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International Journal of Molecular... May 2024Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid... (Meta-Analysis)
Meta-Analysis Review
The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.
Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.
Topics: Humans; Inflammatory Bowel Diseases; Psoriasis; Polymorphism, Single Nucleotide; Biological Products; Arthritis, Rheumatoid; Arthritis, Psoriatic; NLR Family, Pyrin Domain-Containing 3 Protein; Myeloid Differentiation Factor 88
PubMed: 38891983
DOI: 10.3390/ijms25115793 -
European Review For Medical and... May 2024Periimplantitis (PI) is a complex multifactorial chronic disease caused by interactions between bacteria, host immune-inflammatory responses, and genetic or... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Periimplantitis (PI) is a complex multifactorial chronic disease caused by interactions between bacteria, host immune-inflammatory responses, and genetic or environmental factors that modify buccal eutrophism. In daily clinical practice, an increase in the prevalence of PI (8%) determined the need to establish the PI causes and set optimal therapeutic strategies. The interleukin family (IL-1), a group of cytokines, triggers and perpetuates peri-implantitis. Therefore, they could be used as biomarkers for diagnosis and treatment. This systematic review aimed to analyze the correlation between IL-1 allelic polymorphism (IL-1A -889, IL-1β -511, IL-1β +3954) and the PI disease.
MATERIALS AND METHODS
Selected databases were PubMed, Scopus, and Cochrane Library. The search strategy included the following terms: "dental implants"; "periimplantitis"; "interleukin-IL-1"; "polymorphism"; "perimplant bone loss". Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A meta-analysis was conducted on five of 40 review articles. p-values, confidence intervals (CI), and Odds ratios (OR) were assessed. In 4 articles, the p-value was lower than 0.05, confirming the statistical significance of the result.
RESULTS
The prevalence of the selected studies reported the existence of a causal association between polymorphisms of IL-1 and the onset of peri-implantitis, especially for IL-1 allelic variants associated with further polymorphic genes encoding for IL-6, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinases (MMP)-8, IL-1Na, IL-8, IL-18, osteopontin (OPN). In addition, the presence of the IL-1 polymorphism and PI is particularly higher in smokers, diabetes, and autoimmune disease patients.
CONCLUSIONS
The detection of salivary biomarkers is, therefore, a diagnostic tool with a high potential to intercept the PI early and act with appropriate and non-invasive treatment. Due to the continued technological innovation in biomarkers and diagnostic sciences, further studies are needed to investigate the role of these biochemical mediators. The results of studies and the recent technological innovation in biomarkers and diagnostic sciences will allow further research to investigate the role of these biochemical mediators.
Topics: Humans; Peri-Implantitis; Polymorphism, Genetic; Interleukin-1; Dental Implants
PubMed: 38856132
DOI: 10.26355/eurrev_202405_36293 -
Technology in Cancer Research &... 2024Exploring the relationship between the hOGG1 rs1052133 polymorphism and the occurrence of nasopharyngeal carcinoma (NPC). PubMed, Web of Science, Scopus, CNKI,... (Meta-Analysis)
Meta-Analysis
Exploring the relationship between the hOGG1 rs1052133 polymorphism and the occurrence of nasopharyngeal carcinoma (NPC). PubMed, Web of Science, Scopus, CNKI, Wanfangdata, and VIP were used to search for studies and the NOS evaluation scale was used to evaluate the quality. All studies were grouped according to different genotypes. The Cochrane's Q test and I test were used for heterogeneity evaluations. If heterogeneity was small, the fixed effects model was used, and conversely, the random effects model was used. Publication bias was also detected. P < .05 in all results indicated statistically significant. We ultimately included 6 studies with 2021 NPC patients in the study group and 2375 healthy populations in the control group. After meta-analysis, it was found that the total OR value of the "Ser/Cys (CG) vs Ser/Ser (CC)" group was 1.00 (95% CI: 0.85-1.18) and the "Cys/Cys (GG) vs Ser/Ser (CC)" group was 1.06 (95% CI: 0.87-1.28). These results were not statistically significant (P > .05). Furthermore, the integrated total OR values of each group were not statistically significant with or without the smoking history, even in other genotype models (Allele, Dominant, Recessive, and Additive) (P > .05). There is no clear correlation between the hOGG1 rs1052133 polymorphism and the occurrence of NPC, even with or without the smoking history.
