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Cited by 15Renal Diseases and GlomerulopathiesChronic Kidney Disease and DiabetesLipoproteins and Cardiovascular Health

Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations

Open access
Yang, Mingxin, Weng, Qinjie, Pan, Xiaoxia, Hussain, Hafiz Muhammad Jafar, Yu, Shuwen, Xu, Jing, Yu, Xialian, Liu, Yunzi +6 more·2020·Molecular Genetics & Genomic Medicine
DOI 10.1002/mgg3.1281PMC PMC7434605
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Abstract

Background: Lipoprotein glomerulopathy (LPG) is a rare kidney disease caused by APOE mutations. The aim of this study was to correlate the genetic and clinical features of LPG. Methods: Totally eight LPG patients were recruited in this study and Sanger sequencing of APOE was performed for all available family members. Clinical and histological features were analyzed. A literature review of LPG was also conducted. Results: Genetic analysis revealed five patients with APOE‐Kyoto, two with APOE‐Osaka/Kurashiki, and one with APOE‐Chicago mutations. LPG patients with urine protein reduced more than 50% had a slower decrease in renal function than those with less urine protein reduction (estimated glomerular filtration rate reduction rate −5.0 ± 0.8 vs. 1.5 ± 0.7 ml/min per 1.73 m 2⋅month−1, p = .03). We then enrolled 95 LPG patients from previous studies and this study. LPG patients had higher blood pressure (mean arterial pressure: 109.4 ± 19.4 vs. 94.4 ± 11.1 mmHg, p < .001) than the control group. Interestingly, patients with APOE mutations in the LDL receptor binding region had higher serum apolipoprotein E (apoE) levels [ln(apoE): 2.7 ± 0.4 vs. 2.0 ± 0.5 mg/dl, p < .001] in comparison to other domains. Conclusion: Here, we report for the first time APOE‐Osaka/Kurashiki and APOE‐Chicago mutations in the Chinese population. LPG was associated with higher blood pressure and serum apoE levels were higher in patients with mutations in LDL receptor binding region. In addition, the findings further indicated that treatment of proteinuria might slow down renal function progression in these patients.

AI snapshot

Written from the paper’s full text.

TL;DR

This study genetically and clinically characterizes eight Chinese patients with lipoprotein glomerulopathy (LPG) and reviews 87 published LPG cases, identifying APOE-Kyoto, APOE-Osaka/Kurashiki, and APOE-Chicago mutations. It reports that greater urine protein reduction is associated with slower eGFR decline and that mutations in the LDL receptor/HSPG binding region are associated with higher serum apoE levels.

Key findings

Among eight biopsy-proven LPG patients, five had APOE-Kyoto, two had APOE-Osaka/Kurashiki, and one had APOE-Chicago; APOE-Osaka/Kurashiki and APOE-Chicago were reported for the first time in the Chinese population.

  • In three families, asymptomatic carriers were found, with penetrance of 54.5% (six patients and five asymptomatic carriers).
  • Patients whose urine protein decreased ≥50% at 12 months (PR group, n = 2) had slower eGFR decline than nonremission patients (NR group, n = 4): 1.5 ± 0.7 vs. −5.0 ± 0.8 ml/min per 1.73 m²·month, p = .03.
  • In the combined 95 LPG patients versus 60 nephrotic syndrome controls, LPG patients had higher mean arterial pressure (109.4 ± 19.4 vs. 94.4 ± 11.1 mmHg, p < .001), lower ln(Upro) (1.3 ± 0.9 vs. 1.9 ± 0.5 g/24 hr, p < .001), and lower ln(TC) (1.8 ± 0.5 vs. 2.3 ± 0.4 mmol/L, p < .001).
  • Patients with APOE mutations in the LDL receptor binding region had higher serum apoE levels than those with mutations in other domains [ln(apoE): 2.7 ± 0.4 vs. 2.0 ± 0.5 mg/dl, p < .001].

Methods

Single-center study at Ruijin Hospital of eight biopsy-proven LPG patients diagnosed between 1998 and 2019 with available DNA; clinical baseline data were collected at kidney biopsy, and Sanger sequencing covered the four APOE exon regions in patients and available family members.

