Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level.

Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.43). 07/2003; 88(6):2548-51.
Source: PubMed

ABSTRACT The serum level of high-density lipoprotein cholesterol (HDL-c), which protects against the development of atherosclerosis, is under genetic control. However, the genetic components responsible for the serum HDL-c level are yet to be determined. A recent knockout mouse study demonstrated that hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is an essential transcriptional regulator of HDL-c metabolism. In this study, the association of an HNF-1 alpha gene polymorphism, isoleucine (Ile) 27 leucine (Leu), with lipid parameters, in particular with serum HDL-c level, was studied in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the three genotypes, the serum HDL-c level was significantly associated with the genotype (P < 0.01, trend test). Subjects with the Ile/Ile genotype had low serum HDL-c levels, and those with the Leu/Leu genotype had high serum HDL-c levels. These results demonstrate that the HNF-1 alpha gene locus is associated with serum HDL-c level and suggest that the Ile27 allele is a risk marker for atherosclerosis.

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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a genetically heterogeneous disease, hepatocyte nuclear factor-1 homeobox A (HNF1A) single-nucleotide polymorphisms (SNPs) playing a minor role in its pathogenesis. HNF1A is a frequent cause of monogenic diabetes, albeit with early-onset. Some uncommon subgroups like late-onset autosomal dominant diabetes mellitus (LOADDM) may present peculiar inheritance patterns with a stronger familial component. This study aims to investigate the relationship of HNF1A SNPs with cardiovascular risk factors in this group, as well as to characterize them in contrast with classical T2DM (CT2DM). eighteen LOADDM (age at onset > 40 y.o.; diabetes in 3 contiguous generations, uniparental lineage) along with 48 CT2DM patients and 42 normoglycemic controls (N group) have been evaluated for cardiovascular risk factors and SNPs of HNF1A. LOADDM showed significantly higher frequencies of SNPs A98V (22.2% vs 2.1%, p = 0.02) and S487N (72.2% vs 43.8%, p = 0.049) of HNF1A compared to CT2DM. I27L did not show significant difference (66.7% vs 45.8%), but associated with lower risk of hypertriglyceridemia (OR 0.16, 95% CI 0.04-0.65, p = 0.01). "Protective effect" was independent from other well-known predictive risk factors for hypertriglyceridemia, such as waist circumference (OR 1.09 per 1 cm increase, p = 0.01) and HDL (OR 0.01 per 1 mmol/l, p = 0.005), after logistic regression. Late onset autosomal dominant diabetes mellitus is clinically indistinguishable from classical type 2 diabetes individuals. However, LOADDM group is enriched for common HNF1A polymorphisms A98V and S487N. I27L showed "protective effect" upon hypertriglyceridemia in this sample of individuals, suggesting a role for HNF1A on diabetic individuals' lipid profile. These data contribute to the understanding of the complex interactions between genes, hyperglycemia and cardiovascular risk factors development in type 2 diabetes mellitus.
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    ABSTRACT: The common variants p.I27L (rs1169288), p.A98V (rs1800574) and p.S487N (rs2464196) of the hepatocyte nuclear factor 1-α (HNF1A) gene have been inconsistently associated with impaired glucose tolerance and/or an increased risk of type 2 diabetes mellitus (T2DM). The present study aimed to investigate whether these associations are affected by weight.
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