Expressive

rs12143789 (TBX15): Body Fat Distribution Variant

Key takeaways

  • rs12143789 near TBX15 is linked to waist-to-hip ratio in studies of over 200,000 adults
  • Effects on body fat distribution appear stronger in women than in men
  • This variant increases WARS2 gene activity in thyroid, breast, and artery tissue
  • Loci in this region are enriched for genes active in fat (adipose) tissue
  • Smoking may interact with some body fat distribution variants in this chromosomal region

Key takeaways

  • rs12143789 near TBX15 (T-box transcription factor 15) has been linked to waist-to-hip ratio adjusted for body mass index (WHRadjBMI) in studies of over 200,000 adults
  • Effects on body fat distribution appear stronger in women than in men, based on large-scale genetic meta-analyses
  • This variant increases expression of the nearby WARS2 gene (a mitochondrial enzyme involved in protein synthesis) in thyroid, breast, and artery tissue
  • Loci in this region are enriched for genes active in fat (adipose) tissue, pointing to a local cellular mechanism
  • Smoking may interact with some body fat distribution loci in this chromosomal region, though whether this applies specifically to rs12143789 requires further study

What the research says A genome-wide meta-analysis of up to 224,459 individuals identified 49 loci for WHRadjBMI, 33 of which were newly discovered, with associated genes enriched in adipose tissue and in pathways involving fat cell development (adipogenesis), blood vessel formation (angiogenesis), and insulin resistance PMID 25673412. A subsequent meta-analysis of 241,258 individuals (87% European ancestry) that accounted for current smoking status identified 23 additional novel loci for obesity-related traits and 9 loci with significant gene-smoking interactions (GxSMK), including 5 interaction loci specifically affecting WHRadjBMI, suggesting that tobacco use may alter genetic susceptibility to body fat distribution patterns PMID 30054458. Expression quantitative trait locus (eQTL) analysis - a method linking genetic variants to changes in gene activity - shows the ALT allele of rs12143789 increases expression of WARS2 and its antisense transcript WARS2-AS1 across thyroid, breast, nerve, and esophageal tissues GTEx Portal.

Reported associations

  • Waist-to-hip ratio adjusted for BMI (WHRadjBMI): Identified as one of 49 genome-wide significant loci in a meta-analysis of up to 224,459 adults; 20 of the 49 loci showed significant sexual dimorphism, with 19 displaying stronger effects in women, and WHRadjBMI heritability was estimated at h2 = 0.46 in women versus h2 = 0.19 in men in the Framingham Heart cohort PMID 25673412
  • WHRadjBMI with gene-smoking interaction context: A meta-analysis of 241,258 individuals (51,080 current smokers and 190,178 nonsmokers) found 9 loci with significant GxSMK interactions on obesity traits, 5 of which affected WHRadjBMI specifically, indicating that smoking behavior may modify genetic effects on central body fat distribution at loci in this region PMID 30054458

Evidence quality Both source studies are large-scale meta-analyses applying genome-wide significance thresholds (P < 5 x 10-8), providing robust statistical power for detecting associations in this region PMID 25673412. The Justice et al. analysis drew on 57 GWAS cohorts and 22 Metabochip studies, with independent replication confirming consistent direction of effect for 18 of 23 novel loci and 5 of 9 interaction loci PMID 30054458. Both studies enrolled predominantly European-ancestry participants (87% in Justice et al.), limiting generalizability across populations PMID 30054458. Specific per-allele effect sizes for rs12143789 were not available in the study excerpts provided. Whether gene-smoking interactions apply to this specific variant rather than to the broader class of WHRadjBMI loci identified by Justice et al. is unresolved and requires further targeted investigation.

Tissue-specific expression effects

  • WARS2-AS1: The ALT allele is associated with increased expression of this antisense RNA in pituitary gland, esophagus (gastroesophageal junction and muscular layer), tibial nerve, and thyroid tissue GTEx Portal
  • WARS2: The ALT allele is associated with increased expression of WARS2 in thyroid, breast (mammary) tissue, and tibial artery GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Screening

  • waist-to-hip ratio Moderate

    This variant increases waist-to-hip ratio independent of body mass index, indicating altered fat distribution.

    Measure and track waist-to-hip ratio at least annually

Frequently asked questions

What is the TBX15 gene?

TBX15 (T-box transcription factor 15) is a developmental regulatory gene. Variants near it, including rs12143789, have been identified in large genetic studies as associated with body fat distribution, particularly waist-to-hip ratio adjusted for body mass index.

Is rs12143789 linked to obesity?

rs12143789 is primarily linked to body fat distribution - specifically the ratio of waist to hip circumference after accounting for overall body size - rather than to overall body weight or general obesity.

Does rs12143789 affect men and women differently?

Large genetic studies found that many waist-to-hip ratio loci in this region show stronger effects in women than in men. In one major study, heritability of waist-to-hip ratio was estimated at 0.46 in women versus 0.19 in men in the Framingham Heart cohort.

What does the WARS2 gene do and why is it relevant here?

WARS2 encodes a mitochondrial enzyme involved in protein synthesis. rs12143789 increases WARS2 expression in thyroid, breast, and artery tissue according to GTEx data, suggesting a potential biological mechanism, though a direct causal link to body fat distribution has not been established.

Can smoking change the genetic effects of rs12143789?

A large study of 241,258 individuals found that smoking interacts with a subset of waist-to-hip ratio loci to modify their effects on body fat distribution. Whether this interaction applies specifically to rs12143789 has not been confirmed in available study data.