Lipoprotein Lipase Is a Gene for Insulin Resistance in Mexican Americans

Goodarzi, Mark O.; Guo, Xiuqing; Taylor, Kent D.; Quiñones, Manuel J.; Saad, Mohammad F.; Yang, Huiying; Hsueh, Willa A.; Rotter, Jerome I.

doi:10.2337/diabetes.53.1.214

Cited by 100 publications

(78 citation statements)

References 42 publications

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“…Although not convincing, together with the powerful correlation between significantly decreased catalytic activity (B60% of the wild type) and secretion ability (about 50% of the wild type) of N291S mutant and deleterious lipid profile (triglycerides: 32.3% increase and HDL-C: 34.2% decrease), which are risk factors of T2D and CHD, this association may be not a false-positive result and further study is necessary and justifiable. 24 Goodarzi et al 25 analyzed haplotypes of six polymorphisms in LPL and provided compelling evidence that the LPL gene might have a role in determining insulin sensitivity (P¼0.031, haplotype 1: GATTCG) and insulin resistance (P¼0.007, haplotype 4: GAGGGG) in their MexicanAmerican population. Transgenic (Tg) watanabe heritable hyperlipidemic (WHHL) rabbits that overexpress the human LPL gene were generated by Koike et al In addition to dramatically ameliorating hypertriglyceridemia and hypercholesterolemia, overexpression of LPL was able to suppress high-diet-induced obesity and insulin resistance in these Tg WHHL rabbits.…”

Section: Lpl and T2dmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Lpl and T2dmentioning

confidence: 99%

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

et al. 2009

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“…Several indices of insulin sensitivity were obtained, including fasting insulin, glucose infusion rate (GINF) over the last 30 minutes of steady-state insulin and glucose concentrations, and the insulin sensitivity index (S I ), obtained by dividing GINF by body surface area and the increment in plasma insulin from baseline to steady state. 14 …”

Section: Phenotypingmentioning

confidence: 99%

“…14 Family samples were ascertained through a proband with documented coronary artery disease. 14,15 Two generations were enrolled into the study: the proband and proband spouses (parental generation), and their adult (age 18 years or older) offspring and the spouses of those offspring (offspring generation). The offspring were free of diabetes and clinically manifest coronary artery disease, thus avoiding secondary changes in phenotype caused by overt disease.…”

Section: Subjectsmentioning

confidence: 99%

Hypertension Genes Are Genetic Markers for Insulin Sensitivity and Resistance

et al. 2005

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Abstract-Insulin resistance is a determinant of blood pressure variation and risk factor for hypertension. Because insulin resistance and blood pressure cosegregate in Mexican American families, we thus investigated the association between variations in 9 previously reported hypertension genes (ACE, AGT, AGTRI, ADDI, NPPA, ADDRB2, SCNN1A, GNB3, and NOS3) and insulin resistance. Families were ascertained via a coronary artery disease proband in the Mexican American Coronary Artery Disease Project. Individuals from 100 Mexican American families (nϭ656) were genotyped for 14 polymorphisms in the 9 genes and all adult offspring and offspring spouses were phenotyped for insulin sensitivity by hyperinsulinemic euglycemic clamp (nϭ449). AGT M235T and NOS3 A(Ϫ922)G and E298D polymorphisms were significantly associated with insulin sensitivity (Pϭ0.018, 0.036, 0.039) but were not significant after adjusting for body mass index. ADD1 G460W was associated with insulin sensitivity only after adjusting for body mass index. The NPPA T2238C and SCNN1A A663T were associated with decreased fasting insulin levels after adjusting for body mass index (Pϭ0.015 and 0.028). (HTN) is not benign; it is strongly associated with the development of atherosclerosis and left ventricular hypertrophy resulting in congestive heart failure, stroke, and age-related macular degeneration. 1-2 The risk of complications increases with increasing blood pressure (BP), particularly systolic blood pressure (SBP). 3,4 High BP is also a major antecedent for renal failure and, after diabetes, is the second most common cause of chronic renal failure in the adult population. 1,5 Insulin resistance (IR) is a potentially important intermediate phenotype for HTN in certain populations, particularly in Mexican Americans (MAs). Cross-sectional studies have revealed correlations between IR and BP in this and other ethnic groups. 6 -8 Hyperinsulinemia preceded and predicted the development of HTN in an 8-year prospective study of MAs in San Antonio, Texas 6 and has exhibited major gene effects in at least 3 ethnic groups. 9 -11 By path analysis, we have shown that BP and IR cosegregate and have a significant genetic component independent of any relationship to body mass index (BMI). 12 This cosegregation was further confirmed in our genome scan linkage analysis, wherein we identified several regions of coincident linkage of insulin sensitivity and BP. 13 For example, fasting insulin, SBP, and mean arterial blood pressure were all mapped to the same region on chromosome 7 (112 to 128 cM). Considered together, these findings provide strong support for the concept that IR is an intermediate and genetically regulated phenotype for HTN.Although the aforementioned data may suggest that IR is a proximate cause of HTN, an alternative possibility is that both are pleiotropic manifestations of the same underlying susceptibility. In support of this latter hypothesis has been the observation that several large scale clinical trials of pharmacological agents whose targets are t...

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“…108 For example, use of the euglycemic clamp combined with the haplotype approach described has enabled identification of the lipoprotein lipase gene as a gene for insulin resistance. 62 Other detailed phenotypes include the aldosterone response to angiotensin II infusion (the modulating/nonmodulating phenotype) in hypertension 49 and LDL particle size in dyslipidemia. 40,41 Twin studies have traditionally been considered the "gold standard" of human genetic analyses.…”

Section: Genetic Markers: Approaches To Defining Cardiovascular Diseamentioning

confidence: 99%