Genome-Wide Association Analysis Implicates Elastic Microfibrils in the Development of Nonsyndromic Striae Distensae

TO THE EDITOR Striae distensae, or stretch marks, are a common skin condition that appear initially as red, and later on as white, lines on the skin. These lines represent scars of the dermis, and are characterized by linear bundles of collagen lying parallel to the surface of the skin, as well as eventual loss of collagen and elastin. Reports differ on the level of fragmentation of elastic fibers (Zheng et al., 1985; Sheu et al., 1991). Estimates of the prevalence of stretch marks range from 50 to 80% (Atwal et al., 2006; Cho et al., 2006). Although stretch marks are only harmful in extreme cases (Dosal et al., 2012), even mild stretch marks can cause distress to the bearer. The causes of stretch marks are not well understood. Excessive skin distension (such as that which occurs during pregnancy, growth spurts in puberty, or rapid weight gain), prolonged exposure to cortisol (such as in individuals with Cushing syndrome), and genetics may all have a role (Elsaie et al., 2009). A few monogenic connective tissue diseases, including Marfan syndrome and congenital contractural arachnodactyly, are known to be associated with stretch marks. These syndromes are caused by mutations in genes that encode extracellular matrix proteins (fibrillin-1 and fibrillin-2, respectively) that are part of elastic microfibrils present in skin and other tissues. However, to date, no genetic variants are known to be associated with isolated stretch marks that afflict the general population. To identify variants associated with the development of stretch marks, we conducted a genome-wide association analysis of stretch marks in a discovery cohort of 33,930 unrelated 23andMe customers (Supplementary Table S1 online) of European descent. There were a total of 13,068 cases and 20,862 controls. The 18,650 men in the cohort were much less likely to report stretch marks (25% versus 55% of women), which is consistent with other reports (Elsaie et al., 2009). We further evaluated the associated variants in a cohort consisting of 4,967 female 23andMe customers of European descent (disjoint from the first group) who reported on severity of stretch marks during pregnancy (also known as striae gravidarum, a closely related phenotype). See Supplemental Methods for additional details on phenotyping. The protocol for this study was approved by an independent institutional review board (E&I Review Services) and was conducted according to the Declaration of Helsinki Principles; all study participants provided informed consent online, which was recorded in an electronic database. See Supplementary Methods for details on genotyping and imputation. All analyses used logistic (discovery cohort) or linear (pregnancy cohort) regression against imputed allele dosages, controlling for age, population structure (using five principal components), and (except for the pregnancy cohort) sex. Because the prevalence of stretch marks differs between men and women, we checked for but did not observe differing effects for the single-nucleotide polymorphisms (SNPs) in men and women. Four regions were significantly (Po5e 8) associated with stretch marks (Table 1, Figure 1, Supplementary Figure S1 online). The most strongly associated SNP in the first region, rs7787362 (P1⁄4 1.8e 23, odds ratio (OR)1⁄4 0.84), lies 40 kb upstream of the ELN (elastin) gene. It was also associated with striae gravidarum in the pregnancy cohort (P1⁄4 7e 5, b1⁄4 0.072, Supplementary Table S2 online). Elastin is the major component of elastic fibers, which provide reversible extensibility to connective tissue. Mutations in elastin that result in a loss of Accepted article preview online 30 April 2013; published online 11 July 2013 Abbreviations: BMI, body mass index; SNP, single-nucleotide polymorphism JY Tung et al. Genetic Variants Linked to Striae Distensae