Identification of a founder haplotype of APOE Kyoto variant in lipoprotein glomerulopathy
Open accessAbstract
Background: Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant inherited kidney disease with incomplete penetrance, characterized by nephrotic-range proteinuria, hypertriglyceridemia and progressive renal dysfunction with elevated serum apoE level. More than 15 APOE mutations have been associated with LPG, with APOE Kyoto (Arg43Cys) the leading mutation in about 200 patients. We previously observed clustering of “APOE Kyoto causing LPG” in a Han population in China. We now explore the haplotype of the APOE Kyoto heterozygotes and the distribution of LPG patients in China. Methods: A total of 115 APOE Kyoto heterozygotes were enrolled and identified by Sanger sequencing, and in this study, the haplotypes of Kyoto and counterpart alleles were investigated by TA cloning and Sanger sequencing. Results: Overall, 114 out of 115 APOE Kyoto alleles shared an identical haplotype, likely from haplotype 1 in ε3. Among heterozygotes, the counterpart of APOE Kyoto allele showed haplotype diversity, and the difference in haplotype distribution of the counterpart allele was not observed between LPG patients and asymptomatic carriers. Conclusions: This study provides further evidence for the founder effect of APOE Kyoto may play a critical role in the progression of LPG.
AI snapshot
Written from the paper’s full text.
TL;DR
In 115 APOE Kyoto heterozygotes from 68 unrelated Han families, 114 of 115 APOE Kyoto alleles shared an identical haplotype, likely derived from haplotype 1 of ε3, supporting a founder effect. The counterpart APOE allele showed haplotype diversity but did not differ between LPG patients and asymptomatic carriers.
Key findings
- Among 115 APOE Kyoto heterozygotes, 114/115 APOE Kyoto alleles shared the same haplotype, likely from haplotype 1 of ε3; only one allele (F9II1) had a different haplotype, likely from haplotype 5 of ε4.
- In 61 LPG patients versus 54 asymptomatic carriers, the counterpart APOE haplotype distribution did not differ; haplotype 1 of ε3 was the most common counterpart haplotype (31 LPG patients, 30 asymptomatic carriers).
- Genotype distribution was similar: 46/61 LPG patients and 44/54 asymptomatic carriers had ε3/ε3; LPG allele frequencies were ε2 0.8%, ε3 87.7%, ε4 11.5%, versus asymptomatic carriers ε2 0.9%, ε3 89.8%, ε4 9.3%.
- In China, approximately 348 LPG cases were reported from 24 provinces/municipalities; among 184 Chinese LPG patients with APOE variants, 145 had APOE Kyoto, concentrated in Sichuan (128 cases).
Methods
- Recruited 115 APOE Kyoto heterozygotes from 68 unrelated Han families; probands were diagnosed with LPG by renal biopsy.
- Identified APOE Kyoto by Sanger sequencing and performed APOE haplotyping by long-PCR/TA cloning and Sanger sequencing using 23 SNPs described by Fullerton et al. plus one SNP at the APOE Kyoto site.
- Compared haplotype and genotype distributions between LPG patients and asymptomatic carriers using SPSS 19.0 with Pearson’s chi-square test with Yates’s correction; also reviewed PubMed and Chinese journal databases to classify reported Chinese LPG cases by native place.
Limitations
- Stated: more haplotype studies are required to test whether APOE Kyoto may originate from multiple lines and whether c.C127 is a hotspot; further study is required to clarify LPG pathogenesis, including other genetic and/or epigenetic factors.
- Stated: some LPG cases may have been repetitively reported by different hospitals.
- Evident from the text: the haplotype analysis is confined to APOE Kyoto heterozygotes from one Sichuan county/region, and the nationwide case review contains many entries with “no data” for APOE mutation or native place, limiting generalizability and prevalence estimates.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
4 of 13 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Findingown data
APOE Maebashi mutation was concentrated in the northern part of China.
“APOE Maebashi mutation was concentrated in the northern of China.”
Quote in the paperNot a substantial claim - Findingown data
LPG in China presented mainly in the Yangtze River Valley and coastal region.
