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

Rees, Matthew G.; Raimondo, Anne; Wang, Jian; Ban, Matthew R.; Davis, Mindy I.; Barrett, Amy; Ranft, Jessica; Jagdhuhn, David; Waterstradt, Rica; Baltrusch, Simone; Simeonov, Anton; Collins, Francis S.; Hegele, Robert A.; Gloyn, Anna L.

doi:10.1093/hmg/ddu269

Cited by 21 publications

(19 citation statements)

References 30 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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 ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy—a reduction in subcutaneous adipose tissue—it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin–based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10−29), lower HDL cholesterol (β = −0.020; P = 7 × 10−37), greater hepatic steatosis (β = 0.021; P = 3 × 10−4), higher alanine transaminase (β = 0.002; P = 3 × 10−5), lower sex-hormone-binding globulin (β = −0.010; P = 9 × 10−13), and lower adiponectin (β = −0.015; P = 2 × 10−26). The same risk alleles were associated with lower BMI (per-allele β = −0.008; P = 7 × 10−8) and increased visceral-to-subcutaneous adipose tissue ratio (β = −0.015; P = 6 × 10−7). Individuals carrying ≥17 fasting insulin–raising alleles (5.5% population) were slimmer (0.30 kg/m2) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10−13), CAD (OR 1.12; per-allele P = 1 × 10−5), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10−5] and 0.67 mmHg [per-allele P = 2 × 10−4], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the “metabolic syndrome” and point to reduced subcutaneous adiposity as a central mechanism.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…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 .…”

Section: Discussionmentioning

confidence: 99%

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

Esparza

Adams‐Huet

et al. 2019

Journal of the Endocrine Society

View full text Add to dashboard Cite

Context Patients with very severe hypertriglyceridemia (triglyceride levels ≥2000 mg/dL; 22.6 mmol/L) require aggressive treatment. However, little research exists on the underlying etiologies and management of very severe hypertriglyceridemia. Objective We hypothesized (i) very severe hypertriglyceridemia in adults is mostly associated with secondary causes and (ii) most patients with very severe hypertriglyceridemia lack appropriate follow-up and treatment. Design We queried electronic medical records at Parkland Health and Hospital Systems for lipid measurements in the year 2016 and identified patients with serum triglyceride levels ≥2000 mg/dL (22.6 mmol/L). We extracted data on demographics, underlying causes, lipid-lowering therapy, and follow-up. Results One hundred sixty-four serum triglyceride measurements were ≥2000 mg/dL (22.6 mmol/L) in 103 unique patients. Of these, 60 patients were admitted to the hospital (39 for acute pancreatitis). Most were Hispanic (79%). The major conditions associated with very severe hypertriglyceridemia included uncontrolled diabetes mellitus (74%), heavy alcohol use (10%), medication use (7%), and hypothyroidism (2%). Two patients were known to have monogenic causes of hypertriglyceridemia. After the index measurement of triglycerides ≥2000 mg/dL (22.6 mmol/L), the use of triglyceride-lowering drugs increased, most prominently the use of fish oil supplements, which increased by 80%. However, in follow-up visits, hypertriglyceridemia was addressed in only 50% of encounters, and serum triglycerides were remeasured in only 18%. Conclusion In summary, very severe hypertriglyceridemia was quite prevalent (∼0.1% of all lipid measurements) in our large county health care system, especially in Hispanic men. Most cases were related to uncontrolled diabetes mellitus, and follow-up monitoring was inadequate.

show abstract

“…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.…”

Section: Multifactorial Chylomicronemiamentioning

confidence: 99%

Genetics of Hypertriglyceridemia

2020

Self Cite

View full text Add to dashboard Cite

Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of ∼1 in 600 and is at least 50-100-times more common than FCS, results from two different types of genetic variants: (1) rare heterozygous variants (minor allele frequency <1%) with variable penetrance in the five causal genes for FCS; and (2) common variants (minor allele frequency >5%) whose individually small phenotypic effects are quantified using a polygenic score. There is indirect evidence of similar complex genetic predisposition in other clinical phenotypes that have a component of hypertriglyceridemia, such as combined hyperlipidemia and dysbetalipoproteinemia. Future considerations include: (1) evaluation of whether the specific type of genetic predisposition to hypertriglyceridemia affects medical decisions or long-term outcomes; and (2) searching for other genetic contributors, including the role of genome-wide polygenic scores, novel genes, non-linear gene-gene or geneenvironment interactions, and non-genomic mechanisms including epigenetics and mitochondrial DNA.

show abstract

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

Cited by 21 publications

References 30 publications

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

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

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

Genetics of Hypertriglyceridemia

Contact Info

Product

Resources

About