Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

Cheung, Chloe Y. Y.; Tang, Clara S.; Xu, Aimin; Lee, Chi H.; Au, Ka Wing; Lin, Xu; Fong, Carol Ho Yi; Kwok, Kelvin Ho Man; Chow, Wing; Woo, Yu Cho; Yuen, Mantak; Hai, Jo Jo; Jin, Ya Li; Cheung, Bernard M Y; Tan, Kathryn Choon Beng; Cherny, Stacey S.; Zhu, Feng; Zhu, Tong; Thomas, G. Neil; Cheng, Kar Keung; Jiang, Chao Qiang; Lam, Tai Hing; Tse, Hung‐Fat; Sham, Pak C.; Lam, Karen S.L.

doi:10.1007/s00125-016-4132-z

Cited by 23 publications

(27 citation statements)

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“…Dysregulation of two pancreatic hormones, characterized by insulin insufficiency and hyperglucagonemia, leads to hyperglycemia and contributes to increased diabetes incidence (37). Recently, it has been reported (25,38) that single nucleotide polymorphisms and mutations of PAX4 gene are closely associated with diabetes in numerous ethnic groups. Since PAX4 has opposite roles in the development and function of pancreatic endocrine cells (39), we hypothesized that the dysregulation of the SREBP1c-PAX4 axis might be associated with an imbalance of pancreatic endocrine cells.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the overexpression of PAX4 protects b-cells from apoptosis induced by streptozotocin (STZ) (24). Recently, it has been reported that mutations of the PAX4 gene are associated with type 1 and 2 diabetes as well as ketosis-prone diabetes in various ethnic groups (25). Although the correlation between PAX4 dysfunction and diabetes has been demonstrated, the regulatory mechanism of PAX4 expression remains elusive.…”

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confidence: 99%

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SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

et al. 2018

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SREBP1c is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic b-cells are largely unknown. In this study, we demonstrate that SREBP1c regulates b-cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic b-cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated b-cell proliferation through its novel target gene, PAX4. Compared with SREBP1c +/+ mice, SREBP1c 2/2 mice showed glucose intolerance with low insulin levels. Moreover, b-cells from SREBP1c 2/2 mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c-overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating b-cell compensatory responses in obesity.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

et al. 2018

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“…This study consisted of an exome-chip association study evaluating the genetic determinants of the circulating PEDF level in 5,385 Chinese subjects with T2D. The discovery stage involved 2,936 subjects who had been examined in our previous exome-chip association studies (26)(27)(28), followed by a replication study in 2,449 independent subjects with T2D who had not been genotyped with the exome chip. The cross-sectional associations of circulating PEDF levels and the PEDF-associated single nucleotide polymorphisms (SNPs) with diabetes complications were then examined.…”

Section: Methodsmentioning

confidence: 99%

Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes

et al. 2018

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Elevated circulating levels of pigment epithelium-derived factor (PEDF) have been reported in patients with type 2 diabetes (T2D) and its associated microvascular complications. This study aimed to 1) identify the genetic determinants influencing circulating PEDF levels in a clinical setting of T2D, 2) examine the relationship between circulating PEDF and diabetes complications, and 3) explore the causal relationship between PEDF and diabetes complications. An exome-chip association study on circulating PEDF levels was conducted in 5,385 Chinese subjects with T2D. A meta-analysis of the association results of the discovery stage (n = 2,936) and replication stage (n = 2,449) was performed. The strongest association was detected at SERPINF1 (p.Met72Thr; P combined = 2.06 3 10 257 ; b [SE] 20.33 [0.02]). Two missense variants of SMYD4 (p.Arg131Ile; P combined = 7.56 3 10 225 ; b [SE] 0.21 [0.02]) and SERPINF2 (p.Arg33Trp; P combined = 8.22 3 10 210 ; b [SE] 20.15 [0.02]) showed novel associations at genome-wide significance. Elevated circulating PEDF levels were associated with increased risks of diabetic nephropathy and sightthreatening diabetic retinopathy. Mendelian randomization analysis showed suggestive evidence of a protective role of PEDF on sight-threatening diabetic retinopathy (P = 0.085). Our study provided new insights into the genetic regulation of PEDF and further support for its potential application as a biomarker for diabetic nephropathy and sight-threatening diabetic retinopathy. Further studies to explore the causal relationship of PEDF with diabetes complications are warranted. Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein that belongs to the serine protease inhibitor (serpin) superfamily (1). PEDF is widely distributed in multiple organs and tissues, such as kidney, eye, liver, lung, and adipose tissues (1,2). PEDF possesses diverse biological functions in different tissues, including antiangiogenesis, retina protection, anti-inflammation, antifibrosis, stem cell renewal, neurogenesis, and neuroprotection (1,3-5). Previous studies reported that circulating PEDF levels were significantly higher in patients with type 2 diabetes (T2D) than in subjects without diabetes (6). Serum PEDF in T2D patients was also shown to be elevated after treatment with metformin, an antihyperglycemia agent (7). On the other hand, it has been suggested that PEDF plays a protective role against

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“…All subjects were genotyped using the custom Asian exomechip (13,14) with an add-on content of 58,317 single nucleotide polymorphisms (SNPs), including a custom panel of over 30,000 missense or nonsense coding variants on top of the standard content of the Infinium HumanExome Bead-Chip (HumanExome-12v1_A; Illumina, San Diego, CA). Genotyping of the exome array was performed using the Illumina iScan system platform at the Centre for Genomic Sciences of The University of Hong Kong.…”

Section: Genotyping and Data Quality Controlmentioning

confidence: 99%

“…This study sought to identify the genetic determinants of circulating FGF21 levels. We conducted an exome-chip association analysis on circulating FGF21 levels using a specially designed Illumina HumanExome BeadChip (Asian exome-chip) in a Chinese population (13,14). In consideration of the possible difference in circulating FGF21 levels between individuals from the patient groups and those from the general population, possibly due to the intrinsic metabolic stress under disease conditions and the treatment effects on FGF21 expression, we first conducted the association analysis in a community-based and two clinic-based cohorts separately, followed by a combined analysis involving a total of 5,169 individuals.…”

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An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels

Cheung

Tang

et al. 2017

Diabetes

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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, , significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missense variant of, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels after adjustment for age and sex ( = 1.61 × 10; β [SE] = 0.14 [0.02]), which remained significant on further adjustment for BMI ( = 3.01 × 10; β [SE] = 0.15 [0.02]). Leu446 may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA, and via increased glucose-6-phosphate-mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted.

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Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals

Abstract: Aims/hypothesis Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent ad-

Cited by 23 publications

References 46 publications

SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress

Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes

An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels

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