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Original Investigation |

Intrinsic and Extrinsic Risk Factors for Sagging Eyelids

Leonie C. Jacobs, MD1; Fan Liu, PhD2; Isabel Bleyen, MD, PhD3; David A. Gunn, PhD4; Albert Hofman, MD, PhD5; Caroline C. W. Klaver, MD, PhD3,5; André G. Uitterlinden, PhD5,6; H. A. Martino Neumann, MD, PhD1; Veronique Bataille, MD, PhD7,8; Timothy D. Spector, MD, PhD7; Manfred Kayser, PhD2; Tamar Nijsten, MD, PhD1
[+] Author Affiliations
1Department of Dermatology, Erasmus Medical Center, Rotterdam, the Netherlands
2Department of Forensic Molecular Biology, Erasmus Medical Center, Rotterdam, the Netherlands
3Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
4Unilever Research and Development, Colworth Science Park, Sharnbrook, England
5Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
6Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
7Department of Twin Research and Genetic Epidemiology, King’s College London, London, England
8Department of Dermatology, West Hertfordshire Hospitals National Health Service Trust, Hertfordshire, England
JAMA Dermatol. 2014;150(8):836-843. doi:10.1001/jamadermatol.2014.27.
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Importance  Sagging eyelids, or dermatochalasis, are a frequent concern in older adults. It is considered a feature of skin aging, but risk factors other than aging are largely unknown.

Objective  To study nongenetic and genetic risk factors for sagging eyelids.

Design  Upper eyelid sagging was graded in 4 categories of severity using digital photographs. Dermatochalasis was defined as the eyelid hanging over the eyelashes. Age, sex, skin color, tanning ability, hormonal status in women, current smoking, body mass index, and sun protection behavior were analyzed in a multivariable multinomial logistic regression model. Genetic predisposition was assessed using heritability analysis and a genome-wide association study.

Setting and Participants  The study was performed in 2 independent population-based cohorts. The Rotterdam Study included older adults from one district in Rotterdam, the Netherlands, and the UK Adult Twin Registry (TwinsUK) included twins from all over the United Kingdom. Participants were 5578 unrelated Dutch Europeans (mean age, 67.1 years; 44.0% male) from the Rotterdam Study and 2186 twins (mean age, 53.1 years; 10.4% male) from the TwinsUK.

Main Outcomes and Measures  Sagging eyelid severity levels, ranging from 1 (normal control) to 4 (severe sagging).

Results  Among 5578 individuals from the Rotterdam Study, 17.8% showed dermatochalasis (moderate and severe sagging eyelids). Significant and independent risk factors for sagging eyelids included age, male sex, lighter skin color, and higher body mass index. In addition, current smoking was borderline significantly associated. Heritability of sagging eyelids was estimated to be 61% among 1052 twin pairs from the TwinsUK (15.6% showed dermatochalasis). A meta-analysis of genome-wide association study results from 5578 Rotterdam Study and 1053 TwinsUK participants showed a genome-wide significant recessive protective effect of the C allele of rs11876749 (P = 1.7 × 10−8). This variant is located close to TGIF1 (an inducer of transforming growth factor β), which is a known gene associated with skin aging.

Conclusions and Relevance  This is the first observational study to date demonstrating that other risk factors (male sex, genetic variants, lighter skin color, high body mass index, and possibly current smoking) in addition to aging are involved in the origin of sagging eyelids.

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Figure 1.
Four Categories of Severity in Sagging Eyelids

A, Normal (the upper eyelid skin is not touching the eyelashes). B, Mild (the upper eyelid skin is touching the eyelashes). C, Moderate (the upper eyelid skin is hanging over the eyelashes). D, Severe (the upper eyelid skin is hanging over the eye).

Graphic Jump Location
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Figure 2.
Regional Manhattan Plot of 800 kB Around rs11876749 in the Rotterdam Study

The −log10P values of all single-nucleotide polymorphisms (small squares) surrounding the most significant signal (large diamond) were plotted against their physical positions on chromosome 18 according to the reference human genome, version 18 (hg18; http://genome-euro.ucsc.edu). Blue peaks represent known recombination rates in HapMap Central European-like Utahns samples (International HapMap Project; http://hapmap.ncbi.nlm.nih.gov) expressed in cM/Mb. The level of redness represents the strength of linkage disequilibrium (r2) of all single-nucleotide polymorphisms in relation to the top single-nucleotide polymorphism. Known genes are aligned below. cM/Mb indicates centimorgan (genetic distance) per megabase (chromosomal distance); kb indicates kilobase.

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