Topics: Humans; Nasopharyngeal Carcinoma; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; DNA Glycosylases; Genotype; Alleles; Nasopharyngeal Neoplasms; Odds Ratio; Genetic Association Studies; Publication Bias; Case-Control Studies
PubMed: 38836311
DOI: 10.1177/15330338241246457 -
BMC Pregnancy and Childbirth May 2024The causes of infertility have remained an important challenge. The relationship between VDR gene polymorphisms and infertility has been reported, with controversial... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The causes of infertility have remained an important challenge. The relationship between VDR gene polymorphisms and infertility has been reported, with controversial findings.
OBJECTIVE AND RATIONALE
We aimed to determine this relationship by conducting a systematic review and meta-analysis.
SEARCH METHODS
The study was started with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration and the final draft was registered as a protocol in PROSPERO (ID: CRD42023416535). The international electronic databases including PubMed (Medline), Scopus, Web of Sciences, and Cumulative Index to Nursing and Allied Health Literature (CINHAL) were searched until January 30, 2023, by using appropriate keywords. The quality of the final studies was assessed using the NOS Checklist for case-control studies. The odds ratios (ORs) for each of the genetic models were pooled, and a subgroup analysis based on geographical region and types of infertility was carried out by the MetaGenyo online tool.
OUTCOMES
Case-control studies including 18 and 2 studies about infertility in women and men, respectively, and 4 miscarriage studies were entered into the meta-analysis. The VDR gene TaqI polymorphism was associated with infertility susceptibility in women in the allele contrast [OR = 1.2065, 95% CI (1.0846-1.3421); P = 0.0005], Recessive model [OR = 1.3836, 95% CI (1.1197-1.7096); P = 0.002], Dominant model [OR = 1.2146, 95% CI (0.0484-1.4072); P = 0.009], Homozygote [OR = 1.4596, 95% CI (1.1627-1.8325); P = 0.001], and TT vs. Tt [OR = 1.2853, 95% CI (1.0249-1.6117); P = 0.029. ApaI and FokI gene polymorphisms were found to be significantly protective SNPs against women and men infertility in the Dominant model [OR = 0.8379, 95% CI (0.7039- 0.9975); P = 0.046] and Recessive model [OR = 0.421, 95% CI (0.1821-0.9767); P = 0.043], respectively. Sub-group meta-analysis showed a protection association of ApaI in dominant [OR = 0.7738, 95% CI = 0.6249-0.9580; P = 0.018] and AA vs. aa [OR = 0.7404, 95 CI% (0.5860-0.9353) P = 0.011725] models in PCOS subgroup, however, a negative association with idiopathic infertility was found in AA vs. Aa [OR = 1.7063, 95% CI (1.1039-2.6375); P = 0.016187] and Aa vs. aa [OR = 0.6069, 95% CI (0.3761-0.9792); P = 0.040754]. TaqI SNP was significantly associated with infertility in the African population and BsmI was associated with the disease mostly in the Asian population.
CONCLUSION
This meta-analysis showed that the TaqI polymorphism may be linked to women's infertility susceptibility. However, ApaI and FokI might be the protective SNPs against infertility in Women and men, respectively.
Topics: Humans; Receptors, Calcitriol; Female; Genetic Predisposition to Disease; Male; Polymorphism, Genetic; Infertility, Female; Case-Control Studies; Infertility; Infertility, Male
PubMed: 38816754
DOI: 10.1186/s12884-024-06590-0 -
Experimental and Therapeutic Medicine Jul 2024To investigate the association of gene polymorphisms of TNF-α-308G/A rs1800629 with the susceptibility and severity of rheumatoid arthritis (RA), literature from...
Evaluation of genetic polymorphisms in TNF‑α‑308G/A rs1800629 associated with susceptibility and severity of rheumatoid arthritis: A systematic review and meta‑analysis.
