Dataset Information

Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration.

ABSTRACT: Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass index (BMI), and potential associations of C-reactive protein, factor H related-2 (FHR-2) and collectin-11 with AMD. In addition, we confirmed previously described associations and identified new associations of AMD variants with complement levels. New associations include increased C4 levels for rs181705462 at the C2/CFB locus, decreased vitronectin (VTN) levels for rs11080055 at the TMEM97/VTN locus and decreased factor I levels for rs10033900 at the CFI locus. Finally, we detected significant associations between AMD-associated metabolites and complement proteins in plasma. The most significant complement-metabolite associations included increased high density lipoprotein (HDL) subparticle levels with decreased C3, factor H (FH) and VTN levels. The results of our study indicate that demographic factors, genetic variants and circulating metabolites are associated with complement protein components. We suggest that these factors should be considered to design personalized treatment approaches and to increase the success of clinical trials targeting the complement system.

SUBMITTER: Acar IE

PROVIDER: S-EPMC8705464 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration.

Acar I Erkin IE Willems Esther E Kersten Eveline E Keizer-Garritsen Jenneke J Kragt Else E Bakker Bjorn B Galesloot Tessel E TE Hoyng Carel B CB Fauser Sascha S van Gool Alain J AJ Lechanteur Yara T E YTE Koertvely Elod E Nogoceke Everson E Gloerich Jolein J de Jonge Marien I MI Lorés-Motta Laura L den Hollander Anneke I AI

Journal of personalized medicine 20211125 12

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass in ...[more]

PMID: 34945728

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Project description:ObjectiveLipid dysregulation and complement system (CS) activation are 2 important pathophysiology pathways for age-related macular degeneration (AMD). We hypothesized that the relationship between lipids and AMD may also differ according to CS genotype profile. Thus, the objective was to investigate the relationships between lipid-related metabolites and AMD according to CS genotypes.DesignPopulation-based cross-sectional study.ParticipantsA total of 6947 participants from Singapore Epidemiology of Eye Diseases study with complete relevant data were included.MethodsWe investigated a total of 32 blood lipid-related metabolites from nuclear magnetic resonance metabolomics data including lipoproteins and their subclasses, cholesterols, glycerides, and phospholipids, as well as 4 CS single nucleotide polymorphisms (SNPs): rs10922109 (complement factor H), rs10033900 (complement factor I), rs116503776 (C2-CFB-SKIV2L), and rs2230199 (C3). We first investigated the associations between AMD and the 32 lipid-related metabolites using multivariable logistic regression models. Then, to investigate whether the effect of lipid-related metabolites on AMD differ according to the CS SNPs, we tested the possible interactions between the CS SNPs and the lipid-related metabolites.Main outcome measuresAge-related macular degeneration was defined using the Wisconsin grading system.ResultsAmong the 6947 participants, the prevalence of AMD was 6.1%, and the mean age was 58.3 years. First, higher levels of cholesterol in high-density lipoprotein (HDL) and medium and large HDL particles were associated with an increased risk of AMD, and higher levels of serum total triglycerides (TG) and several very-low-density lipoprotein subclass particles were associated with a decreased risk of AMD. Second, these lipids had significant interaction effects on AMD with 2 CS SNPs: rs2230199 and rs116503776 (after correction for multiple testing). For rs2230199, in individuals without risk allele, higher total cholesterol in HDL2 was associated with an increased AMD risk (odds ratio [OR] per standard deviation increase, 1.20; 95% confidence interval (CI), 1.06-1.37; P = 0.005), whereas, in individuals with at least 1 risk allele, higher levels of these particles were associated with a decreased AMD risk (OR, 0.69; 95% CI, 0.45-1.05; P = 0.079). Conversely, for rs116503776, in individuals without risk allele, higher serum total TG were associated with a decreased AMD risk (OR, 0.84; 95% CI, 0.74-0.95; P = 0.005), whereas, in individuals with 2 risk alleles, higher levels of these particles were associated with an increased risk of AMD (OR, 2.3, 95% CI, 0.99-5.39, P = 0.054).ConclusionsLipid-related metabolites exhibit opposite directions of effects on AMD according to CS genotypes. This indicates that lipid metabolism and CS may have synergistic interplay in the AMD pathogenesis.

Project description:BackgroundGiven the relatively high prevalence of age-related macular degeneration (AMD) and the increased incidence of AMD as populations age, the results of trials of novel treatments are awaited with much anticipation. The complement cascade describes a series of proteolytic reactions occurring throughout the body that generate proteins with a variety of roles including the initiation and promotion of immune reactions against foreign materials or micro-organisms. The complement cascade is normally tightly regulated, but much evidence implicates complement overactivity in AMD and so it is a logical therapeutic target in the treatment of AMD.ObjectivesTo assess the effects and safety of complement inhibitors in the prevention or treatment of advanced AMD.Search methodsWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2013), EMBASE (January 1980 to November 2013), Allied and Complementary Medicine Database (AMED) (January 1985 to November 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1990 to November 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 November 2013. We also performed handsearching of proceedings, from 2012 onwards, of meetings and conferences of specific professional organisations.Selection criteriaWe planned to include randomised controlled trials (RCTs) with parallel treatment groups which investigated either the prevention or treatment of advanced AMD by inhibition of the complement cascade.Data collection and analysisTwo authors (MW and GMcK) independently evaluated all the titles and abstracts resulting from the searches. We contacted companies running clinical trials which had not yet reported results to request information. Since no trials met our inclusion criteria, we undertook no assessment of quality or meta-analysis.Main resultsWe identified and screened 317 references but there were no published RCTs that met the inclusion criteria. We identified two ongoing studies: one phase I study and one phase II study.Authors' conclusionsThere is insufficient information at present to generate evidence-based recommendations on the potential safety and efficacy of complement inhibitors for prevention or treatment of AMD. However we anticipate the results of ongoing trials.

Project description:PurposeSeveral genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes.MethodsPlasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complement components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model.ResultsThe highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0.01). Positive associations were found between BMI and plasma C3, CFB, CFH, iC3b, and C3a. There were also significant associations between C5a fragment and LOC387715/ARMS2 and C3 genotypes (P for trend = 0.02, 0.04), respectively. C statistics for models with behavioral and genetic factors increased to 0.94 +/- 0.20 with the addition of C3a, Bb, and C5a.ConclusionsIncreased levels of activation fragments Bb and C5a are independently associated with AMD. Higher BMI is related to increased levels of complement components. C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis.

Dataset Information

Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration.

Publications

Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration.

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