Dataset Information

C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients.

ABSTRACT: Objectives:Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age-at-onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR-FAP Val30Met Portuguese patients. Methods:We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the non-independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene-gene interactions. Results:Two variants for C1QA gene, GA genotype of rs201693493 (P < 0.001) and CT genotype of rs149050968 (P < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1QC, we found three statistically significant results: GA genotype of rs2935537 (P = 0.003), GA genotype of rs201241346 (P < 0.001) and GA genotype of rs200952686 (P < 0.001). The first two were associated with earlier AO, whereas the third was associated with later-onset. Interpretation:C1QA was associated with later onset, whereas C1QC may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR-FAP Val30Met.

SUBMITTER: Dias A

PROVIDER: S-EPMC6469251 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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<i>C1QA</i> and <i>C1QC</i> modify age-at-onset in familial amyloid polyneuropathy patients.

Dias Andreia A Santos Diana D Coelho Teresa T Alves-Ferreira Miguel M Sequeiros Jorge J Alonso Isabel I Sousa Alda A Lemos Carolina C

Annals of clinical and translational neurology 20190307 4

<h4>Objectives</h4>Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age-at-onset (AO), including within families. We hypothesized that variants in <i>C1QA</i> and <i>C1QC</i> genes, might also act as genetic modifiers of AO in TTR-FAP Val30Met Portuguese patients.<h4>Methods</h4>We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimatin ...[more]

PMID: 31019999

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Project description:ImportanceFamilial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro.ObjectiveTo determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy.Design, setting, and participantsInternational randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012.InterventionParticipants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years.Main outcomes and measuresThe primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data.ResultsBy multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007).Conclusions and relevanceAmong patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.Trial registrationclinicaltrials.gov Identifier: NCT00294671.

Project description:ObjectivesTo evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).MethodsIn this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.ResultsThere was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups.ConclusionsAlthough the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.Classification of evidenceThis study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

Dataset Information

C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients.

Publications

<i>C1QA</i> and <i>C1QC</i> modify age-at-onset in familial amyloid polyneuropathy patients.

Similar Datasets

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