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Segregation of a latent high adiposity phenotype in families with a history of type 2 diabetes mellitus implicates rare obesity-susceptibility genetic variants with large effects in diabetes-related obesity

Journal Article


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Abstract


  • Background

    We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH−) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+.

    Methods

    Normoglycaemic participants were categorised either FH+ (≥1 1st degree relative with T2DM, 50F/30M, age 45±14 (SD) yr) or FH− (71F/51M, age 43±14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass (Dual Energy X-ray Absorptiometry) data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH−) and interpreted in a purely genetic model of FH effects.

    Results

    The two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01) without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74%) of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23) in FH−, 0.36 (0.22, 0.48) in FH+ and 0.62 (0.36, 0.88) in unobserved T2DM-affected family members.

    Conclusions

    The segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH− suggests that rare genetic variants could also account for a substantial fraction of the prevalent obesity in this society.

Authors


  •   Jenkins, Arthur
  •   Batterham, Marijka
  •   Samocha-Bonet, Dorit (external author)
  •   Tonks, Katherine (external author)
  •   Greenfield, Jerry R. (external author)
  •   Campbell, Lesley V. (external author)

Publication Date


  • 2013

Citation


  • Jenkins, A. B., Batterham, M., Samocha-Bonet, D., Tonks, K., Greenfield, J. R. & Campbell, L. V. (2013). Segregation of a latent high adiposity phenotype in families with a history of type 2 diabetes mellitus implicates rare obesity-susceptibility genetic variants with large effects in diabetes-related obesity. PLoS One, 8 (8), e70435-1-e70435-9.

Scopus Eid


  • 2-s2.0-84881320900

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2045&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1027

Has Global Citation Frequency


Start Page


  • e70435-1

End Page


  • e70435-9

Volume


  • 8

Issue


  • 8

Place Of Publication


  • United States

Abstract


  • Background

    We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH−) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+.

    Methods

    Normoglycaemic participants were categorised either FH+ (≥1 1st degree relative with T2DM, 50F/30M, age 45±14 (SD) yr) or FH− (71F/51M, age 43±14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass (Dual Energy X-ray Absorptiometry) data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH−) and interpreted in a purely genetic model of FH effects.

    Results

    The two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01) without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74%) of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23) in FH−, 0.36 (0.22, 0.48) in FH+ and 0.62 (0.36, 0.88) in unobserved T2DM-affected family members.

    Conclusions

    The segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH− suggests that rare genetic variants could also account for a substantial fraction of the prevalent obesity in this society.

Authors


  •   Jenkins, Arthur
  •   Batterham, Marijka
  •   Samocha-Bonet, Dorit (external author)
  •   Tonks, Katherine (external author)
  •   Greenfield, Jerry R. (external author)
  •   Campbell, Lesley V. (external author)

Publication Date


  • 2013

Citation


  • Jenkins, A. B., Batterham, M., Samocha-Bonet, D., Tonks, K., Greenfield, J. R. & Campbell, L. V. (2013). Segregation of a latent high adiposity phenotype in families with a history of type 2 diabetes mellitus implicates rare obesity-susceptibility genetic variants with large effects in diabetes-related obesity. PLoS One, 8 (8), e70435-1-e70435-9.

Scopus Eid


  • 2-s2.0-84881320900

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2045&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/1027

Has Global Citation Frequency


Start Page


  • e70435-1

End Page


  • e70435-9

Volume


  • 8

Issue


  • 8

Place Of Publication


  • United States