Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23

Pajukanta, Päivi; Nuotio, Ilpo; Terwilliger, Joseph D.; Porkka, Kimmo; Ylitalo, Kati; Pihlajamäki, Jussi; Suomalainen, Aki J.; Syvänen, Ann‐Christine; Lehtimäki, Terho; Viikari, Jorma; Laakso, Markku; Taskinen, Marja‐Riitta; Ehnholm, Christian; Peltonen, Leena

doi:10.1038/ng0498-369

Cited by 230 publications

(157 citation statements)

References 24 publications

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“…A total of 99 Finnish dyslipidemic families (60 FCHL and 39 low-HDL cholesterol families) were recruited in the Helsinki and Turku University Central Hospitals (14,15,27). All study subjects gave their informed consent.…”

Section: Methodsmentioning

confidence: 99%

Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome

et al. 2006

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Hepatic nuclear factor-4␣ (HNF-4␣), a transcription factor involved in the regulation of serum lipid and glucose levels, has recently been associated with type 2 diabetes. The HNF-4␣ gene (HNF4A) resides on chromosome 20q12-q13.1, which, in addition to type 2 diabetes, has also previously been linked to high triglycerides in Finnish familial combined hyperlipidemia (FCHL) families. FCHL, characterized by elevated levels of serum total cholesterol, triglycerides, or both, is a common dyslipidemia observed in up to 20% of patients with premature coronary heart disease. Considering the clear phenotypic overlap between type 2 diabetes and FCHL, both predisposing to high serum triglycerides and glucose intolerance, we tested this gene for association in dyslipidemic families originating from two distinct populations, Finnish and Mexican, and comprising 1,447 subjects. Our data show that common HNF4A variants and haplotypes are associated with elevated serum lipid levels and the metabolic syndrome (P ‫؍‬ 0.008 -0.04), as well as with elevated glucose parameters (P ‫؍‬ 0.008 -0.03), using family-based association analysis. Importantly, both Finnish and Mexican families shared two common lipid-associated HNF4A haplotypes (P ‫؍‬ 0.005 for total cholesterol and 0.006 for triglycerides). In conclusion, we show for the first time that common HNF4A variants are associated with high serum lipid levels and the metabolic syndrome.

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Section: Methodsmentioning

confidence: 99%

Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome

et al. 2006

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“…Two recent reports, 1 based on families ascertained in Finland and the other based on a mouse model of FCHL, have strongly suggested the existence of a novel gene for FCHL on chromosome 1. 47,48 In addition, Dallinga et al 49 showed that DNA variations in the apo AI-CIII-AIV gene cluster modify plasma TGs, LDL-C, and apo CIII levels in families with FCHL. Recent sib-pair linkage analysis also provides evidence for common genetic influences on LDL size, TG, and HDL-C.…”

Section: Edwards Et Al Quantitative Genetic Analysis Of Lipids/lipoprmentioning

confidence: 99%

Pleiotropic Genetic Effects on LDL Size, Plasma Triglyceride, and HDL Cholesterol in Families

Edwards

Mahaney

Motulsky

et al. 1999

ATVB

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Abstract-The interrelationships among low density lipoprotein (LDL) particle size, plasma triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) are well established and may involve underlying genetic influences. This study evaluated common genetic effects on LDL size, TG, and HDL-C by using data from 85 kindreds participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study. A multivariate, maximum likelihood-based approach to quantitative genetic analysis was used to estimate the additive effects of shared genes and shared, unmeasured nongenetic factors on variation in LDL size and in plasma levels of TG and HDL-C. A significant (PϽ0.001) proportion of the variance in each trait was attributable to the additive effects of genes. Maximum-likelihood estimates of heritability were 0.34 for LDL size, 0.41 for TG, and 0.54 for HDL-C. Significant (PϽ0.001) additive genetic correlations ( G ), indicative of the shared additive effects of genes on pairs of traits, were estimated between all 3 trait pairs: for LDL size and TG G ϭϪ0.87, for LDL size and HDL-C G ϭ0.65, and for HDL-C and TG G ϭϪ0.54. A similar pattern of significant environmental correlations between the 3 trait pairs was also observed. These results suggest that a large proportion of the well-documented correlations in LDL size, TG, and HDL-C are likely attributable to the influence of the same gene(s) in these families. That is, the gene(s) that may contribute to decreases in LDL size also contribute significantly to higher plasma levels of TG and lower plasma levels of HDL-C. These relationships may be useful in identifying genes responsible for the associations between these phenotypes and susceptibility to cardiovascular disease in these families.

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“…USF1 is associated with familial combined hyperlipidemia (FCHL) (16)(17)(18), which is the most common genetic dyslipidemia, and because of its characteristic features such as increased levels of apolipoprotein B, serum triglycerides, and total serum cholesterol (TC), a phenotypic overlap between FCHL, T2DM, and the metabolic syndrome exists (19,20).…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

Holzapfel

Baumert²,

Grallert³

et al. 2008

European Journal of Endocrinology

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Objective: Upstream transcription factor 1 (USF1) regulates genes of glucose and lipid metabolism. Polymorphisms in the USF1 gene showed association with familial combined hyperlipidemia and lipid parameters. The aim of our study was to examine the associations between USF1 polymorphisms and lipid parameters as well as incident type 2 diabetes mellitus (T2DM) in German Caucasians. Design: We genotyped eight polymorphisms in the USF1 gene in 2067 middle-aged (35-74 years) individuals including 498 incident T2DM cases and 1569 non-cases of the population-based casecohort study from the MONICA/KORA Augsburg project. Methods: Six polymorphisms and their haplotypes were analyzed using multivariable linear regression and Cox proportional hazards models. Results: Polymorphism rs3737787 was inversely associated with incident T2DM in women with decreased risk for female heterozygotes compared with women homozygous for the major allele (Hazard ratioZ0.57; 95% confidence intervals: 0.38-0.87; PZ0.008). After correction for multiple testing, significance remained. Polymorphisms rs3813609 and rs1556259 were significantly associated with reduction in low-density lipoprotein (LDL) cholesterol (p NOM Z0.001; p NOM Z0.00002) in women. Analyses also indicated associations of haplotypes with LDL cholesterol in women, but the association lost statistical significance after correction for multiple testing. Total serum cholesterol (TC) and high-density lipoprotein (HDL) cholesterol were weakly associated (P!0.05) with USF1 polymorphisms in women. No significant associations were found in men. Conclusions:In this large population-based study, statistically significant associations of USF1 polymorphisms with incident T2DM and LDL cholesterol were found in women, but not in men. Genetic variants in the USF1 gene showed weak or no associations with TC and HDL cholesterol.European Journal of Endocrinology 159 407-416

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Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23

Cited by 230 publications

References 24 publications

Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome

Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome

Pleiotropic Genetic Effects on LDL Size, Plasma Triglyceride, and HDL Cholesterol in Families

Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

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