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

Weissglas‐Volkov, Daphna; Huertas‐Vazquez, Adriana; Suviolahti, Elina; Lee, Jenny; Plaisier, Christopher L.; Canizales‐Quinteros, Samuel; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Taskinen, Marja‐Riitta; Pajukanta, Päivi

doi:10.2337/db06-0035

Cited by 58 publications

(55 citation statements)

References 47 publications

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“…Taking into consideration that we observed signifi cant gender differences in heritability estimates for TRIGs and in obesity levels, future studies should test for similar HNF4A associations in an independent sample of African ancestry women and those with a wider range in body weight. Nonetheless, similar to our fi ndings, another family study showed that rs3212198 was associated with TRIG in families of European and Mexican ancestry ( 42 ).…”

Section: Discussionsupporting

confidence: 78%

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

Miljkovic

Yerges‐Armstrong

Kuller

et al. 2010

Journal of Lipid Research

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Lipoprotein abnormalities, characterized by elevated levels of LDL cholesterol (LDL-C) and triglycerides (TRIG) and low levels of HDL cholesterol (HDL-C), have a central role in the development of atherosclerotic coronary heart disease (CHD). A recent meta-analysis, including 3,000 individuals with CHD-related deaths, showed that HDL-C and LDL-C are independently associated with CHD risk ( 1 ). There is also considerable evidence that high levels of TRIG are an additional, independent risk factor for CHD ( 2, 3 ), although this is still controversial ( 4 ).Individuals of African ancestry have a more favorable lipoprotein profi le than Caucasians, characterized by lower levels of TRIG and higher levels of HDL-C ( 5-8 ).The mechanisms responsible for these ethnic differences remain to be defi ned. In particular, the differences in TRIG levels are independent of the greater degree of obesity among individuals of African ancestry and several other risk factors and appear to be consistent across African populations in different environments ( 9 ), indicating a possible role of genetic factors. Although genetic factors are important in determining lipoprotein levels, little data Abstract African ancestry individuals have a more favorable lipoprotein profi le than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 AfroCaribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21-113, 3,426 relative pairs). All lipoproteins were signifi cantly heritable ( P < 0.05). Gender-specifi c analysis showed that heritability for triglycerides was much higher ( P < 0.01) in women than in men (women, 0.62 ± 0.18, P < 0.01; men, 0.13 ± 0.17, P > 0.10), but the heritability for LDL cholesterol ( LDL-C) was higher ( P < 0.05) in men than in women (men, 0.79 ± 0.21, P < 0.01; women, 0.39 ± 0.12, P < 0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed signifi cant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9 ) and LDL-C in both the family study and in the replication study. Our fi ndings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals.

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Section: Discussionsupporting

confidence: 78%

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

Miljkovic

Yerges‐Armstrong

Kuller

et al. 2010

Journal of Lipid Research

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“…Two of these regions, 3p26.1 to 3p13 and 20p11.21 to 20q13.32, are located near genes which have been previously associated with either free fatty acid or triglyceride levels in FCHL cohorts. 19,20 No evidence for linkage was obtained for the region containing the SCD1 gene on chromosome 10 ( Figure 1). Additional adjustment of the desaturation index for triglyceride and HDL-C levels did not significantly alter the results (Figure 1 The strongest evidence for linkage was located on chromosome 3 near the PPAR-␥ gene (zϭ2.7, Pϭ0.003).…”

