Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

Rees, Matthew G.; Ng, David; Ruppert, Sarah L.; Turner, Clesson; Beer, Nicola L.; Swift, Amy J.; Morken, Mario A.; Below, Jennifer E.; Blech, Ilana; Mullikin, James C.; McCarthy, Mark I.; Biesecker, Leslie G.; Gloyn, Anna L.; Collins, Francis S.

doi:10.1172/jci46425

Cited by 43 publications

(58 citation statements)

References 65 publications

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“…However, the degree of this cellular defect was most pronounced for p.Q234P, the only variant which demonstrated global defects in protein expression, GCK interaction, F1P affinity and F6P affinity (Figs 1A and 2A–C). Consistent with previous observations (3), the presence of the p.P446L variant in cis with rare variants augmented functional defects, most notably by decreasing nuclear localization and protein levels (Fig. 1B; Supplementary Material, Fig.…”

Section: Resultssupporting

confidence: 92%

“…Seven variants (p.R51Q, p.E77G, p.Q234P, p.A519T, p.S183CfsX34, p.T379NfsX36, p.R540X) overlapped with variants reported in a previous population-based sequencing study of GCKR (3). These seven variants were observed in both hypertriglyceridemia cases ( n = 13 individuals) and controls ( n = 6); the non-overlapping variants ( n = 11) were therefore each unique to a single individual with hypertriglyceridemia.…”

Section: Resultsmentioning

confidence: 66%

“…Emerging work suggests that rare non-synonymous variants are important contributors to complex disease susceptibility (2,3). However, studies focusing on rare variants are by their nature limited by sample size (4).…”

Section: Introductionmentioning

confidence: 99%

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Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families

Rees

Raimondo

Wang

et al. 2014

Human Molecular Genetics

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Significant resources have been invested in sequencing studies to investigate the role of rare variants in complex disease etiology. However, the diagnostic interpretation of individual rare variants remains a major challenge, and may require accurate variant functional classification and the collection of large numbers of variant carriers. Utilizing sequence data from 458 individuals with hypertriglyceridemia and 333 controls with normal plasma triglyceride levels, we investigated these issues using GCKR, encoding glucokinase regulatory protein. Eighteen rare non-synonymous GCKR variants identified in these 791 individuals were comprehensively characterized by a range of biochemical and cell biological assays, including a novel high-throughput-screening-based approach capable of measuring all variant proteins simultaneously. Functionally deleterious variants were collectively associated with hypertriglyceridemia, but a range of in silico prediction algorithms showed little consistency between algorithms and poor agreement with functional data. We extended our study by obtaining sequence data on family members; however, functional variants did not co-segregate with triglyceride levels. Therefore, despite evidence for their collective functional and clinical relevance, our results emphasize the low predictive value of rare GCKR variants in individuals and the complex heritability of lipid traits.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 66%

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Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families

Rees

Raimondo

Wang

et al. 2014

Human Molecular Genetics

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“…At a subset of loci, the association signals map to non-synonymous coding variants (p.Pro446Leu GCKR [53], and p.Arg325Trp at SLC30A8 [54]), providing strong causal candidates for both the variant and the gene. As with both these examples, experimental studies confirm the impact of these variants on protein function and support further mechanistic insights [55][56][57][58].…”

Section: Defining Mechanisms At the Level Of Individual Locisupporting

confidence: 68%

Genome-Wide Association Studies in Type 2 Diabetes

Beer¹,

McCarthy²

2014

Frontiers in Diabetes

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Genome-wide association studies (GWAS) provide important insights into type 2 diabetes (T2D) pathogenesis. The common variant GWAS approach enables capture of disease risk-associated sequence variation on a previously unachievable scale, implicating roughly 70 genomic regions in T2D predisposition. Data gathered from a variety of approaches, including GWAS studies in diverse ethnic groups, indicate that a substantial proportion of the heritable component of T2D risk is attributable to causal common variants of small effect that are shared across populations. Whilst the 70 common variant signals detected at genome-wide significance account for only 5-10% of overall variation in disease predisposition, their discovery infers much about T2D pathophysiology. Genes mapping to T2D susceptibility loci are enriched for transcription factors and cell cycle regulators, yet only partially overlap pathways influencing physiological variation in glycaemic traits. Most affect insulin secretion, and some influence birthweight, linking intrauterine growth to adult metabolic disease. Challenges in identifying the causal variants and mediating transcripts behind common variant GWAS signals remain. However, the increasing sophistication with which non-coding association signals can be mapped onto tissue-specific regulatory annotations, and the growing power of efforts to detect rare variant signals in coding sequence, are providing new opportunities to link common variant GWAS signals to biology.Type 2 diabetes (T2D) is a global health burden. It accounts for 6.8% of deaths worldwide [1], and will rise in prevalence at a rate exceeding that of adult population growth [2]. Despite an influence of obesity [3] and urbanisation [4], a wealth of data supports a substantial inherited contribution to this disorder. For example, first-degree relatives of those with T2D are at increased risk [5], and the concordance for diabetes in monozygotic twins is twice that in dizygotic pairs [6].At the same time, the complex interplay between pancreatic insulin secretory failure and peripheral insulin resistance which characterises T2D implies both phenotypic and genetic heterogeneity [7]. Aetiological complexity, along with inadequate understanding of the processes involved in glucose homeostasis, frustrated early ef-

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“…However, the molecular mechanism has been partially clarified by which GCKR rs1260326 (P446L) variant, an SNP with a strong linkage disequilibrium to GCKR rs780094, is related to glucose and lipid metabolism [26]. Wild type GCKR is supposed to bind GCK and inhibit GCK enzyme activity in the nucleus of the liver at a physiological concentration of fructose-6-phosphate (F6P), while the GKRP P446L is likely to dissociate with GCK even at the same concentration of F6P [27,28]. This means that the GKRP P446L may provide for increased activity of GCK compared to wild-type GKRP.…”

Section: Phenotypementioning

confidence: 99%

Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women

Murata-Mori

Hayashida

Ando

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: The glucokinase regulator gene (GCKR) rs780094 has been shown to be strongly associated with some metabolic traits and atherosclerotic parameters, while the association between GCKR rs780094 and carotid intima-media thickness (CIMT) has not been fully investigated in the general population. The associations between the GCKR rs780094 genotype and metabolic traits including CIMT were examined in a Japanese community-dwelling population. Methods: A total of 2491 Japanese adults (907 men and 1584 women) who participated in a medical screening program for the general population from 29 to 94 years of age during 2008 to 2010 were enrolled. GCKR rs780094 was genotyped by the TaqMan polymerase chain reaction method, and associations with metabolic markers including CIMT were evaluated. Results: GCKR rs780094 AA genotype was significantly associated with higher TG (p < 0.001 vs. GG), lower HDL-C (p = 0.021 vs. GG), and lower HbA 1c (p = 0.023 vs. GG). The AA genotype showed significantly thinner CIMT (p = 0.001 vs. GX). These associations were seen only in men. Conclusions: GCKR rs780094 was associated with TG, HDL-C, and HbA 1c levels, as well as with CIMT in Japanese community-dwelling men, but not women.

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Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

Cited by 43 publications

References 65 publications

Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families

Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families

Genome-Wide Association Studies in Type 2 Diabetes

Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women

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