Dataset Information

Association between the rs1805081 polymorphism of Niemann-Pick type C1 gene and cardiovascular disease in a sample of an Iranian population.

ABSTRACT: The aim of the present study was to investigate the association between a genetic variation, A+644G, in the Niemann-Pick type C1 (NPC1) gene and the risk of cardiovascular disease (CVD) in a Southeast Iranian population. A total of 320 individuals, including 200 patients with CVD and 120 healthy individuals, were involved in the present study. The polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism method. The results indicated that the frequency of the GG genotype was markedly lower in patients with CVD compared with the control group (7 vs. 16.7%), and that the NPC1 rs1805081 polymorphism was associated with reduced risk of CVD [odds ratio (OR)=0.110; 95% confidence interval (CI)=0.017-0.715; P=0.021]. In addition, the prevalence of the minor allele (G) in patients with CVD differed from that of the control group with the frequency of 25.5 and 33.4% for the former and latter, respectively, and this difference reached statistical significance (OR=0.658; 95% CI=0.482-0.971; P=0.037). Furthermore, analysis of clinical characteristics of the individuals according to the NPC1 genotypes revealed an association between the lipid profile and NPC1 gene polymorphism. These findings demonstrated that the NPC1 A+644G variant was associated with reduced risk of CVD and serves a protective role against susceptibility to CVD in the Iranian population.

SUBMITTER: Afzali M

PROVIDER: S-EPMC5244780 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Association between the rs1805081 polymorphism of Niemann-Pick type C1 gene and cardiovascular disease in a sample of an Iranian population.

Afzali Masoumeh M Hashemi Mohammad M Tabatabaei Seyed Payman SP Fakheri Kourosh Tirgar KT Nakhaee Alireza A

Biomedical reports 20161107 1

The aim of the present study was to investigate the association between a genetic variation, A+644G, in the Niemann-Pick type C1 (NPC1) gene and the risk of cardiovascular disease (CVD) in a Southeast Iranian population. A total of 320 individuals, including 200 patients with CVD and 120 healthy individuals, were involved in the present study. The polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism method. The results indicated that the frequenc ...[more]

PMID: 28123713

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Project description:ImportanceNiemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally.ObjectiveTo determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1.Design, setting, and participantsPatients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019.ExposuresOral miglustat at baseline and at follow-up.Main outcomes and measuresOropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively.ResultsOverall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29).Conclusions and relevanceThese data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.

Project description:ObjectivesThe aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood.DesignFifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients.ResultsOver half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function.ConclusionsThis is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Project description:BackgroundNiemann-Pick disease type C1 (NPC1) is a rare autosomal recessive disease characterized by endolysosomal accumulation of unesterified cholesterol with progressive deterioration in swallowing, often leading to premature death. Although documented, the natural history of NPC1 swallowing dysfunction has yet to be delineated systematically. This manuscript aims to provide a comprehensive characterization of the phenotypic spectrum and progression of swallowing dysfunction in NPC1.MethodologyThe National Institutes of Health (NIH) NPC1 natural history study (NCT00344331) enrolled 120 patients, who underwent comprehensive interpretative swallow assessments for swallowing safety, dietary modifications, and aspiration risk. Longitudinal statistical modeling accounted for all outcomes with NPC1 disease covariates (first symptom onset, age at neurological symptom onset, seizure history, duration of neurological symptoms) as well as miglustat use (a glucosylceramide synthase inhibitor) and NIH study duration (NIHSD; the length of time an individual participated in the NIH study). Probabilities for disease progression and time to swallowing decline were conducted for the entire cohort.ResultsTime to swallowing decline with American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH-adapted Penetration Aspiration Scale (NIH-PAS) were identified: [Formula: see text] person-years and [Formula: see text] person-years, respectively. NIHSD and seizure history consistently and significantly were associated with decline (ORNIHSD = 1.34-2.10, 95% CI 1.04-3.4, p = 0.001-0.026; ORSeizure = 3.26-18.22, 1.03-167.79; p = 0.001-0.046), while miglustat use revealed protection (ORMiglustat = 0.01-0.43, 0.007-0.98; p = 0.001-0.044). The probability of decline with NPC1 neurological severity scale and annual severity increment scale were established with the aforementioned covariates, varying amongst subgroups.ConclusionThis study represents the most extensive collection of prospective, instrumental swallowing assessments in NPC1 to date with an interpretive analysis providing an improved understanding of NPC1 disease progression with swallowing function-serving as a foundation for clinical management and future NPC1 therapeutics.

Dataset Information

Association between the rs1805081 polymorphism of Niemann-Pick type C1 gene and cardiovascular disease in a sample of an Iranian population.

Publications

Association between the rs1805081 polymorphism of Niemann-Pick type C1 gene and cardiovascular disease in a sample of an Iranian population.

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