associations of fto and mc4r snps with obesity traits in the indian migration study
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Associations of FTO and MC4R SNPs with obesity traits in the Indian Migration Study. Amy Taylor. Background. Large number of genetic variants associated with obesity traits have been discovered in Europeans FTO and MC4R associations well established

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Presentation Transcript
background
Background
  • Large number of genetic variants associated with obesity traits have been discovered in Europeans
  • FTO and MC4R associations well established
  • Few studies conducted in Indian populations
  • Suggestion of smaller effect of FTO on BMI in a previous study in Pune (western India)
background1
Background
  • Effects of FTO on obesity traits may be modified by energy intake and/or expenditure
  • But effect modification not consistently replicated across studies
  • May reflect true population differences, study sample size or inter-study measurement differences
  • Within population variation of environmental factors may not be large enough
background2
Background
  • India is currently experiencing rapid urbanisation
  • In 2001, almost a third of the population lived in urban areas, but it is estimated that by 2025, half the population will be urban dwellers*
  • Urban living in India associated with lifestyle changes and increases in obesity and diabetes
  • Rural/urban living may be a sufficiently strong exposure to show large interaction effects with genetic factors

*Yadav K, Krishnan A. Obes Rev 2008; 9(5):400-408.

slide5
Aim
  • To replicate associations of key variants in FTO and MC4R

and

To investigate whether urban/rural environment alters the strength of these associations in an Indian population

study population
Study population
  • Indian Migration Study (2005-2007)
  • Four cities across India:

Lucknow, Nagpur, Hyderabad,

Bangalore

  • Sibling pair design:

- Factory workers and spouses who had migrated from rural areas and their siblings who had remained in rural areas

- Lifelong urban dwelling factory workers and their siblings

methods
Methods
  • Study participants attended a clinic at the factory:

Questionnaire- lifestyle and demographics

Anthropometry- height, weight, circumferences, skinfolds

Blood pressure

Fasting blood tests- lipid, glucose

methods genetics
Methods- Genetics
  • Pool of 59 SNPs analysed at Centre for Cellular and Molecular Biology
  • Sequenom based mass array assay
  • 3 obesity related SNPs

- FTO rs9939609

- MC4R rs17782313, rs12970134 (r2=0.90)

methods statistical analysis
Methods: Statistical Analysis
  • Key methodological considerations:

- Sibling pairs

- Population stratification

- Effect Modification

  • STATA, QTDT, MX, UNPHASED
  • HWE calculated on half sibling pairs on whole sample and by city
  • Obesity traits converted to age, sex adjusted

Z-scores

methods statistical analysis1
Methods Statistical Analysis
  • STATA analyses
  • Additive genetic model assumed
  • Multilevel model
  • Sibling pair as random effect, city as a fixed effect
  • Genetic effect is decomposed into between- and within-family effects*
  • Inference performed on the within-family effect
  • Robust to population stratification

* Fulker et al. Am J Hum Genet 1999; 64(1):259-267.

methods statistical analysis2
Methods: Statistical Analysis
  • Effect modification- added an interaction term to the model
  • Rural and urban living -defined according to current dwelling
  • Dietary fat intake (from food frequency questionnaire)
  • Physical activity measures (METs and time spent in moderate- vigorous physical activity)
results
Results

6942 with genotype data

6780 individuals

3390 pairs

162

unrelated individuals

1152

urban urban pairs

241

rural rural pairs

1997

rural urban pairs

results1
Results
  • In Bangalore sample, there was evidence of deviation from HWE for rs9939609
fto interactions with dwelling
FTO: Interactions with dwelling

P for interaction between FTO

and dwelling on weight =0.03

results3
Results
  • No evidence for effect modification by dwelling on associations with MC4R SNPs
  • No evidence for effect modification by physical activity or dietary measures
discussion
Discussion
  • Effect estimates for associations of BMI with FTO and MC4R generally in concordance with European and Indian estimates
  • Effect of FTO strongest on weight and BMI- less evidence for association with regional measures of adiposity/total body fat
  • Is this evidence that FTO more important for overall body size in Indians?
  • May reflect accuracy of regional measures
discussion1
Discussion
  • Possible effect modification by rural/urban environment
  • Siblings share early life environment – suggests that effect modification relates to environmental factors post migration
  • Probably insufficient power to investigate interactions with physical activity/diet
further work
Further work
  • Investigate associations of recently discovered genetic variants of regional adiposity in Europeans
  • Meta analyses of FTO and MC4R associations in Indian populations
  • Replication of effect modification by environmental exposures in other Indian populations
acknowledgements
Acknowledgements
  • Indian Migration Study Group, field staff and participants
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