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The common biological basis for common complex diseases: evidence from lipoprotein lipase gene.

ABSTRACT: The lipoprotein lipase (LPL) gene encodes a rate-limiting enzyme protein that has a key role in the hydrolysis of triglycerides. Hypertriglyceridemia, one widely prevalent syndrome of LPL deficiency and dysfunction, may be a risk factor in the development of dyslipidemia, type II diabetes (T2D), essential hypertension (EH), coronary heart disease (CHD) and Alzheimer's disease (AD). Findings from earlier studies indicate that LPL may have a role in the pathology of these diseases and therefore is a common or shared biological basis for these common complex diseases. To examine this hypothesis, we reviewed articles on the molecular structure, expression and function of the LPL gene, and its potential role in the etiology of diseases. Evidence from these studies indicate that LPL dysfunction is involved in dyslipidemia, T2D, EH, CHD and AD; and support the hypothesis that there is a common or shared biological basis for these common complex diseases.

SUBMITTER: Xie C

PROVIDER: S-EPMC2987160 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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The common biological basis for common complex diseases: evidence from lipoprotein lipase gene.

Xie Cui C Wang Zeng Chan ZC Liu Xiao Feng XF Yang Mao Sheng MS

European journal of human genetics : EJHG 20100101 1

The lipoprotein lipase (LPL) gene encodes a rate-limiting enzyme protein that has a key role in the hydrolysis of triglycerides. Hypertriglyceridemia, one widely prevalent syndrome of LPL deficiency and dysfunction, may be a risk factor in the development of dyslipidemia, type II diabetes (T2D), essential hypertension (EH), coronary heart disease (CHD) and Alzheimer's disease (AD). Findings from earlier studies indicate that LPL may have a role in the pathology of these diseases and therefore is ...[more]

PMID: 19639021

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Project description:The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease.To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD).In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305?699 individuals of the Global Lipids Genetics Consortium and up to 120?600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis.Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels.Circulating lipid levels and CAD.Among 46?891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32?646 control participants (0.32%) and 83 of 14?245 participants with early-onset CAD (0.58%). Compared with 46?703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio?=?1.84; 95% CI, 1.35-2.51; P?<?.001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P?=?1.1?×?10-22) per 1-SD increase in triglycerides.The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.

Dataset Information

The common biological basis for common complex diseases: evidence from lipoprotein lipase gene.

Publications

The common biological basis for common complex diseases: evidence from lipoprotein lipase gene.

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