Genetic Variant of AMD1 Is Associated with Obesity in Urban Indian Children

Abstract

BackgroundHyperhomocysteinemia is regarded as a risk factor for cardiovascular diseases, diabetes and obesity. Manifestation of these chronic metabolic disorders starts in early life marked by increase in body mass index (BMI). We hypothesized that perturbations in homocysteine metabolism in early life could be a link between childhood obesity and adult metabolic disorders. Thus here we investigated association of common variants from homocysteine metabolism pathway genes with obesity in 3,168 urban Indian children.Methodology/Principal FindingsWe genotyped 90 common variants from 18 genes in 1,325 children comprising of 862 normal-weight (NW) and 463 over-weight/obese (OW/OB) children in stage 1. The top signal obtained was replicated in an independent sample set of 1843 children (1,399 NW and 444 OW/OB) in stage 2. Stage 1 association analysis revealed association between seven variants and childhood obesity at P<0.05, but association of only rs2796749 in AMD1 [OR = 1.41, P = 1.5×10-4] remained significant after multiple testing correction. Association of rs2796749 with childhood obesity was validated in stage 2 [OR = 1.28, P = 4.2×10-3] and meta-analysis [OR = 1.35, P = 1.9×10-6]. AMD1 variant rs2796749 was also associated with quantitative measures of adiposity and plasma leptin levels that was also replicated and corroborated in combined analysis.Conclusions/SignificanceOur study provides first evidence for the association of AMD1 variant with obesity and plasma leptin levels in children. Further studies to confirm this association, its functional significance and mechanism of action need to be undertaken.

Obesity and Dyslipidemia in South Asians

“…In another important study, LMNA 1908T/T and C/T genotypes emerged as independent genetic risk factors for generalized obesity in non-diabetic Asian Indians in north India [132]. Association of AMD1 variant with obesity has been shown in Asian Indian children [133]. Further, there is recent evidence for genetic associations of NAFLD with SREBP-2 1784 G>C genotype [134] and peroxisome proliferator activated receptor-γ (Pro12Ala and C161T) polymorphisms [135] in Asian Indians.…”

“…A recent study has shown DOK5 as a susceptibility gene for obesity and T2DM in Asian Indians in north India [136]. Finally, genetic susceptibility of Asian Indians to development of dyslipidemia has been shown in some studies [131,132,133,136,137,138,139]. …”

Genetic variations in SEC16B, MC4R, MAP2K5 and KCTD15 were associated with childhood obesity and interacted with dietary behaviors in Chinese school-age population

“…In our study, to achieve a power of not less than 80%, the SNPs which were reported significantly associated with BMI or WC in GWAS (P ≤ 10 × 10 − 8 ) and minor allele frequencies N 0.10 in Chinese population in the HapMap database, were selected. Nineteen SNPs (rs6548238(TMEM18) (Willer et al, 2009), rs10838738(MTCH2) (Willer et al, 2009), rs10938397(GNPDA2) (Willer et al, 2009), rs11084753(KCTD15) (Willer et al, 2009), rs2815752(NEGR1) (Willer et al, 2009), rs2605100(LYPLAL1) (Lindgren et al, 2009), rs545854(MSRA) (Lindgren et al, 2009), rs987237(TFAP2B) (Lindgren et al, 2009), rs17782313(MC4R) (Meyre et al, 2009), rs2241423(MAP2K5) (Speliotes et al, 2010), rs4929949(RPL27A) (Speliotes et al, 2010), rs6265(BDNF) (Thorleifsson et al, 2009), rs543874(SEC16B) 32, rs7647305(ETV5) (Thorleifsson et al, 2009), rs16933812(PAX5) (Graff et al, 2013), rs9356744(CDKAL1) (Wen et al, 2012), rs2796749(AMD1) (Tabassum et al, 2012), rs9299(HOXB5) (Bradfield et al, 2012) and rs9568856(OLFM4) (Bradfield et al, 2012)) were included in this study (Supplementary Table 1).…”

Foetal programming by methyl donor deficiency produces steato-hepatitis in rats exposed to high fat diet

“…Studies in India and Nepal found vitamin B12 deficiency during pregnancy to be the most significant predictor of small birth weight, abdominal fat and insulin resistance in children aged 6 to 8 years456. A variant of SAM decarboxylase was associated with childhood obesity, in another Indian study7. In addition, the rates of methylation of homocysteine and transmethylation of methionine were significantly lower in 15 subjects with NASH compared with 19 healthy age-matched controls8.…”