Annual Meeting of the NCI Cohort Consortium (Abstract Submission): Submission #11

Lightning Talks Abstract
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Presenter's First Name: : Ruolin
Presenter's Last Name:: Zhang
Title (eg: professor, assistant professor, chair, etc):: {Empty}
Degree(s): M.S.
Contact Email:: rzhang25@bwh.harvard.edu
Organization:: Brigham and Women's Hospital
Project Title:: Genetic Risk of Obesity and Low-Carbohydrate Diets on Long-Term Weight Gain: A Gene-Environment Interaction Analysis in the Women's Genome Health Study 
Additional Authors:
1. First Name: Daniel
   Middle Initial: I
   Last Name: Chasman
   Degree(s): Ph.D.
   Organization: Brigham and Women's Hospital
2. First Name: Deirdre
   Middle Initial: K
   Last Name: Tobias
   Degree(s): ScD
   Organization: Brigham and Women's Hospital

Abstract::
Background
Obesity, a modifiable cancer risk factor, drives metabolic dysregulation. Although both genes and diet influence weight gain, it‘s uncertain whether carbohydrate-restricted diets mitigate long-term weight gain and obesity in genetically susceptible individuals. We assessed whether low-carbohydrate diets (LCD) modify the genetic risk of obesity and weight gain.

Method
We analyzed the prospective Women’s Genome Health Study with baseline diet, genotyping, lifestyle, and annual self-reported weight (1992–2021). We derived the LCD score (LCDS) by ranking participants’ intake (%kcal/day) of carbohydrate (descending) and fat and protein (ascending). We developed genome-wide (gwPRS) and pathway-specific PRSs (pPRSs) from previous BMI GWAS. Multivariable-adjusted linear regression, Cox, and mixed-effects models tested gene–diet interactions on baseline BMI, incident obesity (BMI≥30kg/m2), and BMI change, with control for multiple testing by effective independent test number (Meff).

Results
We analyzed 22,472 women of European ancestry. Baseline carbohydrate intake was 48.9 (SD=7.24) and BMI was 25.9 (4.9). There was a significant LCDS×gwPRS interaction for baseline BMI (β=0.12, 95% CI 0.06–0.17) and BMI change (−0.002, −0.003 to −0.001), but not for incident obesity (HR=0.98, 0.94–1.02), indicating a higher LCDS was related to greater weight gain for women with a higher gwPRS. After multiple testing corrections, 7 KEGG legacy pathways and LCDS interactions remained significant for BMI change.

Conclusions
Lower-carbohydrate diets amplified genetic risk for long-term weight gain in women. Future research is needed to clarify diet quality, rather than total carbohydrate restriction, in mitigating weight gain for cancer prevention.