title: Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population.
abstract: Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Black and Mixed Ancestry populations of South Africa. Recently, three genome-wide association studies in Chinese populations identified five new OSCC susceptibility loci, including variants at PLCE1, C20orf54, PDE4D, RUNX1 and UNC5CL, but their contribution to disease risk in other populations is unknown. In this study, we report testing variants from these five loci for association with OSCC in the South African Black (407 cases and 849 controls) and Mixed Ancestry (257 cases and 860 controls) populations. The RUNX1 variant rs2014300, which reduced risk in the Chinese population, was associated with an increased risk of OSCC in the Mixed Ancestry population [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.09-1.63, P = 0.0055], and none of the five loci were associated in the Black population. Since PLCE1 variants increased the risk of OSCC in all three Chinese studies, this gene was investigated further by sequencing in 46 Black South Africans. This revealed 48 variants, 10 of which resulted in amino acid substitutions, and much lower linkage disequilibrium across the PLCE1 locus than in the Chinese population. We genotyped five PLCE1 variants in cases and controls, and found association of Arg548Leu (rs17417407) with a reduced risk of OSCC (OR = 0.74, 95% CI = 0.60-0.93, P = 0.008) in the Black population. These findings indicate several differences in the genetic contribution to OSCC between the South African and Chinese populations that may be related to differences in their genetic architecture.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, King's Health Partners, Guy's Hospital, London, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Bye
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Prescott
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Marco
authors.initials: M
authors.lastname: Matejcic
authors.forename: Loven
authors.initials: L
authors.lastname: Moodley
authors.forename: Barbara
authors.initials: B
authors.lastname: Robertson
authors.forename: Christo van
authors.initials: Cv
authors.lastname: Rensburg
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Parker
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004247:DNA / Q000032:analysis / Q000235:genetics; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D054801:Phosphoinositide Phospholipase C / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D013019:South Africa / Q000453:epidemiology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; C493728:RUNX1 protein, human; C548553:SLC52A3 protein, human; C486467:UNC5CL protein, human; D004247:DNA; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human