  • Literature review searched MEDLINE, EMBASE, Wanfang Data, and CNKI from 1 January 1989 to 30 September 2018; 28 articles were retrieved from 327 records, yielding 87 LPG patients with APOE mutations, of whom 52 had individual baseline data.
  • A control group of 60 non-LPG nephrotic syndrome patients (27 FSGS and 33 MCD) from 2013–2015 was enrolled; analyses used means ± SD, t-tests, log transformation for non-normal variables, chi-square tests, and linear regression for mean arterial pressure, with p < .05 considered significant.

Limitations

The authors state that the study had a small sample size, limiting power to detect more genotype–phenotype correlations; that only APOE was Sanger-sequenced, so pathogenic mutations in other unknown genes may have been missed; and that no functional studies were performed to reveal mechanisms of the mutations.

  • Evident from the text: the PR/NR follow-up comparison included only six patients (n = 2 vs. n = 4), one patient was lost to follow-up, and another had too short an interval from biopsy to data collection.
  • Evident from the text: the literature review relied on previously published cases with incomplete data, including apoE data available for 83 of 95 LPG patients and individual baseline data for only 52 of 87 reviewed patients.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/mgg3.1281

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 31 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Findingcitation

    APOE-Osaka/Kurashiki was reported for the first time outside of Japan.

    “For the first time we report APOE‐Osaka/Kurashiki outside of Japan (Saito & Matsunaga, 2011).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Saito & Matsunaga, 2011 source
  • Premisecitation

    Almost all other mutations were located on the ε3 allele except for APOE-Toyonaka.

    “Almost all other mutations were located on the ε3 allele except for a new reported mutation APOE‐Toyonaka (Fukunaga et al., 2018; Hirashima et al., 2018).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Fukunaga et al., 2018 source

      The Case Presentation (Analysis of ApoE Mutation; page unavailable) identifies APOE-Toyonaka as a novel mutation in a patient with an ε2/2 genotype, supporting the exception. The paper does not establish that almost all other mutations occur on the ε3 allele. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Hirashima et al., 2018 source

      The Case presentation > Analysis of ApoE mutation (page unavailable) identifies APOE-Toyonaka in a patient with an ε2/2 genotype, supporting its distinction from mutations on an ε3 allele. The paper does not establish that almost all other mutations are located on ε3 alleles; its Discussion contrasts Toyonaka with other mutations by protein region, not allele. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    All eight LPG patients presented with moderate to nephrotic range proteinuria (range, 1.5-10.5 g/24 hr).

    “All the patients presented with moderate to nephrotic range proteinuria (range, 1.5–10.5 g/24 hr).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Light microscopy of the renal tissues revealed expansion of the capillary lumen.

    “Light microscopy of the renal tissues revealed the expansion of the capillary lumen.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Immunofluorescence microscopy showed deposition of apoE and apoB.

    “Furthermore, immunofluorescence microscopy showed deposition of apoE and apoB.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 28

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LPG-related mutations found in China include APOE-Kyoto, APOE-Tokyo/Maebashi, APOE-Guangzhou, and APOE-Chengdu.

    “LPG‐related mutations found in China include APOE‐Kyoto, APOE‐Tokyo/Maebashi, APOE‐Guangzhou, and APOE‐Chengdu (Han et al., 2010; Wu, Yang, & Hu, 2018).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Han et al., 2010 source
    • cites Wu, Yang, & Hu, 2018 source

      The Introduction identifies apoE Kyoto as LPG-related and reports apoE Chengdu in a Chinese patient; the Discussion also identifies apoE Guangzhou as LPG-related. The References list an LPG-associated apoE Tokyo mutation, but the paper does not establish that Tokyo was found in China, and it does not mention Maebashi. It therefore does not support the full list as mutations found in China. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    APOE-Chicago was first reported in a male Mexican-American patient and later in a Japanese female patient.

    “APOE‐Chicago was also first reported in Chinese LPG patients which was first reported in a male Mexican‐American patient (Sam et al., 2006) and later in a Japanese female patient (Kodera et al., 2017).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Sam et al., 2006 source
    • cites Kodera et al., 2017 source

  • May combine two claims.