To investigate the association of gene polymorphisms of TNF-α-308G/A rs1800629 with the susceptibility and severity of rheumatoid arthritis (RA), literature from PubMed, EMBASE, Web of Science and CNKI databases was searched. Two authors screened the literature independently, extracted data and evaluated the risk of bias of the included studies. According to the inclusion and exclusion criteria, five genetic models were established: The allelic model (A vs. G), dominant model (GA + AA vs. GG), recessive model (AA vs. GG + GA), co-dominant model (AA vs. GG) and super-dominant model (GG + AA vs. GA). Stata 17.0 software was used for the meta-analysis. A total of 34 eligible studies with 12,611 subjects were included, including 6,030 cases in the RA group and 6,581 controls. Meta-analysis calculations revealed that the genetic polymorphisms of TNF-α-308G/A rs1800629 were not significantly associated with susceptibility to RA, with an odds ratio and 95% confidence interval (CI) for each genetic model [A vs. G: 0.937 (0.762-1.152); GA + AA vs. GG: 0.918 (0.733-1.148); AA vs. GG + GA: 1.131 (0.709-1.802); AA vs. GG: 1.097 (0.664-1.813); and GG + AA vs. GA: 1.108 (0.894-1.373)]. For the association between TNF-α-308G/A rs1800629 gene polymorphisms and the severity of RA, the results of subgroup analysis calculations showed that TNF-α-308G/A rs1800629 gene polymorphisms were associated with the severity of RA in European populations, with the gene model and 95% CI [GA + AA vs. GG: 0.503 (0.297-0.853); and GG + AA vs. GA: 2.268 (1.434-3.590)]. When assessing the confidence in the positive results of the present study through the false-positive report probability, the positive results were observed to be reliable. No significant association was observed between genetic polymorphisms in TNF-α-308G/A rs1800629 and susceptibility to RA. However, a significant association exists with the severity of RA in European populations.
PubMed: 38800041
DOI: 10.3892/etm.2024.12567 -
F1000Research 2024Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains inconsistent. This study examines knee OA risk and ACE gene I/D polymorphism.
METHODS
We explored Europe PMC, Medline, Scopus, and Cochrane Library using keywords. Three assessment bias factors were assessed using the Newcastle-Ottawa Scale (NOS). Criteria for inclusion: (1) Split the study population into knee OA patients and healthy controls; (2) Analysed the ACE gene I/D polymorphism; (3) Case-control or cross-sectional surveys. Studies with non-knee OA, incomplete data, and no full-text were excluded. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using random-effect models.
RESULTS
A total of 6 case-control studies consist of 1,226 patients with knee OA and 1,145 healthy subjects as controls were included. Our pooled analysis revealed that a significant association between ACE gene I/D polymorphism and risk of knee OA was only seen in the dominant (DD + ID vs. II) [OR 1.69 (95% CI 1.14 - 2.50), p = 0.009, I2 = 72%], and ID vs. II [OR 1.37 (95% CI 1.01- 1.86), p = 0.04, I2 = 43%] genotype models. Other genotype models, including recessive (DD vs. ID + II), alleles (D vs. I), DD vs. ID, and DD vs. II models did not show a significant association with knee OA risk. Further regression analysis revealed that ethnicity and sex may influence those relationships in several genotype models.
CONCLUSIONS
Dominant and ID vs. II ACE gene I/D polymorphism models increased knee OA risk significantly. More research with larger samples and different ethnic groups is needed to confirm our findings. After ethnicity subgroup analysis, some genetic models in our study showed significant heterogeneities, and most studies are from Asian countries with Asian populations, with little evidence on Arabs.
Topics: Humans; Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; INDEL Mutation; Osteoarthritis, Knee; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors
PubMed: 38779312
DOI: 10.12688/f1000research.140233.1 -
Experimental and Therapeutic Medicine Jun 2024The pathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear. It has been found that interleukin-6 (IL-6) rs1800795 locus and matrix metalloproteinase-3...
The pathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear. It has been found that interleukin-6 (IL-6) rs1800795 locus and matrix metalloproteinase-3 (MMP-3) rs3025058 locus gene polymorphisms may be associated with AIS susceptibility, which has been controversial and needs to be further confirmed by updated meta-analysis. The aim of the present study was to investigate the association of MMP-3 rs3025058 and IL-6 rs1800795 single nucleotide polymorphisms (SNPs) with susceptibility to AIS. All relevant articles that met the criteria were retrieved and included, and the publication dates were limited from January 2005 to December 2023. The allele frequencies and different genotype frequencies of IL-6 rs1800795 and MMP-3 rs3025058 loci in each study were extracted and statistically analyzed by ReviewManager 5.4 software, and the odds ratio (OR) and 95% confidence interval (95% CI) of different genetic models were calculated. The results of the meta-analysis showed that there was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS. The allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility (5A vs. 6A, OR=1.18; 95% CI, 1.04-1.33; 5A5A vs. 6A6A, OR=1.65; 95% CI, 1.23-2.21; and 5A5A vs. 5A6A + 6A6A, OR=1.54; 95% CI, 1.19-1.99). Results of subgroup analysis revealed that the allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility in the Caucasian population, and the susceptibility of AIS was associated with the genotype 5A5A of MMP-3 rs3025058 SNP in an Asian population. There was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS, while the allele 5A of MMP-3 rs3025058 locus was associated with the susceptibility to AIS, especially in the Caucasian population.
PubMed: 38756907
DOI: 10.3892/etm.2024.12555 -
Ophthalmic Research 2024Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to... (Meta-Analysis)
Meta-Analysis Review
Association of the Complement Factor H Y402H Polymorphism and Response to Anti-Vascular Endothelial Growth Factor Treatment in Age-Related Macular Degeneration: An Updated Meta-Analysis.
INTRODUCTION
Anti-vascular endothelial growth factor (anti-VEGF) agents have a variable effect on patients with age-related macular degeneration (AMD) that has been attributed to several causes, including genetic factors. We evaluated the effects of Complement Factor H (CFH) rs1061170/Y402H polymorphism on the response to anti-VEGF therapy among AMD patients.
METHODS
PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were used for a literature search. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated to assess the effects of CFH Y402H polymorphism on the response to anti-VEGF therapy in AMD. I2 was used to present the amount of heterogeneity. We used STATA version 14.0 software.
RESULTS
Twenty-five papers reporting data for 4,681 patients were included in this study. Better response to anti-VEGF therapy was seen in T over C (OR = 1.25, 95% CI = 1.04-1.50), TT over CC (OR = 1.60, 95% CI = 1.06-2.4), and TT + TC over CC (OR = 1.68, 95% CI = 1.23-2.28) genotypes. There was no significant difference in the three other genetic models (TT vs. TC, TT vs. TC + CC, TC vs. TT + CC). In Asians, no significant difference was observed in all six genetic models. Ranibizumab and bevacizumab had similar efficacy; however, conbercept was more effective in homozygous genotypes. The literature indicated that TT and TC genotypes and T allele were associated with a better functional response, while the CC genotype and C alleles had a better anatomical response. The combination of risk alleles in ARMS2 A69S (rs10490924), VEGF-A (rs699947), and VEGF-A (rs833069) with Y420H is a predictor of non-respondents.
CONCLUSION
In patients with AMD, the CFH Y402H is a predictor of the response to anti-VEGF agents and should be considered in the treatment plan.
Topics: Humans; Complement Factor H; Vascular Endothelial Growth Factor A; Angiogenesis Inhibitors; Polymorphism, Single Nucleotide; Macular Degeneration; Genotype
PubMed: 38754401
DOI: 10.1159/000539377 -
Frontiers in Endocrinology 2024Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Depression and coronary heart disease (CHD) have common risk mechanisms. Common single nucleotide polymorphisms (SNPs) may be associated with the risk of depression combined with coronary heart disease.
METHODS
This study was designed according to the PRISMA-P guidelines. We will include case-control studies and cohort studies investigating the relationship between gene SNPs and depression and coronary heart disease comorbidities. The Newcastle-Ottawa Scale (NOS) will be used to assess the risk of bias. When measuring dichotomous outcomes, we will use the odds ratio (OR) and 95% confidence interval (95%CIs) in a case-control study. Five genetic models (allele model, homozygous model, co-dominant model, dominant model, and recessive model) will be evaluated for each included study. Subgroup analysis by ethnicity will be performed. If necessary, analysis will be made according to different types.
