Publications by authors named "Shaofeng Huo"

8 Publications

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The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Changes in Plasma Metabolome Profiles Following Oral Glucose Challenge among Adult Chinese.

Nutrients 2021 Apr 27;13(5). Epub 2021 Apr 27.

Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Little is known about changes in plasma metabolome profiles during the oral glucose tolerance test (OGTT) in Chinese. We aimed to characterize plasma metabolomic profiles at 0 and 2 h of OGTT and their changes in individuals of different glycemic statuses. A total of 544 metabolites were detected at 0 and 2 h of OGTT by a nontarget strategy in subjects with normal glucose ( = 234), prediabetes ( = 281), and newly diagnosed type 2 diabetes (T2D) ( = 66). Regression model, mixed model, and partial least squares discrimination analysis were applied. Compared with subjects of normal glucose, T2D cases had significantly higher levels of glycerone at 0 h and 22 metabolites at 2 h of OGTT (false discovery rate (FDR) < 0.05, variable importance in projection (VIP) > 1). Seven of the twenty-two metabolites were also significantly higher in T2D than in prediabetes subjects at 2 h of OGTT (FDR < 0.05, VIP > 1). Two hours after glucose challenge, concentrations of 35 metabolites (normal: 18; prediabetes: 23; T2D: 13) significantly increased (FDR < 0.05, VIP > 1, fold change (FC) > 1.2), whereas those of 45 metabolites (normal: 36; prediabetes: 29; T2D: 18) significantly decreased (FDR < 0.05, VIP > 1, FC < 0.8). Distinct responses between cases and noncases were detected in metabolites including 4-imidazolone-5-acetate and 4-methylene-L-glutamine. More varieties of distinct metabolites across glycemic statuses were observed at 2 h of OGTT compared with fasting state. Whether the different patterns and responsiveness of certain metabolites in T2D reflect a poor resilience of specific metabolic pathways in regaining glucose homeostasis merits further study.
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http://dx.doi.org/10.3390/nu13051474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146292PMC
April 2021

Genetic susceptibility, dietary cholesterol intake, and plasma cholesterol levels in a Chinese population.

J Lipid Res 2020 11 12;61(11):1504-1511. Epub 2020 Aug 12.

Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, China

Accompanied with nutrition transition, non-HDL-C levels of individuals in Asian countries has increased rapidly, which has caused the global epicenter of nonoptimal cholesterol to shift from Western countries to Asian countries. Thus, it is critical to underline major genetic and dietary determinants. In the current study of 2,330 Chinese individuals, genetic risk scores (GRSs) were calculated for total cholesterol (TC; GRS, 57 SNPs), LDL-C (GRS, 45 SNPs), and HDL-C (GRS, 65 SNPs) based on SNPs from the Global Lipid Genetics Consortium study. Cholesterol intake was estimated by a 74-item food-frequency questionnaire. Associations of dietary cholesterol intake with plasma TC and LDL-C strengthened across quartiles of the GRS (effect sizes: -0.29, 0.34, 2.45, and 6.47; = 0.002) and GRS (effect sizes: -1.35, 0.17, 5.45, and 6.07; = 0.001), respectively. Similar interactions with non-HDL-C were observed between dietary cholesterol and GRS ( = 0.001) and GRS ( = 0.004). The adverse effects of GRS on TC (effect sizes across dietary cholesterol quartiles: 0.51, 0.82, 1.21, and 1.31; = 0.023) and GRS on LDL-C (effect sizes across dietary cholesterol quartiles: 0.66, 0.52, 1.12, and 1.56; = 0.020) were more profound in those having higher cholesterol intake compared with those with lower intake. Our findings suggest significant interactions between genetic susceptibility and dietary cholesterol intake on plasma cholesterol profiles in a Chinese population.
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http://dx.doi.org/10.1194/jlr.RA120001009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604728PMC
November 2020

Associations of Amino Acid and Acylcarnitine Profiles With Incident Hyperuricemia in Middle-Aged and Older Chinese Individuals.

