Gender flip-flop association between genetic variations of NEDD4L and metabolic syndrome in the Kazakh general population

Abstract

ABSTRACT. Genetic variation is thought to contribute to etiology of metabolic syndrome (MS). Neural precursor cell expressed developmentally downregulated 4-like gene (NEDD4L) is a candidate gene for MS. This study investigated the relationship between variations of NEDD4L and MS in the Kazakh, which is an ideal population to study the genetic mechanisms of complex diseases such as MS. We screened the promoter and exons of NEDD4L in 48 Kazakh individuals with MS to identify representative variations. By genotyping the representative variations [271420T>C (rs2288774), 271454A>G (rs2288775), and 296921-296923delTTG] in the Kazakh general population, we conducted a case-control study. In female subjects, the distribution of genotypes and alleles of rs2288775 and 296921-296923delTTG differed significantly between the MS pacients and controls. In male subjects, the genotype distributions of 296921-296923delTTG were significantly different between the MS pacients and controls in the dominant model (P = 0.047). After adjustment for age, smoking, and drinking, multivariate logistic regression analysis showed that rs2288775 was significantly associated with MS [for the A/A genotype, odds ratio (OR) = 3.296, P = 0.011] in female subjects. For 296921-296923delTTG, the I/D+D/D genotype was the high-risk genotype for MS in female subjects (OR = 2.791, P = 0.035) and was a protective factor for MS in male subjects (OR = 0.580, P = 0.045). The 296921-296923delTTG variation of NEDD4L is a gender flipflop associated with MS in Kazakh individuals. The A allele of rs2288775 may be an independent risk factor for MS in Kazakh women. The results suggest that the genetic variations of NEDD4L might be involved in the pathogenesis of MS.

A Genome-wide study of blood pressure in African Americans accounting for gene-smoking interaction

“…In addition, a SNP close to NEDD4L is strongly associated with the serum level of a liver enzyme, gamma-glutamyl transferase (p-value of 3 × 10 −12 ) in a GWAS 34 . In other genomic studies, NEDD4L has also been shown to be associated with hypertension 35 , obesity 36 , smoking and cancer 37 among a homogeneous population of Chinese Kazakh herders. Although these informative studies shed light on the associations of NEDD4L and hypertension and smoking independently, our study expands this work by examining and the independent and interactive effects of genetics and smoking on blood pressure among an African American population.…”

Inter-Individual Variation and Cardioprotection in Anthracycline-Induced Heart Failure

“…However, an independent and much larger GWAS study of 3431 patients with breast cancer found significant association ( p = 4.1 × 10 −6 ) but with the opposite allele. This is highly relevant for transfer to the clinic, and we note here that there are many examples in the literature with a flip-flop effect in which the opposite alleles of the same variant are associated with increased risk of disease, which occur when the investigated variant is correlated with the true causative/functional variant through interactive effects or linkage disequilibrium which differs between populations [ 57 , 58 , 59 , 60 ]. Therefore, what may be required to truly move this gene towards clinical guidance is additional fine mapping and exon sequencing across different populations of patients with anthracycline-induced heart failure.…”