“we found that LPG presented mainly in the Yangtze River Valley and coastal region.”
- Also stated in: § DISCUSSION · plain
“As shown in Table 2, LPG patients in China were mostly reported in the Yangtze River and coastal areas.”
Quote in the paperNot a substantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
The difference in haplotype distribution of the counterpart APOE allele was not observed between LPG patients and asymptomatic carriers.
“the difference in haplotype distribution of the counterpart allele was not observed between LPG patients and asymptomatic carriers.”
- Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · plain
“In addition, the difference in haplotype distribution was not observed between “APOE Kyoto causing LPG” patients and asymptomatic carriers (Fig. 3B and C).”
Quote in the paperSubstantial claim - Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · plain
- Findingown data
The difference in APOE genotype and allele frequency between LPG patients and asymptomatic carriers was not observed.
“The difference of APOE genotype and allele frequency between LPG patients and asymptomatic carriers was not observed.”
Quote in the paperSubstantial claim - Findingown data
The Sichuan basin hosts most of the clustering LPG patients.
“The Sichuan basin, located in the upper stream region of Yangtze River, hosts most of the clustering LPG patients.”
- Also stated in: § DISCUSSION · plain
“The Sichuan basin, located upstream of the Yangtze River, was the most concentrated area of LPG patients and APOE Kyoto.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
Among APOE Kyoto heterozygotes, the counterpart APOE allele showed haplotype diversity.
“Among heterozygotes, the counterpart of APOE Kyoto allele showed haplotype diversity”
- Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · plain
“As shown in Table 1, haplotype 1 of ε3 was observed to be a common haplotype of the counterpart allele and existed in 31 LPG patients and 30 asymptomatic carriers, followed by the haplotype 2 of APOE3 and haplotype 5 of APOE4. Other haplotypes were present in only individual cases.”
Quote in the paperNot a substantial claim - Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · plain
- Interpretationown data
The identification of a carrier with APOE Kyoto from haplotype 5 in ε4 provides evidence that APOE Kyoto may originate from multiple lines.
“On the other hand, the identification of the carrier with APOE Kyoto from haplotype 5 in ε4 provided evidence that APOE Kyoto may originate from multiple lines”
Quote in the paperSubstantial claim - Interpretationreasoning
The geographical distributions of LPG patients and APOE Kyoto mutation suggest that APOE Kyoto may have spread from Sichuan along the Yangtze River.
“The geographical distributions of LPG patients and APOE Kyoto mutation suggest that APOE Kyoto may have spread from Sichuan along the Yangtze River.”
- Also stated in: § DISCUSSION · hedged
“APOE Kyoto may have spread along this route.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · hedged
- Interpretationown data
The founder effect of APOE Kyoto may play a critical role in the progression of LPG.
“This study provides further evidence for the founder effect of APOE Kyoto may play a critical role in the progression of LPG.”
- Also stated in: § Conclusions · hedged
“The founder effect of APOE Kyoto may play a critical role in the progression of LPG.”
Quote in the paperNot a substantial claim - Also stated in: § Conclusions · hedged
- Interpretationreasoning
The c.C127 locus could be a hot spot for the APOE Kyoto mutation.
“and the c.C127 locus could be a hot spot.”
Quote in the paperNot a substantial claim- Rests on an assumption: The c.127C>T mutation in APOE Kyoto leads to amino acid substitution of Cys (TGC) to Arg (CGC) at codon 43.
- Interpretationown data
The APOE Kyoto variant in this Han population exhibits a founder effect.
“This study provides further evidence for the founder effect of APOE Kyoto may play a critical role in the progression of LPG.”
- Also stated in: § DISCUSSION · hedged
“A founder effect was therefore assumed.”
- Also stated in: § DISCUSSION · boosted
“In conclusion, we provide further evidence for the pathogenic founder variant of APOE Kyoto in a Han population with lipoprotein glomerulopathy among the Sichuan basin.”
Quote in the paperSubstantial claim- The authors state this as an assumption: APOE Kyoto carriers survived the historical population decline in Sichuan, preserving a high allele frequency, which was a critical factor for the founder effect.