Arthritis Care Res (Hoboken) 2020 09;72(9):1305-1314

University of Chinese Academy of Sciences, Shanghai, China.

Objective: Little is known about how metabolic perturbations are linked to hyperuricemia in the general population. Therefore we aimed to examine metabolomics profiles in relation to uric acid change and incident hyperuricemia.

Methods: This study included 1,621 community-dwelling Chinese participants ages 50-70 years without hyperuricemia at baseline, with a mean duration of follow-up of 6 years. A total of 56 metabolites (22 amino acids and 34 acylcarnitines) at baseline were quantified by gas or liquid chromatography coupled to mass spectrometry. Annual change in uric acid was calculated, and incident hyperuricemia was defined as plasma uric acid >420 μmoles/liter in men and >360 μmoles/liter in women.

Results: The mean ± SD annual change in uric acid was 9.6 ± 12.1 μmoles/liter and the incidence of hyperuricemia was 23.1% (375 of 1,621). After adjustment for conventional risk factors, 9 metabolites (cysteine, glutamine, phenylalanine, threonine, and long-chain acylcarnitines C14:1OH, C18, C18:2, C20, and C20:4) were significantly associated with uric acid change (Bonferroni corrected P < 0.05) and with incident hyperuricemia (relative risks ranged from 1.14 to 1.21 per SD increment of metabolites; P < 0.05). A network analysis showed significant associations between the module containing long-chain acylcarnitines and incident hyperuricemia. Moreover, levels of these 9 metabolites were specifically correlated with intake of foods, including red and processed meat or soy products.

Conclusion: Plasma cysteine, glutamine, phenylalanine, threonine, and long-chain acylcarnitines are positively associated with incident hyperuricemia. The levels of these metabolites may be partially driven by intakes of meat and soy products that are associated with hyperuricemia.
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http://dx.doi.org/10.1002/acr.24013DOI Listing
September 2020

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Nat Commun 2018 11 28;9(1):5052. Epub 2018 Nov 28.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
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http://dx.doi.org/10.1038/s41467-018-07345-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261994PMC
November 2018

Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet-induced insulin-resistant mice.

Hepatology 2018 10 18;68(4):1361-1375. Epub 2018 May 18.

CAS Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Insulin is critical for the regulation of de novo fatty acid synthesis, which converts glucose to lipid in the liver. However, how insulin signals are transduced into the cell and then regulate lipogenesis remains to be fully understood. Here, we identified CREB/ATF bZIP transcription factor (CREBZF) of the activating transcription factor/cAMP response element-binding protein (ATF/CREB) gene family as a key regulator for lipogenesis through insulin-Akt signaling. Insulin-induced gene 2a (Insig-2a) decreases during refeeding, allowing sterol regulatory element binding protein 1c to be processed to promote lipogenesis; but the mechanism of reduction is unknown. We show that Insig-2a inhibition is mediated by insulin-induced CREBZF. CREBZF directly inhibits transcription of Insig-2a through association with activating transcription factor 4. Liver-specific knockout of CREBZF causes an induction of Insig-2a and Insig-1 and resulted in repressed lipogenic program in the liver of mice during refeeding or upon treatment with streptozotocin and insulin. Moreover, hepatic CREBZF deficiency attenuates hepatic steatosis in high-fat, high-sucrose diet-fed mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced insulin resistance or genetically obese ob/ob mice and humans with hepatic steatosis, which may underscore the potential role of CREBZF in the development of sustained lipogenesis in the liver under selective insulin resistance conditions.

Conclusion: These findings uncover an unexpected mechanism that couples changes in extracellular hormonal signals to hepatic lipid homeostasis; disrupting CREBZF function may have the therapeutic potential for treating fatty liver disease and insulin resistance. (Hepatology 2018).
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http://dx.doi.org/10.1002/hep.29926DOI Listing
October 2018

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

Nat Genet 2018 04 9;50(4):559-571. Epub 2018 Apr 9.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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http://dx.doi.org/10.1038/s41588-018-0084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898373PMC
April 2018
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