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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.

Author information

1
Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT, USA.
2
College of Medicine and Health, University of Exeter, RILD Building, Barrack Road, Exeter, UK.
3
Center on Aging, University of Connecticut Health, Farmington, CT, USA.
4
National Institute on Aging, Baltimore, MD, USA.
5
Center on Aging, University of Connecticut School of Medicine, Farmington, CT, USA.

Abstract

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.

KEYWORDS:

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

PMID:
31428775
DOI:
10.1093/gerona/glz191

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