    Premisecitation

    APOE-Okayama (R150G) and APOE-Modena (R150C) were located on the ε2 allele.

    “We found that both APOE‐Okayama (R150G; Kinomura et al., 2008) and APOE‐Modena (R150C; Magistroni et al., 2013; Russi et al., 2009) were located on the ε2 allele, while APOE allele of APOE‐Guangzhou (R150P) was not reported (Luo et al., 2008).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Kinomura et al., 2008

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Magistroni et al., 2013 source
    • cites Russi et al., 2009 source

  • May combine two claims.

    Premisecitation

    Mutations on APOE3 (variant ε3) of LPG induce thermodynamic destabilization and enhanced aggregation.

    “This finding is consistent with reports that mutations on APOE3 (variant ε3) of LPG induce thermodynamic destabilization and enhanced aggregation (Georgiadou et al., 2013; Katsarou, Stratikos, & Chroni, 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Georgiadou et al., 2013 source
    • cites Katsarou, Stratikos, & Chroni, 2018 source

  • May combine two claims.

    Findingown data

    Average eGFR of the eight LPG patients was 83.6 ± 20.2 ml/min per 1.73 m2 (range 51.9-110.8 ml/min per 1.73 m2) at kidney biopsy, while eGFRs of two patients were less than 60 ml/min per 1.73 m2.

    “Average eGFR of patients was 83.6 ± 20.2 ml/min per 1.73 m2 (range of 51.9–110.8 ml/min per 1.73 m2) at the time of kidney biopsy, while eGFRs of two patients were less than 60 ml/min per 1.73 m2.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Deposition of immunoglobulin A (IgA) antibody was found in the glomerulus of one LPG patient (F16A1578-II1).

    “Deposition of the immunoglobulin A (IgA) antibody was found in the glomerulus of one patient (F16A1578‐II1; Figures 1h–j and 2h–k).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    APOE-Osaka/Kurashiki and APOE-Chicago mutations were reported for the first time in the Chinese population.

    “Here, we report for the first time APOE‐Osaka/Kurashiki and APOE‐Chicago mutations in the Chinese population.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Family history was found in five of the eight LPG patients.

    “Interestingly family history was found in five cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Genetic analysis revealed five patients with APOE-Kyoto, two with APOE-Osaka/Kurashiki, and one with APOE-Chicago mutations.

    “Genetic analysis revealed five patients with APOE‐Kyoto, two with APOE‐Osaka/Kurashiki, and one with APOE‐Chicago mutations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Five LPG patients had heterozygous APOE-Kyoto mutation (chr19-45411100, c.127C>T, p.R43C) which could substitute the amino acid at position 25 from arginine (Arg) to cysteine (Cys).

    “Sequencing of the entire APOE coding region revealed that five patients (F171101‐II4, F17A0528‐II2, F15A1307‐II1, F15A1558‐II1, and F98034‐III1) had heterozygous APOE‐Kyoto mutation (chr19‐45411100, c.127C>T, p.R43C) which could substitute the amino acid at position 25 from arginine (Arg) to cysteine (Cys).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Three of the APOE-Kyoto patients had an APOE genotype of ε3/ε3 and two had ε3/ε4.

    “Three of them had an APOE genotype of ε3/ε3 and two ε3/ε4.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Asymptomatic carriers were found in three families (F171101, F17A0528, and F16A0702), and the penetrance was 54.5% (six patients and five asymptomatic carriers of the three families).

    “Interestingly, we found asymptomatic carriers in three families (F171101, F17A0528, and F16A0702), and the penetrance was 54.5% (six patients and five asymptomatic carriers of the three families; Figures 1a,b and 2a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One LPG patient was detected with heterozygous APOE-Chicago mutation (chr19-45412047, c.494G>C, p.R165P) which could replace Arg by Pro in position 147 at protein level, with a genotype of ε3/ε3.

    “Moreover, one patient (F19A0312‐II4) was detected with heterozygous APOE‐Chicago mutation (chr19‐45412047, c.494G>C, p.R165P) which could replace Arg by Pro in position 147 at protein level, with a genotype of ε3/ε3.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Patients in the high apoE group showed a trend of younger onset age (31.1 ± 19.1 vs. 34.9 ± 14.0 years old, p = .4).

