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J Gerontol A Biol Sci Med Sci. 2019 Aug 20. pii: glz191. doi: 10.1093/gerona/glz191. [Epub ahead of print]

The Longevity Associated Sh2b3 (LNK) Genetic Variant: Selected Aging Phenotypes in 379,758 Subjects.

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Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT, USA.
College of Medicine and Health, University of Exeter, RILD Building, Barrack Road, Exeter, UK.
Center on Aging, University of Connecticut Health, Farmington, CT, USA.
National Institute on Aging, Baltimore, MD, USA.
Center on Aging, University of Connecticut School of Medicine, Farmington, CT, USA.


Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disease. To better understand the SH2B3-related aging pathway and its potential as an intervention target, we undertook a phenotype-wide association study (PheWAS) of 52 aging traits. Data were from 379,758 European-descent UK Biobank participants, aged 40 to 70 at baseline: 27% of participants were CC homozygotes and 23% TT at rs3184504. Parental extreme longevity (mothers aged ≥98 years, fathers ≥96) was more common in CC versus TT (Odds Ratio =1.18, 95% CI: 1.07 to 1.29) with an additive per allele effect. The C allele associated with better cognitive function and white blood cell counts were more likely to be normal. The C allele reduced risks of coronary heart disease (OR= 0.95, 95% CI: 0.93 to 0.96) but was also associated with a modestly higher cancer rate (OR=1.03, 95% CI: 1.02 to 1.04), suggesting a trade-off across aging outcomes and limiting its potential as an anti-aging target.


IGF-1; UK Biobank; anti-aging; cancer; centenarian


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