- Also stated in: § DISCUSSION · hedged
- Interpretationown data
The counterpart APOE allele is not associated with the pathogenesis of LPG.
“These results suggest that the counterpart APOE allele is not associated with pathogenesis.”
- Also stated in: § DISCUSSION · hedged
“In addition, the counterpart allele function may not influence the penetrance of APOE Kyoto.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · hedged
- Premisecitation
The APOE Kyoto mutation site is located outside the LDLR binding region (136-150).
“APOE Kyoto is a common LPG mutation, and the mutation site is located outside the LDLR binding region (136–150) [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Saito, 2014, Topics in lipoprotein glomerulopathy: an overview, Clin Exp Nephrol source
- Interpretationreasoning
The low LDLR binding and thermodynamic instability may be a common mechanism underlying APOE mutations associated with lipoprotein glomerulopathy.
“which may be a common mechanism underlying the APOE mutations associated with lipoprotein glomerulopathy.”
Quote in the paperSubstantial claim - Premisecitation
The authors previously observed clustering of APOE Kyoto-causing LPG in a Han population in China.
“We previously observed clustering of “APOE Kyoto causing LPG” in a Han population in China.”
- Also stated in: § INTRODUCTION · plain
“In 2014, we reported the largest group of “APOE Kyoto causing LPG” patients living in a small, fairly isolated county of Sichuan, a basin in Southwest China [7].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Hu, 2014, Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation, Kidney Int source
- Also stated in: § INTRODUCTION · plain
- Classified as probably not a substantial claim. 3
- May combine two claims. 15
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe c.C127 is located in a CpG dinucleotide and can be methylated at the 5 carbon, yielding 5-methylcytosine, and deaminated to produce thymine.
“The c.C127 is located in the CpG dinucleotide and can be methylated at the 5 carbon, yielding 5-methylcytosine, and deaminated to produce thymine [25].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Frommer, 1992, A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands, Proc Natl Acad Sci USA source
The paper’s method description (p. 1827) discusses 5-methylcytosine and tests methylation at CpG dinucleotides. It does not identify c.C127 or state that 5-methylcytosine deaminates to thymine; its thymine result instead concerns PCR amplification after bisulfite converts unmethylated cytosine to uracil. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe APOE Kyoto mutation exhibits marked thermodynamic instability and a higher propensity for polymerization compared with wild-type, likely due to an unstable alpha-helical structure.
“Additionally, the APOE Kyoto mutation exhibited marked thermodynamic instability and a higher propensity for polymerization compared with the wild-type, likely due to an unstable alpha-helical structure [29].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [29] Katsarou, 2018, Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy, J Lipid Res source
May combine two claims.
PremisecitationAPOE Kyoto has been distributed worldwide, not only among Asians in China and Japan, but also among Caucasians in Europe and the USA.
“Furthermore, APOE Kyoto has been distributed worldwide, not only among Asians in China and Japan, but also among Caucasians in Europe and the USA [5, 16, 26].”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [5] Batal, 2019, Unusual case of lipoprotein glomerulopathy first diagnosed in a protocol kidney allograft biopsy, Kidney Int Rep source
The Case Presentation (Follow-up; page unavailable) identifies APOE Kyoto in a European-American patient, and the Introduction says most lipoprotein glomerulopathy cases were reported in East Asia, with a few in the United States. The paper does not report APOE Kyoto in people living in Europe, so it does not establish the full geographic distribution claimed. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [16] Saito, 2014, Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis, Kidney Int source
- cites [26] Rovin, 2007, APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy, N Engl J Med source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMore than 15 APOE mutations, or eighteen APOE variants, have been associated with LPG.
