👤 Li-Lian Kwok

RNA G-quadruplexes (rG4s) are non-canonical secondary nucleic acid structures found in the transcriptome. They play crucial roles in gene regulation by interacting with G4-binding proteins (G4BPs) in cells. rG4-G4BP complexes have been associated with human diseases, making them important targets for drug development. Generating innovative tools to disrupt rG4-G4BP interactions will provide a unique opportunity to explore new biological mechanisms and potentially treat related diseases. Here, we have rationally designed and developed a series of rG4-based proteolytic targeting chimeras (rG4-PROTACs) aimed at degrading G4BPs, such as DHX36, a specific G4BP that regulates gene expression by binding to and unraveling rG4 structures in messenger RNAs (mRNAs). Our comprehensive data and systematic analysis reveals that rG4-PROTACs predominantly and selectively degrade DHX36 through a proteosome-dependent mechanism, which promotes the formation of the rG4 structure in mRNA, leading to the translation inhibition of rG4-containing transcripts. Notably, rG4-PROTACs inhibit rG4-mediated APP protein expression, and impact the proliferative capacity of skeletal muscle stem cells by negatively regulating Gnai2 protein expression. In summary, rG4-PROTACs provide a new avenue to understand rG4-G4BP interactions and the biological implications of dysregulated G4BPs, promoting the development of PROTACs technology based on the non-canonical structure of nucleic acids. Show less

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution. Show less

RNA Guanine-quadruplexes (rG4s) are important nucleic acid structures that govern vital biological processes. Although numerous tools have been developed to target rG4s, few specific tools are capable of discerning individual rG4 of interest. Herein, we design and synthesize the first L-aptamer-antisense oligonucleotide (ASO) conjugate, L-Apt.4-1c-ASO15nt(APP), with a focus on recognizing the amyloid precursor protein (APP) rG4 region as an example. The L-aptamer module binds with the rG4 structure, whereas ASO hybridizes with flanking sequences. Together, these two modules enhance the precise recognition of APP rG4. We demonstrate that the L-Apt.4-1c-ASO15nt(APP) conjugate can interact with the APP rG4 region with sub-nanomolar binding affinity, and distinguish APP rG4 from other G4s and non-G4s in vitro and in cells. We also show that L-Apt.4-1c-ASO15nt(APP) can inhibit APP protein expression. Notably, we investigate the inhibitory mechanism of this newly developed tool, and reveal that it controls gene expression by hindering DHX36 protein from unraveling the rG4, as well as by promoting translational inhibition and RNase H-mediated mRNA knockdown activity. Our novel L-aptamer-ASO conjugate tool not only enables the specific recognition of rG4 region of interest, but also allows efficient gene control via targeting rG4-containing transcripts in cells. Show less

RNA structure constitutes a new layer of gene regulatory mechanisms. RNA binding proteins can modulate RNA secondary structures, thus participating in post-transcriptional regulation. The DEAH-box helicase 36 (DHX36) is known to bind and unwind RNA G-quadruplex (rG4) structure but the transcriptome-wide RNA structure remodeling induced by DHX36 binding and the impact on RNA fate remain poorly understood. Here, we investigate the RNA structurome alteration induced by DHX36 depletion. Our findings reveal that DHX36 binding induces structural remodeling not only at the localized binding sites but also on the entire mRNA transcript most pronounced in 3'UTR regions. DHX36 binding increases structural accessibility at 3'UTRs which is correlated with decreased post-transcriptional mRNA abundance. Further analyses and experiments uncover that DHX36 binding sites are enriched for N6-methyladenosine (m Show less

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. FCS was relatively common in non-Europeans and those with parental consanguinity ( The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS. Show less

Breast cancer, when advancing to a metastatic stage, involves the liver, impacting over 50% of cases and significantly diminishing survival rates. Presently, a lack of tailored therapeutic protocols for breast cancer liver metastasis (BCLM) underscores the need for a deeper understanding of molecular patterns governing this complication. Therefore, by analyzing differentially expressed genes (DEGs) between primary breast tumors and BCLM lesions, we aimed to shed light on the diversities of this process. This research investigated breast cancer liver metastasis relapse by employing a comprehensive approach that integrated data filtering, gene ontology and KEGG pathway analysis, overall survival analysis, identification of the alteration in the DEGs, visualization of the protein-protein interaction network, Signor 2.0, identification of positively correlated genes, immune cell infiltration analysis, genetic alternation analysis, copy number variant analysis, gene-to-mRNA interaction, transcription factor analysis, molecular docking, and identification of potential treatment targets. This study's integrative approach unveiled metabolic reprogramming, suggesting altered Show less

