Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1

Merry-Lynn Noelle McDonald*, Sungho Won, Manuel Mattheisen, Peter J. Castaldi, Michael H. Cho, Erica Rutten, Megan Hardin, Wai-Ki Yip, Stephen I. Rennard, David A. Lomas, Emiel F. M. Wouters, Alvar Agusti, Richard Casaburi, Christoph P. Lange, George O'Connor, Craig P. Hersh, Edwin K. Silverman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Web of Science)

Abstract

Background There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (Delta BMI) among cancer and COPD by using GWAS data in the Framingham Heart Study.

Methods A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate Delta BMI in participants over 40 years of age with three consecutive BMI time points (n = 4162). Four GWAS of Delta BMI using generalized estimating equations were performed among 1085 participants with a cancer diagnosis, 204 with gastrointestinal (GI) cancer, 112 with lung cancer, and 237 with COPD to test for association with 418 365 single-nucleotide polymorphisms (SNPs).

Results Two SNPs reached a level of genome-wide significance (P <5x10(-8)) with Delta BMI: (i) rs41526344 within the CNTN4 gene, among COPD cases (beta = 0.13, P = 4.3x10(-8)); and (ii) rs4751240 in the gene Dedicator of Cytokinesis 1 (DOCK1) among GI cancer cases (beta = 0.10, P = 1.9x10(-8)). The DOCK1 SNP association replicated in the Delta BMI GWAS among COPD cases (beta(meta-analyis)= 0.10, Pmeta-analyis = 9.3x10(-10)). The DOCK1 gene codes for the dedicator of cytokinesis 1 protein, which has a role in myoblast fusion.

Conclusions In sum, one statistically significant common variant in the DOCK1 gene was associated with Delta BMI in GI cancer and COPD cases providing support for at least partially shared aetiology of Delta BMI in complex diseases.

Original languageEnglish
Pages (from-to)428-436
Number of pages9
JournalJournal of cachexia, sarcopenia and muscle
Volume8
Issue number3
DOIs
Publication statusPublished - Jun 2017

Keywords

  • GWAS
  • COPD
  • Cancer
  • Longitudinal
  • BMI
  • Cachexia
  • FTO GENE
  • EXTREME OBESITY
  • MYOBLAST FUSION
  • ADULT OBESITY
  • CACHEXIA
  • VARIANTS
  • POLYMORPHISMS
  • POPULATION
  • CONTACTINS
  • CHILDHOOD

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