RESULTS
A total of 13 studies were included in this study, and the types of genes included are FKBP5 and SGK1 genes that act on glucocorticoid; miR-146a, IL-4-589, IL-6-174, TNF-α-308, CRP-717 genes that act on inflammatory mechanisms; eNOS genes from endothelial cells; HSP70 genes that act on the autoimmune response; ACE2 and MAS1 genes that act to mediate Ang(1-7) in the RAS system; 5-HTTLPR gene responsible for the transport of serotonin 5-HT and neurotrophic factor BDNF gene. There were three studies on 5-HTTLPR and BDNF genes, respectively, while there was only one study targeting FKBP5, SGK1, miR-146a, IL-4-589, IL-6-174, TNF-alpha-308, CRP-717, eNOS, HSP70, ACE2, and MAS1 genes. We did not perform a meta-analysis for genes reported in a single study, and meta-analysis was performed separately for studies exploring the 5-HTTLPR and BDNF genes. The results showed that for the 5-HTTLPR gene, there was a statistically significant association between 5-HTTLPR gene polymorphisms and depression in combination with coronary diseases (CHD-D) under the co-dominant model (LS vs LL: OR 1.76, 95%CI 1.20-2.59; SS vs LL: OR 2.80, 95%CI 1.45 to 5.41), the dominant model (LS+SS vs LL: OR 2.06, 95%CI 1.44 to 2.96), and the homozygous model (SS vs LL: OR 2.80 95%CI 1.45 to 5.5.41) were statistically significant for CHD-D, demonstrating that polymorphisms in the 5-HTTLPR gene are associated with the development of CHD-D and that the S allele in the 5-HTTLPR gene is likely to be a risk factor for CHD-D. For the BDNF gene, there were no significant differences between one of the co-dominant gene models (AA vs GG: OR 6.63, 95%CI 1.44 to 30.64), the homozygous gene model (AA vs GG: OR 6.63,95% CI 1.44 to 30.64), the dominant gene model (GA+AA vs GG: OR4.29, 95%CI 1.05 to 17.45), recessive gene model (AA vs GG+GA: OR 2.71, 95%CI 1.16 to 6.31), and allele model (A vs G: OR 2.59, 95%CI 1.18 to 5.67) were statistically significant for CHD-D, demonstrating that BDNFrs6265 gene polymorphisms are associated with the CHD-D development and that the A allele in the BDNFrs6265 gene is likely to be a risk factor for CHD-D. We analyzed the allele frequencies of SNPs reported in a single study and found that the SNPs in the microRNA146a gene rs2910164, the SNPs in the ACE2 gene rs2285666 and the SNPs in the SGK1 gene rs1743963 and rs1763509 were risk factors for the development of CHD-D. We performed a subgroup analysis of three studies involving the BDNFrs6265 gene. The results showed that European populations were more at risk of developing CHD-D than Asian populations in both dominant model (GA+AA vs GG: OR 10.47, 95%CI 3.53 to 31.08) and co-dominant model (GA vs GG: OR 6.40, 95%CI 1.98 to 20.73), with statistically significant differences. In contrast, the studies involving the 5-HTTLPR gene were all Asian populations, so subgroup analyses were not performed. We performed sensitivity analyses of studies exploring the 5-HTTLPR and BDNF rs6265 genes. The results showed that the results of the allele model, the dominant model, the recessive model, the homozygous model and the co-dominant model for both 5-HTTLPR and BDNF rs6265 genes were stable. Due to the limited number of studies of the 5-HTTLPR and BDNF genes, it was not possible to determine the symmetry of the funnel plot using Begg's funnel plot and Egger's test. Therefore, we did not assess publication bias.
DISCUSSION
SNPs of the microRNA146a gene at rs2910164, the ACE2 gene at the rs2285666 and the SGK1 gene at rs1743963 and rs1763509, and the SNPs at the 5-HTTLPR and BDNF gene loci are associated with the onset of comorbid depression in coronary heart disease. We recommend that future research focus on studying SNPs' impact on comorbid depression in coronary heart disease, specifically targeting the 5-HTTLPR and BDNF gene at rs6265.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42021229371.
Topics: Humans; Polymorphism, Single Nucleotide; Depression; Coronary Disease; Genetic Predisposition to Disease
PubMed: 38745947
DOI: 10.3389/fendo.2024.1369676 -
Brain : a Journal of Neurology Jun 2024Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair...
Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.
Topics: Animals; Female; Humans; Male; Mice; Acyltransferases; Carboxylic Ester Hydrolases; Mutation, Missense; Phenotype; Phospholipases; Retinal Diseases
PubMed: 38735647
DOI: 10.1093/brain/awae055