however, there was no difference in the carotid IMT measures. Among non-smokers ( n = 222), carotid IMT was 0.051 mm (95% CI: 0.005; 0.096) lower in carriers compared to non-carriers ( P = 0.03), which remained after adjustment for iron parameters. Within the subgroup of carriers, higher carotid IMT values were observed across sex-specific quartiles of ferritin (mean IMT: 0.789, 0.787, 0.814, and 0.865 mm; P-trend = 0.08), whereas this association was absent in non-carriers. Conclusion Overall, we found no association of HFE genotype with carotid IMT, despite higher iron status. Interestingly, C282Y carriers may be hyper responsive to vascular damage which needs to be confirmed in prospective cohort studies.

Abnormal motor cortex plasticity in premanifest and very early manifest Huntington disease

BackgroundCognition is affected early in Huntington disease (HD), and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. The authors investigated whether there is any evidence...

Prognosis in BRCA1, BRCA2 associated breast cancer (BC): a prospective Breast Cancer Family Registry (BCFR) international population-based cohort study.

Abstract Abstract #2072 Hereditary BC occurs at a younger age and is associated with more adverse tumor-related features than sporadic breast cancer (BC) (defined here as BC in those with no 1st or 2nd degree family history of breast or ovarian cancer). Using pre-specified criteria, we assembled a population-based cohort of newly diagnosed BC at 3 centers: Ontario, Canada (1996-98), San Francisco Bay area, USA (1995-2000), Melbourne/Sydney, Australia (1991-1998). Medical information was obtained from medical records; women were followed prospectively for recurrence, new cancers and death. Pathology data were obtained from central review or pathology reports. BRCA1 and BRCA2 mutation testing was performed on 77% and 70% of cases, respectively (sporadic BC cases were not tested at 2 centers). Hereditary and sporadic BC cases were compared using Cox proportional hazards (stratified by center). 3215 eligible cases were enrolled in the BCFR, with a mean age at diagnosis of 46.9 years. Median follow-up was 7.61 years; 565 women had distant recurrences and 547 died. There were 92 cases with BRCA1 and 72 with BRCA2 mutations; 1549 (48.2%) had sporadic BC; the remainder had familial BC as defined above. BRCA1 mutations were associated with young age, estrogen and progesterone receptor (ER and PgR) negativity and high grade; BRCA2 mutations were associated with node positivity and high grade. Distant disease-free survival (DDFS) and overall survival (OS) did not differ significantly between BRCA1 carriers and sporadic cases in univariate or multivariate analyses. DDFS and OS were worse in BRCA2 carriers than in sporadic cases (HR 1.6, p=0.04 and HR 1.8, p=0.01, respectively) in univariate analyses but not in multivariate analyses (DDFS HR 1.0, p=0.98; OS HR 1.13, p=0.61). The small group of BRCA2 carriers who did not receive adjuvant chemotherapy had a significantly worse OS (multivariate HR 3.63, p = 0.005). Furthermore, BRCA2 carriers who received adjuvant tamoxifen had significantly worse OS than women with sporadic BC (HR=2.0, p=0.03). We conclude that BRCA1 and BRCA2 mutations do not independently impact DDFS or OS. Significantly worse outcomes were seen in BRCA2 carrier subgroups defined by adjuvant treatment; this requires further investigation and may have implications for clinical practice. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2072.

Striatal Dopamine Transporter Availability Associated with Polymorphisms in the Dopamine Transporter Gene SLC6A3

Polymorphisms in the dopamine transporter (DAT) gene SLC6A3 are associated with human striatal DAT expression, but the exact effects on DAT expression are not clear. A variable number of tandem repeats (VNTR) in the 3' untranslated region of the DAT gene was previously investigated in relation to striatal DAT availability, but the results were inconclusive. Other polymorphisms in the DAT gene were not extensively studied. Therefore, we investigated whether polymorphisms in both 3' and 5' ends of the DAT gene show association with in vivo striatal DAT expression. The subjects were an ethnically homogeneous group of 79 healthy young adults. Striatal DAT availability was measured with 123I-(2-beta-carbomethoxy-3-beta(4-iodophenyl)-tropane) (123I-beta-CIT) SPECT. The 40-base-pair VNTR in the 3' untranslated region of the DAT gene and the 2 single nucleotide polymorphisms (SNPs) rs2652511 and rs2937639 in the 5' end of the DAT gene were genotyped. Multiple-regression analysis was performed for each of the 3 polymorphisms. Analysis of the combination of the polymorphisms (haplotype analysis) was conducted for the triad rs2652511-rs2937639-VNTR. For the VNTR, the 9-repeat (9R) allele was associated with significantly higher striatal DAT expression than was the 10-repeat (10R) allele (P=0.002). Subanalysis suggested a dominant effect for the 9R allele. Neither SNP rs2652511 nor SNP rs2937639 was associated with striatal DAT availability. The haplotype T-A-9R (rs2652511-rs2937639-VNTR) was significantly more associated with higher striatal DAT expression than were the other haplotypes (P=0.009). The DAT VNTR 9R carriers have higher striatal DAT availability than do 10R homozygotes. This finding replicates former studies that included healthy subjects and also used 123I-beta-CIT SPECT. Our haplotype analysis identified a subgroup of 9R carriers, the T-A-9R, which appears to be mainly responsible for the association with higher striatal DAT availability. Thus, a combination of polymorphisms in both the 3' and the 5' ends of the DAT gene is associated with in vivo striatal DAT expression. This finding in healthy subjects may contribute to research on DAT availability and genotype in neuropsychiatric disorders.

Association of RFC1 A80G and MTHFR C677T polymorphisms with Alzheimer's disease

We examined polymorphisms in reduced folate carrier gene ( RFC1) and methylenetetrahydrofolate reductase gene ( MTHFR) for association with sporadic AD (SAD) in Chinese population. Significant associations of RFC1 A80G G allele and GG genotype with SAD ( p = 0.008, OR = 1.312, 95%CI = 1.072–1.605, and p = 0.042, OR = 1.383, 95%CI = 1.012–1.890) were found. Further stratification of total samples by APOE ɛ4 carrier status, age/age at onset and gender revealed that RFC1 A80G G allele was an APOE ɛ4-independent risk factor for late-onset AD, and it might increase the risk of AD in females. No significant associations of MTHFR C677T allele and genotype with AD were observed in total samples, but significant associations of T allele and TT genotype with AD ( p = 0.031, OR = 1.586, 95%CI = 1.042–2.414, and p = 0.028, OR = 2.250, 95%CI = 1.074–4.712) were identified in APOE ɛ4 carrier subgroup, suggesting that MTHFR 677 T allele and APOE ɛ4 allele may synergistically act to increase AD risk. No significant effect of RFC1 G80A and MTHFR C677T polymorphisms on plasma folate and homocysteine levels was detected.