“More than 15 APOE mutations have been associated with LPG”
- Also stated in: § INTRODUCTION · plain
“Eighteen APOE variants have been associated with LPG since the first variant was identified in 1997 [1, 13, 15].”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [1] Saito, 2014, Topics in lipoprotein glomerulopathy: an overview, Clin Exp Nephrol source
- cites [13] Wu, 2018, The novel apolipoprotein E mutation ApoE Chengdu (c.518TC, p.L173P) in a Chinese patient with lipoprotein glomerulopathy, J Atheroscler Thromb source
- cites [15] Oikawa, 1997, Apolipoprotein E Sendai (arginine 145–>proline): a new variant associated with lipoprotein glomerulopathy, J Am Soc Nephrol source
- Also stated in: § INTRODUCTION · plain
May combine two claims.
Findingown dataThe ε3/ε3 genotype was common among APOE Kyoto heterozygotes, including 46 of 61 LPG patients and 44 of 54 asymptomatic carriers.
“Further analysis showed 46 out of 61 LPG patients presented ε3/ε3 genotype, 14 with ε4/ε3, 1 with ε2/ε3”
- Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · plain
“In addition, 44 out of 54 asymptomatic carriers presented ε3/ε3 genotype, 8 with ε4/ε3, 1 with ε4/ε4, and 1 with ε2/ε3”
- Also stated in: § Conclusions · plain
“ε3/ε3 genotype was common among APOE Kyoto heterozygotes.”
Quote in the paperSubstantial claim- Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenApproximately 348 LPG cases have been reported from 24 provinces and municipalities in China.
“To date, approximately 348 LPG cases have been reported from 24 provinces and municipalities in China, as shown in Table 2”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmong 115 APOE Kyoto heterozygotes from 68 unrelated Han families, 114 of 115 APOE Kyoto alleles shared an identical haplotype, likely derived from haplotype 1 of ε3.
“Overall, 114 out of 115 APOE Kyoto alleles shared an identical haplotype, likely from haplotype 1 in ε3.”
- Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · hedged
“The results showed that 114 out of 115 APOE Kyoto alleles shared the identical haplotype, likely derived from haplotype 1 of ε3.”
Quote in the paperSubstantial claim- Also stated in: § Presence of common origin in the majority of APOE Kyoto alleles · hedged
May combine two claims.
Findingown dataAPOE Kyoto was reported nationwide and concentrated in Sichuan (128 cases), with neighboring regions (Chongqing and Hubei) having three cases.
“APOE Kyoto was reported nationwide and concentrated in Sichuan (128 cases), with neighboring regions (Chongqing and Hubei) having three cases.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataA total of 15 LPG-related APOE variants were reported in 184 Chinese patients with LPG, including 145 with APOE Kyoto, 10 with APOE Maebashi, 4 with APOE Osaka/Kurashiki, 4 with APOE Guangzhou, 5 with APOE Tokyo and 3 with the APOE deletion mutation (p.161_163delKLR).
“A total of 15 LPG-related APOE variants were reported in 184 Chinese patients with LPG, including 145 with APOE Kyoto, 10 with APOE Maebashi, 4 with APOE Osaka/Kurashiki, 4 with APOE Guangzhou, 5 with APOE Tokyo and 3 with the APOE deletion mutation (p.161_163delKLR).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOnly one APOE Kyoto allele (F9II1) had a different haplotype, likely derived from haplotype 5 of ε4.
“Only one APOE Kyoto allele (F9II1) had a different haplotype, likely derived from haplotype 5 of ε4.”
- Also stated in: § DISCUSSION · hedged
“Only one asymptomatic carrier had a different APOE Kyoto haplotype, likely derived from haplotype 5 of ε4.”
Quote in the paperSubstantial claim- Also stated in: § DISCUSSION · hedged
May combine two claims.
InterpretationreasoningThe thermodynamic instability of mutant APOE proteins promotes their deposition, leading to accumulation of apoE-rich lipoprotein thrombi in dilated capillary loops.
“Furthermore, the thermodynamic instability of the mutant proteins promotes their deposition, leading to the accumulation of apoE-rich lipoprotein thrombi in dilated capillary loops”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe APOE Kyoto mutation probably existed historically for a longer time and in more expansive areas within China.
