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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.

Original publication

DOI

10.1093/hmg/ddu269

Type

Journal article

Journal

Hum Mol Genet

Publication Date

15/10/2014

Volume

23

Pages

5570 - 5578

Keywords

Adaptor Proteins, Signal Transducing, Algorithms, Animals, COS Cells, Case-Control Studies, Cercopithecus aethiops, Genetic Variation, HeLa Cells, Humans, Hyperlipoproteinemia Type IV, Mice, Models, Molecular, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Sequence Analysis, DNA, Triglycerides