| 1. |
- Yang, Muyi, et al.
(författare)
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Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma
- 2022
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:1, s. 157-169
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. Methods: We performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. Results: We identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. Conclusion: Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.
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| 2. |
- Zhou, Yitian
(författare)
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Assessing the importance of rare genetic variants for drug response
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inter-individual variability in drug response is commonly observed in pharmacological treatment, resulting in 40-70% of patients suffering from low drug efficacy or adverse drug reactions. These negative therapeutic effects significantly contribute to patient morbidity and mortality and constitute an important reason of post-market drug withdrawal. It is estimated that 20-30% of such variability can be explained by genetic factors, i.e., genetic variations in genes that involved in pharmacokinetics, pharmacodynamics and immune-related idiosyncratic drug response. In this thesis, frequencies of common alleles in clinically important pharmacogenes were analyzed based on Next Generation Sequencing (NGS) data from major human populations. Specifically, frequencies of 176 star alleles in 12 clinically relevant CYP genes across European, African, East Asian, South Asian and Latino populations were evaluated and translated into population-specific functional variability data (Paper I). This variability specifically in the genetically isolated Ashkenazi Jewish population was further studied using an extended pharmacogene list and the unique pharmacogenetic profile of Ashkenazi Jews compared to the European population was revealed (Paper II). In addition, frequencies of four common HLA risk alleles (HLA-B*57:01, HLA-B*15:02, HLA-A*31:01 and HLA-B*58:01) that are strongly associated with drug hypersensitivity reactions were analyzed in up to 74 countries. Based on frequency data, a global cost-effectiveness model was established to inform conditionally cost-effectiveness of preemptive HLA risk allele genotyping in all studied countries (Paper III). Next, my projects focused on identifying and functional characterizing rare variants in pharmacogenes using NGS data. Specifically, I and my colleagues established a computational prediction framework by first, optimizing classification thresholds of 18 current prediction algorithms using 337 experimentally characterized variants across 44 pharmacogenes, and second, obtaining the combination of optimized algorithms that generates result with highest prediction performance. The resulted optimized framework can quantitatively predict functional effect of pharmacogenetic variants, particularly the rare ones, with predictive power outperformed all other algorithms (Paper IV). This optimized prediction framework was further employed to evaluate variants in two extremely conserved pharmacogenes DPYD and TPMT. While the predictive accuracy being demonstrated using a benchmark dataset containing 70 in vivo characterized DPYD and TPMT variants, this framework was used to analyze genetic encoded functional complexity of the two genes as well as profile population-scale phenotype frequencies using NGS data (Paper V). In addition, this framework was applied to interrogating functionality of variants in a whole set of pharmacogenes (n=208). This study demonstrated that rare variants significantly contribute to pharmacogenomic variability in more than half of studied pharmacogenes and are important in predicting abnormal drug response (Paper VI). Finally, genetic variability of drug targets targeted by all FDA-approved drugs were studied. Particularly, it was revealed that one in six individuals carries at least one missense variant locating in drug-target binding sites and demonstrated that such variants are functionally important and can modulate pharmacological response and guide development of new candidate drugs (Paper VII). Overall, the findings in this thesis provide a valuable resource for population pharmacogenetic variability and can guide the optimization of population-specific sequencing strategies. Furthermore, I and my colleagues developed a computational tool to interpret the functional impact of pharmacogenetic variability and demonstrated that rare variants in pharmacokinetic and pharmacodynamic genes significantly contribute to variability in drug response. Combined, these findings underscore the importance of incorporating NGS-based pharmacogenomic interpretation into clinical decision making to refine personalized medicine.
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| 3. |
- Zhou, Yitian, et al.
(författare)
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Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk
- 2018
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Ingår i: Journal of Lipid Research. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0022-2275 .- 1539-7262. ; 59:10, s. 1987-2000
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal plasma apolipoprotein levels are consistently implicated in CVD risk. Although 30% to 60% of their interindividual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identify further 6,875 genetic variants, 33% of which are novel and 98.7% of which are rare with minor allele frequencies <1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM (Coronary Artery Disease Genomewide Replication and Meta-analysis) and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits, and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.
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