RUNX1T1 rs34269950 is associated with obesity and metabolic syndrome

Background: Runt-related transcription factor 1 (RUNX1T1) isoforms are involved in adipogenesis. RUNX1T1 is mediated by the fat mass and obesity-associated (FTO). However, the extent to which RUNX1T1 single nucleotide polymorphisms (SNPs), are associated with obesity risk or metabolic abnormalities in a community population basis is unknown. Methods: Samples were obtained from the Australian Crossroads study bio-bank. SNPs located in the coding region and 3’untranslated regions of RUNX1T1 with minor allele frequency (MAF) ≥ 0.05 were analysed using Taqman genotyping assays. Results: 8 candidate SNPs were genotyped successfully in 1440 participants. Of these SNPs only rs34269950 located in the “RRACH” motif, the most common N6-methyladenosine (m6A) methylation modification site (recognized by FTO), was significantly associated with obesity risk and metabolic abnormalities. Specifically, compared to AA genotype, rs34269950 del/del genotype was associated with a 1.47 (95% CI: 1.01-2.14, P = 0.042) fold higher rate of obesity risk. Additionally, the del/del genotype was associated with a 60% increased risk of metabolic syndrome (MetS) (OR = 1.60, 95% CI: 1.10 - 2.32, P = 0.015), in comparison to the AA genotype. Finally, rs34269950 del/del increased the risk of a larger waist circumference (OR = 1.65, 95% CI: 1.15 – 2.36, P = 0.007), but not other components of MetS. Conclusion: Our study demonstrates that RUNX1T1 rs34269950, located in a potential FTO recognition motif, is significantly associated with waist circumference. This provides novel evidence to suggest SNPs located in RRACH motif may be involved in RNA m6A modification and mechanistic pathways that influence abdominal obesity.