Joint effects of differentiation factor 15 and substance use of alcohol, betel quid and cigarette on risk of head and neck cancer.

  Growth differentiation factor 15 (GDF15) is susceptible to areca nut exposure in oral cells and contributes to the progression of oral tumours. Here, we determined whether independent and combined effects between GDF15 and substance use of alcohol, betel quid and cigarette (ABC) influence the incidence of squamous cell carcinoma of the head and neck (SCCHN). Serum level and genetic variants of GDF15 and substance use habits were evaluated in the risk of SCCHN using a case-control study with 1191 hospital-based volunteers. Serum GDF15 level showed an increasing trend among controls and SCCHN patients with different cancer stages (Ptrend < 0.0001). Furthermore, it was positively correlated with lifetime consumption of ABC in SCCHN patients (P < 0.05). An AA homozygote of rs1059369 showed significant association with laryngeal cancer [odds ratio (OR) = 3.43] and had combined effects with substance use of ABC in addictive interaction [synergy index (SI) = 1.54–2.85]. The CC homozygotes of rs1054564 and rs1054221 were susceptible to SCCHN (ORs = 2.09 and 2.08, respectively) and had combined effects with substance use of cigarette and betel quid in the risk of SCCHN (SI = 1.39–2.01). The risk genotypes of both single-nucleotide polymorphisms were significantly modified by cigarette smoking or betel chewing in oral cancer risk (SI = 1.62–1.93) and by alcohol drinking in laryngeal cancer risk (SI = 3.84 and 3.85); however, no combined effect was found in the risk of pharyngeal cancer. GDF15 may influence the incidence and development of SCCHN by combined effects between substance use of ABC and individual genetic variants.