    “Furthermore, although not statistically significant, patients in the high apoE group showed a trend of younger onset age (31.1 ± 19.1 vs. 34.9 ± 14.0 years old, p = .4), higher MAP (106.8 ± 15.1 vs. 101.7 ± 15.6 mmHg, p = .4), higher Upro [ln(Upro): 1.0 ± 0.9 vs. 0.8 ± 1.2 g/24 hr, p = .5], and higher TG levels [ln(TG): 1.1 ± 0.5 vs. 0.9 ± 0.6 mmol/L, p = .2] compared with patients in the low apoE”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Patients in the high apoE group showed higher MAP (106.8 ± 15.1 vs. 101.7 ± 15.6 mmHg, p = .4).

    “Furthermore, although not statistically significant, patients in the high apoE group showed a trend of younger onset age (31.1 ± 19.1 vs. 34.9 ± 14.0 years old, p = .4), higher MAP (106.8 ± 15.1 vs. 101.7 ± 15.6 mmHg, p = .4), higher Upro [ln(Upro): 1.0 ± 0.9 vs. 0.8 ± 1.2 g/24 hr, p = .5], and higher TG levels [ln(TG): 1.1 ± 0.5 vs. 0.9 ± 0.6 mmol/L, p = .2] compared with patients in the low apoE”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patient F171101-II4 stopped fenofibrate therapy because of temporarily elevated serum creatinine or liver enzyme levels; his proteinuria once decreased to 0.4 g/24 hr but increased after he ceased the treatment, as well as his apoE level.

    “Patient F171101‐II4 stopped fenofibrate therapy because of temporarily elevated serum creatinine or liver enzyme levels. His proteinuria once decreased to 0.4 g/24 hr but increased after he ceased the treatment, as well as his apoE level.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two LPG patients had heterozygous APOE-Osaka/Kurashiki mutation (chr19-45412080, c.527G>C, p.R176P) which could substitute the amino acid at position 158 from Arg to proline (Pro).

    “Additionally, two patients (F16A0702‐II2 and F16A1578‐II1) had heterozygous APOE‐Osaka/Kurashiki mutation (chr19‐45412080, c.527G>C, p.R176P) which could substitute the amino acid at position 158 from Arg to proline (Pro).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two LPG patients (F17A0528-II2 and F16A0702-II2) went through plasma exchange or blood lipid adsorption and their Upro and serum lipid levels went down for a while, but shortly after treatment the values returned to baseline.

    “Two of them (F17A0528‐II2 and F16A0702‐II2) went through plasma exchange or blood lipid adsorption and their Upro and serum lipid levels went down for a while. But shortly after the treatment, the values returned to baseline.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Patients in the high apoE group showed higher TG levels [ln(TG): 1.1 ± 0.5 vs. 0.9 ± 0.6 mmol/L, p = .2].

    “Furthermore, although not statistically significant, patients in the high apoE group showed a trend of younger onset age (31.1 ± 19.1 vs. 34.9 ± 14.0 years old, p = .4), higher MAP (106.8 ± 15.1 vs. 101.7 ± 15.6 mmHg, p = .4), higher Upro [ln(Upro): 1.0 ± 0.9 vs. 0.8 ± 1.2 g/24 hr, p = .5], and higher TG levels [ln(TG): 1.1 ± 0.5 vs. 0.9 ± 0.6 mmol/L, p = .2] compared with patients in the low apoE”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The two APOE-Osaka/Kurashiki patients had genotypes of ε3/ε3 and ε3/ε4 respectively.

    “They had genotypes of ε3/ε3 and ε3/ε4 respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Patients in the high apoE group showed higher Upro [ln(Upro): 1.0 ± 0.9 vs. 0.8 ± 1.2 g/24 hr, p = .5].

