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The enzyme nicotidamide-N-methyltransferase (NNMT) regulates adipose tissue energy expenditure through increasing nicotinamide adenosine dinucleotide (NAD + ) content. NNMT methylates nicotinamide to  N   1  -methylnicotidamide (MNA-1) using S-adenosyl methionine. The  rs 694539  NNMT  polymorphism is associated with non-alcoholic steatohepatitis, and  rs 1941404 is associated with hyperlipidemia. The  rs 1421085  FTO  is related to poor eating behaviors, and rs3751723  IRX3  is associated with obesity. To investigate the association of rs694539 and rs1941404  NNMT , rs140285  FTO  and rs3751723  IRX3  polymorphisms with MNA-1 concentrations, resting energy expenditure (REE) and BMI, we included clinically healthy Mexican subjects 30 to 50 years old, 100 subjects (35 men/65 women) with BMI > 30 kg/m 2  and 100 subjects (32 men/68 women) with BMI < 25 kg/m 2 . Glucose, lipid profile, insulin, leptin, acylated ghrelin, and MNA-1 (LC–MS) were quantified. Resting energy expenditure (REE) was estimated using indirect calorimetry with a Fitmate instrument. Genotyping was performed using PCR–RFLP, and allelic discrimination was examined using TaqMan probes. MNA-1 concentrations and REE were significantly higher in obese subjects. Subjects with the rs694539AA  NNMT  genotype (recessive model) had lower weight, BMI, and REE. BMI showed an association with HDL-C, triglycerides, MNA-1, acetylated ghrelin, leptin, insulin concentrations, HOMA-IR, REE, and rs1421085. Subjects with the TC or CC genotypes of rs1421085  FTO  showed 6 kg and 2 units of BMI more than did those with the TT wild type. The CG of the rs1421085 and rs3751723 haplotypes was associated with BMI. These findings showed that BMI was strongly associated with REE, rs1421085  FTO  and the CG rs1421085  FTO  and rs3751723  IRX3  haplotypes. We used the GMDR approach in obesity phenotype to show the interaction of four SNPs and metabolic variables.

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Associations of nicotidamide-N-methyltransferase, FTO, and IRX3 genetic variants with body mass index and resting energy expenditure in Mexican subjects