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

Abstract

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.

Genetic Evidence for a Normal-Weight “Metabolically Obese” Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes

“…The variant in FTO provides a proof-of-principle example of how a BMI-associated variant can be separated from variants associated with fasting insulin through mechanisms other than higher BMI. The GCKR variant shows how the use of multiple metabolic phenotypes can be used to separate out different mechanisms—we know this variant is likely to operate through a particular mechanism linking glucose to lipid metabolism ( 31 ) in the liver and it was individually associated with multiple liver-based phenotypes ( Supplementary Table 4 ).…”

Very Severe Hypertriglyceridemia in a Large US County Health Care System: Associated Conditions and Management

“…Common small-effect variants in GCKR are associated with small elevations in triglyceride levels in genome-wide association studies and contribute to polygenic susceptibility to severe hypertriglyceridemia [37–40]. Certain rare large-effect variants in GCKR are seen in some families with severe hypertriglyceridemia [38, 39], but these patients with type 1 hypolipoproteinemia due to balletic mutations do not behave as typical in LPL , APOC2 , APOA5 , LMF1, and GPIHBP1 .…”

Genetics of Hypertriglyceridemia

“…For completeness, we mention that signals for enrichment of heterozygous rare variants in non-canonical (i.e., non-FCS) genes, such as CREB3L3 ( 48 , 49 ) and GCKR ( 50 ) have been detected in hypertriglyceridemic cohorts. While statistical association with higher mean TG levels is strong, these variants do not co-segregate with the lipid profile across generations in family pedigrees ( 48 , 50 ), similar to the situation for heterozygous variants of LPL . The extent of contribution to severe hypertriglyceridemia by rare variants of these non-canonical genes has not been determined.…”