Section: Resultsmentioning

confidence: 99%

Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Mar‐Heyming

Miyazaki

Weissglas‐Volkov

et al. 2008

ATVB

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Objective-Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme involved in the synthesis of monounsaturated fatty acids, and in mice SCD1 activity is associated with plasma triglyceride levels. We used the fatty acid desaturation index (the plasma ratio of 18:1/18:0) as a marker of SCD1 activity to investigate the relationship of SCD1 to familial combined hyperlipidemia (FCHL). Methods and Results-The fatty acid desaturation index was measured in 400 individuals from 18 extended FCHL pedigrees. FCHL-affected individuals exhibited increased SCD1 activity when compared to unrelated controls (PϽ0.0001). The fatty acid desaturation index was found to be highly heritable (h 2 ϭ0.48, Pϭ2.2ϫ10 Ϫ11 ) in this study sample. QTL analysis in 346 sibling pairs from 18 FCHL families revealed suggestive linkage of the desaturation index to chromosomes 3p26.1 to 3p13 (zϭ2.7, Pϭ0.003), containing the peroxisome proliferator-activated receptor gamma (PPAR␥) gene, and 20p11.21 to 20q13.32 (zϭ1.7, Pϭ0.04), containing the hepatocyte nuclear factor 4, alpha (HNF4␣) gene. A specific haplotype of HNF4␣ was found to be associated with the desaturation index in these FCHL families (Pϭ0.002). Conclusion-Our results demonstrate that the fatty acid desaturation index is a highly heritable trait that is associated with the dyslipidemia observed in FCHL. (Arterioscler Thromb Vasc Biol 2008;28:1193-1199)Key Words: familial combined hyperlipidemia Ⅲ genetics Ⅲ Stearoyl-CoA desaturase 1 Ⅲ peroxisome proliferator-activated receptor gamma Ⅲ hepatocyte nuclear factor 4 alpha S tearoyl-coenzyme A (CoA) desaturase (SCD) is the major enzyme which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. The primary products of SCD-1, palmitate and oleate, are the most abundant monounsaturated fatty acids of phospholipids, triglycerides, wax esters, and cholesterol esters. 1 Mice homozygous for either a naturally occurring mutation or a targeted disruption of the SCD1 gene exhibit a marked reduction in VLDL triglycerides. 2 SCD1 Ϫ/Ϫ mice on a leptin-deficient ob/ob background exhibit reduced adiposity and increased fatty acid oxidation when compared to control animals, demonstrating a key role for SCD1 in the regulation of lipid homeostasis. 2 Familial combined hyperlipidemia (FCHL) is characterized by elevated plasma triglyceride or cholesterol levels. 3 FCHL often occurs in combination with insulin resistance, central adiposity, altered fatty acid metabolism, and other dyslipidemic phenotypes that predispose to early coronary artery disease (CAD). 4,5 The observed role of SCD1 in the regulation of VLDL metabolism and its involvement in many of the lipid parameters that are perturbed in FCHL suggest that the activity of this enzyme may be altered in FCHL subjects. In fact, the desaturation index was strongly correlated with both triglyceride and HDL levels in a human cohort of which approximately 60% of the subjects had FCHL. 6 In mice, studies of SCD activity in the HYPLIP mouse model of hyperlipidemia showed that hepa...

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“…5). In addition to IBD, human HNF4A variants are associated with metabolic syndrome (Weissglas-Volkov et al 2006) and type 2 diabetes (Ma et al 2016). Interestingly, microbiota have also been implicated in both of these diseases (Qin et al 2012;Vrieze et al 2012), raising the possibility that microbiota suppression of HNF4A trans activity could play a role in these diseases as well.…”

Section: Discussionmentioning

confidence: 99%

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

et al. 2017

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Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of nuclear receptor transcription factors with important roles in human metabolic and inflammatory bowel diseases, but a role in host response to microbes is unknown. Using an unbiased screening strategy, we found that zebrafish Hnf4a specifically binds and activates a microbiota-suppressed intestinal epithelial transcriptional enhancer. Genetic analysis revealed that zebrafish hnf4a activates nearly half of the genes that are suppressed by microbiota, suggesting microbiota negatively regulate Hnf4a. In support, analysis of genomic architecture in mouse intestinal epithelial cells disclosed that microbiota colonization leads to activation or inactivation of hundreds of enhancers along with drastic genome-wide reduction of HNF4A and HNF4G occupancy. Interspecies meta-analysis suggested interactions between HNF4A and microbiota promote gene expression patterns associated with human inflammatory bowel diseases. These results indicate a critical and conserved role for HNF4A in maintaining intestinal homeostasis in response to microbiota.

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

Cited by 58 publications

References 47 publications

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry

Association of Stearoyl-CoA Desaturase 1 Activity With Familial Combined Hyperlipidemia

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

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