    “Furthermore, although not statistically significant, patients in the high apoE group showed a trend of younger onset age (31.1 ± 19.1 vs. 34.9 ± 14.0 years old, p = .4), higher MAP (106.8 ± 15.1 vs. 101.7 ± 15.6 mmHg, p = .4), higher Upro [ln(Upro): 1.0 ± 0.9 vs. 0.8 ± 1.2 g/24 hr, p = .5], and higher TG levels [ln(TG): 1.1 ± 0.5 vs. 0.9 ± 0.6 mmol/L, p = .2] compared with patients in the low apoE”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    F16A0702-I2 had normal Upro level at first hospital visit; one year later, when validated she had the APOE-Osaka/Kurashiki mutation, her Upro had reached 2.1 g/24 hr.

    “We screened family members of F16A0702 (Figure 2a) at their first hospital visit and found that F16A0702‐I2 had normal Upro level at that time. One year later, when we validated that she had the APOE‐Osaka/Kurashiki mutation by Sanger sequencing, and her Upro had reached 2.1 g/24 hr.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The literature review included 87 LPG patients and they all had APOE mutations.

    “By inclusion and exclusion criteria, we included 87 LPG patients and they all had APOE mutations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Plasma exchange or blood lipid adsorption was performed in two patients and their Upro and serum lipid levels relieved only for a short time.

    “Meanwhile, plasma exchange or blood lipid adsorption was performed in two patients and their Upro and serum lipid levels relieved only for a short time, so the effect of this treatment was uncertain as reported (Li et al., 2014; , Oikawa, Sato, & Sasaki, 1999).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    One patient received glucocorticoid treatment for more than three years and appeared to have steroid-dependent nephrotic syndrome.

    “Furthermore, one patient received glucocorticoid treatment for more than three years and appeared to have steroid‐dependent nephrotic syndrome.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    APOE has three variants ε2, ε3, and ε4, depending on different amino acids at positions 112 and 158, and APOE ε3 is regarded as the wild type.

    “APOE has three variants ε2, ε3, and ε4, depending on the different amino acids at positions 112 and 158, and the APOE ε3 is regarded as the wild type (Bennet et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bennet et al., 2007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    More than 10 types of LPG-related mutations have been identified in APOE showing autosomal dominant inheritance patterns with incomplete penetrance.

    “More than 10 types of LPG‐related mutations have been identified in APOE showing autosomal dominant inheritance patterns with incomplete penetrance (Matsunaga & Saito, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Matsunaga & Saito, 2014 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Systemic manifestations of type III hyperlipidemia, such as xanthoma, are hardly seen in patients with LPG.

    “The systemic manifestations of type III hyperlipidemia, such as xanthoma, are hardly seen in patients with LPG (Matsunaga & Saito, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Matsunaga & Saito, 2014 source

  • May combine two claims.

    Premisecitation

    Clinical manifestations of LPG patients include mild nephrotic problem initially but later progress to nephrotic syndrome with elevated levels of serum apoE, hyperlipidemia, hypertension and microscopic hematuria.

    “Clinical manifestations of LPG patients include mild nephrotic problem initially but later progress to nephrotic syndrome with elevated levels of serum apolipoprotein E (apoE), hyperlipidemia, hypertension and microscopic hematuria (Hu et al., 2014; Saito & Matsunaga, 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hu et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Saito & Matsunaga, 2014 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One LPG patient (F98034-III1) was lost to follow-up, and the interval of patient F19A0312-II4 from renal biopsy to data collection was too short.

    “One (F98034‐III1) of the six patients was lost to follow‐up, and the interval of patient F19A0312‐II4 from renal biopsy to the data collection was too short.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Sanger sequencing was performed for F171101-II4, F17A0528-II2, F98034-III1 and F16A0702-II2 families to validate the inheritance pattern.

    “Furthermore, Sanger sequencing was performed for F171101‐II4, F17A0528‐II2, F98034‐III1 and F16A0702‐II2 families to validate the inheritance pattern.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Most LPG-related mutations are in or around the LDL receptor binding region of APOE, indicating a mechanistic insight for their roles in the pathogenesis of LPG.

    “Most LPG‐related mutations are in or around the LDL receptor binding region of APOE, indicating the mechanistic insight for their roles in the pathogenesis of LPG (Figure 4).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Written informed consent was obtained from all participants.

