Dataset Information

Identification of ASAH1 as a susceptibility gene for familial keloids.

ABSTRACT: Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.

SUBMITTER: Santos-Cortez RLP

PROVIDER: S-EPMC5602022 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Identification of ASAH1 as a susceptibility gene for familial keloids.

Santos-Cortez Regie Lyn P RLP Hu Ying Y Sun Fanyue F Benahmed-Miniuk Fairouz F Tao Jian J Kanaujiya Jitendra K JK Ademola Samuel S Fadiora Solomon S Odesina Victoria V Nickerson Deborah A DA Bamshad Michael J MJ Olaitan Peter B PB Oluwatosin Odunayo M OM Leal Suzanne M SM Reichenberger Ernst J EJ

European journal of human genetics : EJHG 20170726 10

Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that ...[more]

PMID: 28905881

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Project description:BackgroundWomen with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk variants have a relatively modest effect on risk and show limited potential for predicting FBC development. As an alternative, we hypothesized that additional genomic data types, such as gene-expression levels, which can reflect genetic and epigenetic variation, could contribute to classifying a person's risk status. Specifically, we aimed to identify common patterns in gene-expression levels across individuals who develop FBC.MethodsWe profiled peripheral blood mononuclear cells from women with a family history of breast cancer (with or without a germline BRCA1/2 variant) and from controls. We used the support vector machines algorithm to differentiate between patients who developed FBC and those who did not. Our study used two independent datasets, a training set of 124 women from Utah (USA) and an external validation (test) set from Ontario (Canada) of 73 women (197 total). We controlled for expression variation associated with clinical, demographic, and treatment variables as well as lymphocyte markers.ResultsOur multigene biomarker provided accurate, individual-level estimates of FBC occurrence for the Utah cohort (AUC = 0.76 [0.67-84]) . Even at their lower confidence bounds, these accuracy estimates meet or exceed estimates from alternative approaches. Our Ontario cohort resulted in similarly high levels of accuracy (AUC = 0.73 [0.59-0.86]), thus providing external validation of our findings. Individuals deemed to have "high" risk by our model would have an estimated 2.4 times greater odds of developing familial breast cancer than individuals deemed to have "low" risk.ConclusionsTogether, these findings suggest that gene-expression levels in peripheral blood cells reflect genomic variation associated with breast cancer risk and that such data have potential to be used as a non-invasive biomarker for familial breast cancer risk.

Dataset Information

Identification of ASAH1 as a susceptibility gene for familial keloids.

Publications

Identification of ASAH1 as a susceptibility gene for familial keloids.

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