Pigmentation-Independent Susceptibility Loci for Actinic Keratosis Highlighted by Compound Heterozygosity Analysis

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• 作者：Kaiyin Zhong¹ ; Joris A.C. Verkouteren² ; Leonie C. Jacobs² ; Andre G. Uitterlinden³ ; ⁴ ; Albert Hofman⁴ ; Fan Liu¹ ; ⁵ ; Tamar Nijsten² ; ⁶ ; ^{t.nijsten@erasmusmc.nl} ; Manfred Kayser¹ ; ⁶ ; ^{m.kayser@erasmusmc.nl}
• 关键词：AK ; actinic keratosis ; CH ; compound heterozygote ; GCDH ; generalized collapsed double heterozygosity ; GST ; glutathione-S-transferases ; GWAS ; Genome-Wide Association Study ; RS ; Rotterdam Study ; SCC ; squamous cell carcinoma ; SNP ; single nucleotide polymorphism
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：1
• 页码：77-84
• 全文大小：944 K
• 卷排序：137

文摘

Actinic keratosis (AK) is a skin disease frequently found in European elderly, and it represents the precursor of cutaneous squamous cell carcinoma. Our recent genome-wide association study highlighted DNA variants in two pigmentation genes, IRF4 and MC1R, that confer AK risk in Europeans. Here, we performed a genome-wide search for relaxed forms of compound heterozygosity in association with AK using our recently developed software CollapsABEL. In a discovery dataset of 3,193 Dutch Europeans, a total of 15 genetic loci showed genome-wide significant association with AK (P < 1.25 × 10–10). Of those, three loci (6p21.2, 6p12.2, and 6q13) were confirmed in a replication dataset that included 624 additional Dutch Europeans (P < 0.05). These replicated loci harbored six genes (KCNK5/KCNK17, PAQR8/GSTA2, and KCNQ5/KHDC1), none of them known to be involved in pigmentation. A candidate compound heterozygosity analysis for 12 pigmentation loci highlighted SLC24A4 at 14q32.12 as showing significant association with AK (P = 8.83 × 10–9). The four significantly AK-associated compound heterozygosity single-nucleotide polymorphism pairs together explained 4.37% of the total AK variation, which was 2.62 times greater than the two top-associated individual single nucleotide polymorphisms together (1.67%) identified in the previous conventional genome-wide association study. In conclusion, CollapsABEL showed compound heterozygosity in non–pigmentation- and pigmentation-related loci conferring genetic risk of AK.