“Although APOE Kyoto carriers in the Sichuan basin represent the largest clustering group, the mutation probably existed historically for longer time and in more expansive areas within China.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationThe low LDLR binding ability of mutant ApoE may lead to impaired clearance of apoE-rich lipoproteins, resulting in hyperlipidemia.
“These findings suggested that the low LDLR binding ability of mutant ApoE may lead to impaired clearance of apoE-rich lipoproteins, resulting in hyperlipidemia.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMutant apoE can exhibit reduced LDLR binding ability and high endothelial affinity compared with wild-type apoE3.
“Studies have shown that the mutant apoE could exhibit reduced LDLR binding ability and high endothelial affinity compared with wild-type apoE3 [28].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Matsunaga, 1999, A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy, Kidney Int source
May combine two claims.
InterpretationcitationAPOE Kyoto carriers in whom the disease develops may have a second defect that reduces clearance of abnormal lipoprotein through pathways independent of the LDL receptor, allowing excessive accumulation of thrombi and the development of clinical kidney disease.
“Rovin et al. [26] reported that the glomerular lipoprotein deposition could be seen in renal biopsy of asymptomatic carrier, which suggested that APOE Kyoto carriers in whom the disease develops may have a second defect that reduces clearance of abnormal lipoprotein through pathways that are independent of the LDL receptor, which allows for excessive accumulation of thrombi and the development of”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Rovin, 2007, APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy, N Engl J Med source
May combine two claims.
PremisecitationAPOE Kyoto is the leading mutation in about 200 patients and is the most common APOE variant worldwide.
“with APOE Kyoto (Arg43Cys) the leading mutation in about 200 patients.”
- Also stated in: § INTRODUCTION · plain
“Among these variants, APOE Kyoto (Arg43Cys) is most common worldwide [16].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Saito, 2014, Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis, Kidney Int source
- Also stated in: § INTRODUCTION · plain
The authors state this as an assumption.
APOE Kyoto carriers survived the historical population decline in Sichuan, preserving a high allele frequency, which was a critical factor for the founder effect.
“It was assumed that APOE Kyoto carriers survived the huge population decline, preserving high allele frequency, which was a critical factor for the founder effect.”
The paper relies on this without support.
The c.127C>T mutation in APOE Kyoto leads to amino acid substitution of Cys (TGC) to Arg (CGC) at codon 43.
“The c.127C>T mutation in APOE Kyoto leads to amino acid substitution of Cys (TGC) to Arg (CGC) at codon 43.”
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.
APOE Kyoto amino-acid substitution is stated in opposite directions
MinorThe discussion says the mutation changes cysteine to arginine, whereas Arg43Cys denotes a change from arginine to cysteine. The codons printed in the discussion also support the latter direction for a C>T mutation.
“The c.127C>T mutation in APOE Kyoto leads to amino acid substitution of Cys (TGC) to Arg (CGC) at codon 43.”
“APOE Kyoto (Arg43Cys)”
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Flagged first, then by citations
Research works printed but not linked: 1
- Zizhong county Annals compilation committee, sichuan province, 1997, Zizhong Annals
Cited by
Still being checked.
- Authors
- Wu, H., He, Z., Yang, J., Zhou, Y., Yang, Z., Hu, Z., & Yang, Y.
- Affiliations
- Sichuan University (CN)
- Corresponding author
- Yang, Jing
- Hu, Zhangxue
- Venue
- Clinical Kidney Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-07-21
- Volume
- 18
- Issue
- 8
- Pages
- sfaf234-sfaf234
- ISSN
- 2048-8505 (ISSN-L)
- 2048-8513
- PMC
- PMC12343104
- OpenAlex
- W4412872280
- Semantic Scholar
- 6cf5a937eab7825e9e78b142a11c854d5243f2b9
- Cited by
- 0
- References
- 28
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Clinical Kidney Journal (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (82300813)
- National Key Research and Development Program of China (2021YFC2501302)
- West China Hospital, Sichuan University (zyjc21018)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- lipoprotein glomerulopathy, founder effect, founder haplotype, APOE haplotypes, heterozygotes, nephrotic-range proteinuria, Han Chinese, carrier distribution
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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