Abstract
NEDD4L is a candidate gene for hypertension, both functionally and genetically. Recently, studies showed evidence for the association of NEDD4L with obesity, a key intermediate phenotype in hypertension. To further investigate the relationship between NEDD4L and body mass-related phenotypes, we genotyped three common variants (rs2288774, rs3865418 and rs4149601) in a population-based study of 892 unrelated Han Cantonese using the Sequenom MALDI-TOF-MS platform. Allele frequencies and genotype distribution were calculated in lean controls and overweight/obese cases and analyzed for association by the Chi-squared test and Logistic regression. Linear regression analysis was used to analyze the effect of individual genotypes on quantitative traits. Multivariate analyses demonstrated that the minor allele of rs4149601(A = 20.9%) was associated with a 2.60 kg, 2.78 cm and 0.97 kg/m2 decrease per allele copy in weight, waist and BMI, respectively. Carriers of this allele also had a significant lower risk of overweight/obesity (p < 0.0001, OR = 0.52, 95% CI: 0.37–0.74) as compared to non-carriers. However, no significant association between genotypes at rs2288774 and rs3865418 and covariate-adjusted overweight/obesity or any related phenotypes was observed. These results suggested that the functional variant of NEDD4L, rs4149601, may be associated with obesity and related phenotypes, and further genetic and functional studies are required to understand its role in the manifestation of obesity.
Highlights
Numerous linkage studies have indicated NEDD4L as a candidate gene for essential hypertension among different populations [1,2,3,4]
A common polymorphism located at exon 1 of the NEDD4L gene was shown to be associated with obesity in Kazakh [10] and to not be associated in the same group for another common polymorphism located at intron 12 [15]
A test for Hardy-Weinberg Equilibrium (HWE) suggested that the genotypes for all the single-nucleotide polymorphisms (SNPs) were in Hardy-Weinberg proportions, and there was no deviation from HWE among normal weight subjects (p = 0.79, 0.71 and 0.49 for rs2288774, rs3865418 and rs4149601, respectively)
Summary
Numerous linkage studies have indicated NEDD4L as a candidate gene for essential hypertension among different populations [1,2,3,4]. No other studies and replications are available on the issue of whether NEDD4L genetic variation is a contributing factor to the risk of obesity. These common variants may become involved in obesity-related phenotypes. The effect of the NEDD4L genetic variation on obesity-related phenotypes remains unclear, and there was no association analysis of common variants in NEDD4L with BMI in non-Asian populations. Our study focused on the association of genetic variation in NEDD4L with obesity and 11 related phenotypes in a genetically isolated Han Chinese population, which we have previously used successfully to identify single-nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes. Three common variants (rs4149601, rs3865418 and rs2288774) were selected from dbSNP and from NCBI, based on their position in the gene, minor allele frequency and previous studies
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