    “Written informed consent was obtained from all participants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was approved by the Institutional Review Board of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and was conducted in accordance with the principle of the Helsinki Declaration.

    “The study was approved by the Institutional Review Board of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine and was conducted in accordance with the principle of the Helsinki Declaration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Only three mutations (APOE Okayama/Modena/Guangzhou) were inside the LDL receptor binding region and outside the binding region of HSPG, and they were all at position 150 at the protein level.

    “Only three mutations (APOE Okayama/Modena/Guangzhou) were inside the LDL receptor binding region and outside the binding region of HSPG, and they were all at position 150 at the protein level.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Studies also reported higher blood pressure associated with LPG.

    “Studies also reported such phenomenon (Hu et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hu et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Mutations in APOE could alter the configuration of the APOE protein and further impact its binding ability to the LDL receptor, which could explain the formation of lipoprotein thrombi in the glomerulus.

    “As serum apoE plays its role in lipid metabolism through the LDL receptor, the HSPG and LDL receptor‐related protein (LRP) pathway (Mahley & Rall Jr., 2000), mutations could alter the configuration of the APOE protein and further impact its binding ability to LDL receptor, which could explain the formation of lipoprotein thrombi in the glomerulus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mahley & Rall Jr., 2000 source
    • Rests on an assumption: LPG is an APOE-related disorder.

  • May combine two claims.

    Premisecitation

    Fibrates and ACEI/ARB may be effective for LPG remission.

    “Though no effective treatment has been established, fibrates and ACEI/ARB may be effective for LPG remission (Arai et al., 2003; Ieiri, Hotta, & Taguma, 2003; Matsunaga et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Arai et al., 2003 source
    • cites Ieiri, Hotta, & Taguma, 2003 source
    • cites Matsunaga et al., 2009 source

  • May combine two claims.

    Interpretationreasoning

    The three mutations (APOE Okayama/Modena/Guangzhou) change the APOE three-dimensional structure and lead to the disease.

    “These results indicate that the three mutations change the APOE three‐dimensional structure and lead to the disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The APOE mutations identified in LPG patients are pathogenic.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Literature review found mutations in different domains of APOE (within or out of the LDL receptor binding region) led to different serum apoE levels.

    “Furthermore, literature review found mutations in different domains of APOE (within or out of the LDL receptor binding region) led to different serum apoE levels.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Our study showed the essentiality of genetic testing for LPG.

    “Our study showed the essentiality of genetic testing for LPG.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: LPG is an APOE-related disorder.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study did not carry out functional studies to reveal the mechanisms of these mutations.

    “Finally, we did not carry out functional studies to reveal the mechanisms of these mutations.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    Few studies have dealt with the relation between genotypes and phenotypes in LPG.

    “However, few studies have dealt with the relation between genotypes and phenotypes.”

  • The paper relies on this without support.

    APOE includes an LDL receptor binding region (amino acids 136–150) and an HSPG binding region (amino acids 142–147) in the N-terminal domain.

    “APOE is a ligand for the low‐density lipoprotein (LDL) receptor, heparan sulphate proteoglycan (HSPG) and LDL receptor‐related protein and it includes an LDL receptor binding region (amino acids 136–150) and a HSPG binding region (amino acids 142–147) in the N‐terminal domain.”

  • The paper relies on this without support.

    LPG is an APOE-related disorder.

    “Although LPG is one of apoE related lipoprotein disorders, it affects predominantly in kidney and the histological features are dilated glomerular capillaries with lipoprotein thrombi.”
    “By genetic testing, several pathogenic APOE mutations of LPG have been reported.”

  • The paper relies on this without support.

    The APOE mutations identified in LPG patients are pathogenic.

    “By genetic testing, several pathogenic APOE mutations of LPG have been reported.”
    “By Sanger sequencing of APOE, we found three APOE mutations including APOE‐Kyoto (R25C), APOE‐Osaka/Kurashiki (R158P) and APOE‐Chicago (R147P).”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Patients with LPG with mutations in the LDL receptor binding region have relatively high blood pressure and serum ApoE levels.