Precision medicine in paediatric cardiac channelopathy and cardiomyopathy has a rapid advancement over the past years. Compared to conventional gene panel and exome-based testing, whole genome sequencing (WGS) offers additional coverage at the promoter, intronic regions and the mitochondrial genome. However, the data on use of WGS to evaluate the genetic cause of these cardiovascular conditions in children and adolescents are limited. In a tertiary paediatric cardiology center, we recruited all patients diagnosed with cardiac channelopathy and cardiomyopathy between the ages of 0 and 18 years old, who had negative genetic findings with prior gene panel or exome-based testing. After genetic counselling, blood samples were collected from the subjects and both their parents for WGS analysis. A total of 31 patients (11 cardiac channelopathy and 20 cardiomyopathy) were recruited. Four intronic splice-site variants were identified in three cardiomyopathy patients, which were not identified in previous whole exome sequencing. These included a pathogenic variant in WGS plays a role in identifying additional intronic splice-site variants in paediatric patients with isolated cardiomyopathy. With the demonstrated low extra yield of WGS albeit its ability to provide potential clinically important information, WGS should be considered in selected paediatric cases of cardiac channelopathy and cardiomyopathy in a cost-effective manner. Show less

Establishing the sex-specific efficacy of cardiovascular medications is pivotal to evidence-based clinical practice, potentially closing the gender gap in longevity. Trials large enough to establish sex differences are unavailable. This study evaluated sex-specific effects of commonly prescribed cardiovascular medications on lifespan. In a two-sample Mendelian randomization study, established genetic variants mimicking effects of lipid-lowering drugs, antihypertensives, and diabetes drugs were applied to genetic associations with lifespan proxied by UK Biobank maternal (n=412 937) and paternal (n=415 311) attained age. Estimates were obtained using inverse variance weighting, with sensitivity analyses where possible. For lipid-lowering drugs, genetically mimicked PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors were associated with longer lifespan, particularly in men (2.39 years per SD low-density lipoprotein cholesterol reduction [95% CI, 0.42-4.36], PCSK9 inhibitors, β-blockers, and calcium channel blockers may prolong lifespan in the general population, particularly men. Treatments targeting Show less

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics. Show less

RNA G-quadruplex (rG4) structures in the 5' untranslated region (5'UTR) play crucial roles in fundamental cellular processes. ADAR is an important enzyme that binds to double-strand RNA and accounts for the conversion of Adenosine to Inosine in RNA editing. However, so far there is no report on the formation and regulatory role of rG4 on ADAR expression. Here, we identify and characterize a thermostable rG4 structure within the 5'UTR of the ADAR1 mRNA and demonstrate its formation and inhibitory role on translation in reporter gene and native gene constructs. We reveal rG4-specific helicase DHX36 interacts with this rG4 in vitro and in cells under knockdown and knockout conditions by GTFH (G-quadruplex-triggered fluorogenic hybridization) probes and modulates translation in an rG4-dependent manner. Our results further substantiate the rG4 structure-DHX36 protein interaction in cells and highlight rG4 to be a key player in controlling ADAR1 translation. Show less

Adult muscle stem cells, also known as satellite cells (SCs), play pivotal roles in muscle regeneration, and long non-coding RNA (lncRNA) functions in SCs remain largely unknown. Here, we identify a lncRNA, Lockd, which is induced in activated SCs upon acute muscle injury. We demonstrate that Lockd promotes SC proliferation; deletion of Lockd leads to cell-cycle arrest, and in vivo repression of Lockd in mouse muscles hinders regeneration process. Mechanistically, we show that Lockd directly interacts with RNA helicase DHX36 and the 5'end of Lockd possesses the strongest binding with DHX36. Furthermore, we demonstrate that Lockd stabilizes the interaction between DHX36 and EIF3B proteins; synergistically, this complex unwinds the RNA G-quadruplex (rG4) structure formed at Anp32e mRNA 5' UTR and promotes the translation of ANP32E protein, which is required for myoblast proliferation. Altogether, our findings identify a regulatory Lockd/DHX36/Anp32e axis that promotes myoblast proliferation and acute-injury-induced muscle regeneration. Show less

Gut microbiome may influence tumor growth and cancer treatment efficacy, so it is a potential target for tumor prevention/treatment. This pilot study investigated the preventive and therapeutic effects of a probiotic strain, Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9), against murine mammary cancer. Thirty-six female mice were randomly divided into three groups (n = 12 per group): control (without tumor transplantation), model (tumor transplantation; no probiotic administration), and probiotic (30-day oral gavage of probiotic, started seven days before tumor transplantation). Changes in tumor size were recorded, and blood, tumor tissue, and stool samples were collected at the end of the trial for analyses. Comparing with the model group, the probiotic group had a significantly smaller tumor volume (p < 0.05), a higher fecal microbiota Shannon diversity index, with significant modifications in the gut microbiota structure (p < 0.05), characterized by more Alistipes sp.₂, Porphyromonadaceae bacterium₇, and Bacteroidales bacterium 55₉ (p < 0.05). Additionally, Probio-M9 administration elevated the serum IFN-γ, IL-9, IL-13, and IL-27 levels and several metabolites (e.g., pyridoxal, nicotinic acid, 3-hydroxybutyric acid, glutamine; p < 0.05), while reducing IL-5 (p < 0.05). These changes might be associated with the protective effect of Probio-M9 against mammary tumor growth. Thus, probiotic administration could harness host gut microbiome in anti-cancer responses. Show less

Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells (also called satellite cells, SCs). SCs are normally quiescent; when stimulated by damage, they activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that DHX36, a helicase that unwinds RNA G-quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. DHX36 (initially named RHAU) is barely expressed at quiescence but is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs reveals DHX36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling shows that DHX36 promotes mRNA translation via 5'-untranslated region (UTR) rG4 binding. Furthermore, we demonstrate that DHX36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5' UTR rG4 structures and identify GNAI2 as a downstream effector of DHX36 for SC expansion. Altogether, our findings uncover DHX36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration acting through binding and unwinding rG4 structures at 5' UTR of target mRNAs. Show less

Development of pharmacological treatments to mitigate ischemic heart disease (IHD) has encompassed disappointing results and expensive failures, which has discouraged investment in new approaches to prevention and control. New treatments are most likely to be successful if they act on genetically validated targets. We assessed whether existing pharmacological treatments for IHD reduction are acting on genetically validated targets and whether all such targets for IHD are currently being exploited. Genes associated with IHD were obtained from the loci of single nucleotide polymorphisms reported in either of two recent genome wide association studies supplemented by a gene-based analysis (accounting for linkage disequilibrium) of CARDIoGRAMplusC4D 1000 Genomes, a large IHD case (n=60,801)-control (n=123,504) study. Treatments targeting the products of these IHD genes and genes with products targeted by current IHD treatments were obtained from Kyoto Encyclopedia of Genes and Genomes and Drugbank. Cohen's kappa was used to assess agreement. We identified 173 autosomal genes associated with IHD and 236 autosomal genes with products targeted by current IHD treatments, only 8 genes (PCSK9, EDNRA, PLG, LPL, CXCL12, LRP1, CETP and ADORA2A) overlapped, i.e. were both associated with IHD and had products targeted by current IHD treatments. The Cohen's kappa was 0.03. Interventions related to another 29 IHD genes exist, including dietary factors, environmental exposures and existing treatments for other indications. Closer alignment of IHD treatments with genetically validated physiological targets may represent a major opportunity for combating a leading cause of global morbidity and mortality through repurposing existing interventions. Show less

Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56-105 using immunoassays and explored relationships with APOE polymorphism ε2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE ε4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE ε4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals. Show less

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10-8), including a novel DPYD variant (rs75267292; P = 1.57 × 10-10), and variants in the MACF1 (rs183324967, P = 4.80 × 10-11; rs148221738, P = 5.73 × 10-10) and SPRY2 (rs117876855, P < 1.01 × 10-8; rs139544515, P = 1.30 × 10-8) genes involved in wound healing. Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. clinicaltrials.gov Identifier: NCT00486213. Show less

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, Show less

Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4-22.6%) that associates with reduced spine BMD (P=1.0 × 10(-11), β=-0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P=6.6 × 10(-10), β=0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus. Show less

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C. Show less

Apolipoprotein A-V (apoA-V) is an important regulator of plasma levels of triglyceride (TG) in mice. In humans, APOA5 genetic variation is associated with TG in several populations. In this study, we determined the effects of the p.185Gly>Cys (c.553G>T; rs2075291) polymorphism on plasma TG levels in subjects of Chinese ancestry living in the United States and in a group of non-Chinese Asian ancestry. The frequency of the less common cysteine allele was 4-fold higher (15.1% vs. 3.7%) in Chinese high-TG subjects compared with a low-TG group (Chi-square = 20.2; P < 0.0001), corresponding with a 4.45 times higher risk of hypertriglyceridemia (95% confidence interval, 2.18-9.07; P < 0.001). These results were replicated in the non-Chinese Asians. Heterozygosity was associated, in the high-TG group, with a doubling of TG (P < 0.001), mainly VLDL TG (P = 0.014). All eleven TT homozygotes had severe hypertriglyceridemia, with mean TG of 2,292 +/- 447 mg/dl. Compared with controls, carriers of the T allele had lower postheparin lipoprotein lipase activity but not hepatic lipase activity. In Asian populations, this common polymorphism can lead to profound adverse effects on lipoprotein profiles, with homozygosity accounting for a significant number of cases of severe hypertriglyceridemia. This specific apoA-V variant has a pronounced effect on TG metabolism, the mechanism of which remains to be elucidated. Show less