Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa K.; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, Nigel W.; Robertson, Neil; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noél P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt J.; Onofrio, Robert C.; Small, Kerrin S.; Stringham, Heather M.; Syvänen, Ann‐Christine; Trakalo, Joseph; Abecasis, Gonçalo R.; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Hanis, Craig L.; Seielstad, Mark; Wilson, James G.; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L.; Doney, Alex S.F.; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E.; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D.; Morris, Andrew D.; Palmer, Colin N.A.; Collins, Francis S.; Mohlke, Karen L.; Bergman, Richard N.; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M.; Prokopenko, Inga; Dupuis, Josée; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, José C.; Morris, Andrew P.; Altshuler, David; Meigs, James B.; Boehnke, Michael; McCarthy, Mark I.; Lindgren, Cecilia M.; Gloyn, Anna L.

doi:10.1371/journal.pgen.1004876

Cited by 102 publications

(131 citation statements)

References 42 publications

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“…These two hypertriglyceridemic haplotypes, ACCAC and ACGCC , are characterized by the presence of allele C of rs651821/ ApoA5 , but have different changes in ZNF259 (rs964184 C>G) or ApoA5 (rs2075291 C>A). Conventional genetic analysis based on single SNPs might underestimate or even mislead an association when multiple functional variants are present on a haplotype including the locus, particularly when the directions of the functional loci confl ict ( 27 ). The substitutions of allele C>G at the rs603446/ ZNF259 and A>C at the rs11216126/ BUD13 are expected to lower TG based on our fi ndings.…”

Section: Discussionmentioning

confidence: 71%

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Bayasgalan

Lee

Kho

et al. 2016

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 71%

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Bayasgalan

Lee

Kho

et al. 2016

Journal of Lipid Research

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“…RREB1 has recently been implicated by GWAS as a regulatory factor associated with glucose levels ( 37 ). Mass spectrometrybased analysis of the human proteome (Proteomics DB) has demonstrated that heart, pancreas, lymphocytes, and colon express RREB1 ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis

Manichaikul

Wang

Zhao

et al. 2016

Journal of Lipid Research

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The enzyme long-chain acyl-CoA synthetase 1 (ACSL1), which catalyzes conversion of free long-chain fatty acids into their acyl-CoA derivatives, has emerged as a metabolic rheostat in mouse skeletal muscle, heart, and adipose tissue ( 1-3 ). Thus, mice defi cient in ACSL1 in skeletal muscle exhibit a marked reduction in fatty acid utilization through ␤ -oxidation and a concomitant increase in glucose utilization during fasting, and they are hypoglycemic during endurance training ( 4 ). In the heart, which relies heavily on fatty acids as an energy source, ACSL1 deficiency results in reduced fatty acid oxidation and increased glucose utilization ( 1, 2 ). Mice with adipose tissue-selective ACSL1 defi ciency have reduced blood glucose levels during cold exposure ( 3 ). Furthermore, an inducible wholebody ACSL1-defi cient mouse model exhibits lower blood glucose levels than matched controls ( 1 ). Thus, mouse studies have revealed a clear relationship between reduced blood glucose levels and reduced ACSL1 activity in several tissues due to metabolic fl exibility in these tissues.ACSL1 is ubiquitously expressed, with high levels in typical insulin target tissues, such as skeletal muscle, liver, and adipose tissue ( 5 ). ACSL1 is also expressed in myeloid cells, Abstract Long-chain acyl-CoA synthetase 1 (ACSL1) converts free fatty acids into acyl-CoAs. Mouse studies have revealed that ACSL1 channels acyl-CoAs to ␤ -oxidation, thereby reducing glucose utilization, and is required for diabetesaccelerated atherosclerosis. The role of ACSL1 in humans is unknown. We therefore examined common variants in the human ACSL1 locus by genetic association studies for fasting glucose, diabetes status, and preclinical atherosclerosis by using the MAGIC and DIAGRAM consortia; followed by analyses in participants from the Multi-Ethnic Study of Atherosclerosis, the Penn-T2D consortium, and a meta-analysis of subclinical atherosclerosis in African Americans; and finally, expression quantitative trait locus analysis and identifi cation of DNase I hypersensitive sites (DHS). The results show that three SNPs in ACSL1 (rs7681334, rs735949, and rs4862423) are associated with fasting glucose or diabetes status in these large (>200,000 subjects) data sets. Furthermore, rs4862423 is associated with subclinical atherosclerosis and coincides with a DHS highly accessible in human heart. SNP rs735949 is in strong linkage disequilibrium with rs745805, signifi cantly associated with ACSL1 levels in skin, suggesting tissue-specifi c regulatory mechanisms. This study provides evidence in humans of ACSL1 SNPs associated with fasting glucose, diabetes, and subclinical atherosclerosis and suggests links among these traits and acyl-CoA synthesis.

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“…Developments in genotyping and sequencing technologies have further enabled the study of lowfrequency and rare genetic variation [18,21,22]. However, given that most loci contribute only modest effects in the studied populations, the sample sizes required to obtain sufficient statistical power are enormous, reaching >500,000 European or Asian individuals.…”

Section: Gwas In Population Isolatesmentioning

confidence: 99%

Diabetes in Population Isolates: Lessons from Greenland

Grarup¹,

Moltke²,

Albrechtsen³

et al. 2015

Rev Diabet Stud

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■ AbstractType 2 diabetes (T2D) is an increasing health problem worldwide with particularly high occurrence in specific subpopulations and ancestry groups. The high prevalence of T2D is caused both by changes in lifestyle and genetic predisposition. A large number of studies have sought to identify the genetic determinants of T2D in large, open populations such as Europeans and Asians. However, studies of T2D in population isolates are gaining attention as they provide several advantages over open populations in genetic disease studies, including increased linkage disequilibrium, homogeneous environmental exposure, and increased allele frequency. We recently performed a study in the small, historically isolated Greenlandic population, in which the prevalence of T2D has increased to more than 10%. In this study, we identified a common nonsense variant in TBC1D4, which has a population-wide impact on glucose-stimulated plasma glucose, serum insulin levels, and T2D. The variant defines a specific subtype of non-autoimmune diabetes characterized by decreased post-prandial glucose uptake and muscular insulin resistance. These and other recent findings in population isolates illustrate the value of performing medical genetic studies in genetically isolated populations. In this review, we describe some of the advantages of performing genetic studies of T2D and related cardio-metabolic traits in a population isolate like the Greenlandic, and we discuss potentials and perspectives for future research into T2D in this population.

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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Cited by 102 publications

References 42 publications

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Multiple susceptibility loci at chromosome 11q23.3 are associated with plasma triglyceride in East Asians

Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis

Diabetes in Population Isolates: Lessons from Greenland

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