    “patients with LPG with mutations in the LDL receptor binding region were reported to have relatively high blood pressure and serum ApoE levels [12].”

    From Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice (2021) · cites this paper as [12]

    The Results (Literature review; page unavailable) report higher serum apoE in LPG patients with LDL receptor binding-region mutations than in patients with mutations elsewhere. They also report higher blood pressure for LPG patients overall than for controls, but do not establish higher blood pressure specifically for the binding-region subgroup. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Only five cases harboring the Osaka/Kurashiki APOE variant have been described so far.

    “Only five cases harboring the Osaka/Kurashaki variant have been described so far (Table 2) [8–11].”

    From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [10]

    The Results > Genotyping section reports two patients with the APOE-Osaka/Kurashiki variant, establishing that this paper describes cases with the variant. It does not state that only five cases had been described overall; the five patients counted in that section had the different APOE-Kyoto variant. No page number is available in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The APOE mutation NM_000041.4:c.494G>C (p.Arg165Pro) is in exon 4 of APOE and is known as APOE Chicago mutation.

    “which is in the exon 4 of the APOE gene and also known as APOE Chicago mutation, a rare mutation of LPG.”

    From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [9]

    The Results (Genotyping; page unavailable) identify c.494G>C (p.R165P) as the APOE-Chicago mutation in a patient with lipoprotein glomerulopathy. The Methods (Sanger sequencing; page unavailable) say the authors sequenced APOE’s four exons using reference sequence NM_000041.4, but our copy does not specify that this mutation is in exon 4. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The APOE Chicago mutation has only been reported in five patients/families so far.

    “which has only been reported in five patients/families so far and their characteristics are summarized in Table 1.”

    From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [9]

    The Discussion (page unavailable) describes APOE-Chicago in a Mexican-American patient, a Japanese patient, and, for the first time in China, a patient in this study. The Results > Genotyping section (page unavailable) identifies one Chicago patient; its count of five refers to APOE-Kyoto, not Chicago. The source supports that Chicago was rarely reported, but not the claimed count of five patients or families. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The study could not correctly assess the influence of environmental factors and modifier genes on penetrance of APOE mutations.

    “Meanwhile, it also prevents the correct and comprehensive assessment of the influence of environmental factors and modifier genes on the penetrance of APOE mutations9,18, 19, 20, 21”

    From The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility (2026) · cites this paper as [21]

    The Results (Genotyping; page unavailable) report asymptomatic APOE mutation carriers and 54.5% penetrance. The Discussion (page unavailable) suggests additional factors may be involved and acknowledges that sequencing only APOE could have missed mutations in other genes. It does not specifically say that the study could not assess environmental factors or the effects of modifier genes on penetrance. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • HSPG binding region has two different boundaries

    Minor

    The region is defined as amino acids 142-147 in the Introduction and Figure 4, but as 142-146 in the Results.

  • Abstract reverses the renal-function results for the remission groups

    Minor

    The abstract assigns −5.0 to patients whose urine protein fell by more than 50%, but the Results section assigns 1.5 to that partial-remission group and −5.0 to the nonremission group. This reverses the values supporting the stated conclusion about slower renal-function decline.

2 of 2

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Authors
Yang, M., Weng, Q., Pan, X., Hussain, H. M. J., Yu, S., Xu, J., Yu, X., Liu, Y., Jin, Y., Zhang, C., Li, X., Ren, H., Chen, N., & Xie, J.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
Xie, Jingyuan
ORCID
Venue
Molecular Genetics & Genomic Medicine
Publisher
Wiley
Published
2020-05-22
Volume
8
Issue
8
Pages
e1281-e1281
ISSN
2324-9269 (ISSN-L)
DOI
10.1002/mgg3.1281
PMC
PMC7434605
OpenAlex
W3028515002
Cited by
15
References
34
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 5
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Genetics & Genomic Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81370015, 81570598, 81870460)
Topics
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
lipoprotein glomerulopathy, proteinuria, estimated glomerular filtration rate decline, blood pressure, renal function progression, Chinese patients
MeSH terms
Adolescent, Adult, Apolipoproteins E, Blood Pressure, Female, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Middle Aged, Mutation, Pedigree

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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