Differential gender-related impact of PNPLA3 and CD14 polymorphism on the risk of developing alcoholic cirrhosis

Background and aims. Most studies on genetic predisposition to alcoholic cirrhosis (AC) are cross-sectional. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been strongly associated with AC predisposition. Conflicting data exist on the association of AC with the CD14 C159T (rs2569190) polymorphism which is associated with protein overexpression on Kupffer cells promoting cell activation and inflammation. Methods. At-risk alcohol drinkers, defined as with ≥2 and ≥3 alcohol units/day for females (n=178) and males (n=498), respectively were retrospectively examined. Detailed alcohol consumption history was obtained by the Lifetime Drinking History. The diagnosis of AC was defined by examining patients’ past and present clinical data (physical examination, blood tests, imaging, endoscopy) at first visit or at follow-up. The association among each polymorphism and the incidence of AC over time was separately tested using multivariable Cox regression introducing as covariates age, gender, BMI, diabetes, alcohol daily consumption and age at onset of at-risk alcohol consumption. Results. AC diagnosis was done in 109 males and 39 females. Allele frequencies in males and females were for PNPLA3 0.36 and 0.35, respectively and for CD14 0.52 and 0.53, respectively. The association between AC development and the PNPLA3 variant allele was stronger in females (HR 2.40; 95% CI 1.42-4.05 P=0.001) than in males (HR 1.72; 95% CI 1.25-2.37 P=0.001). This gender difference was even more evident when the PNPLA3 variant homozygous carriers were compared to the wild types being stronger in females (HR 5.88; 95% CI 1.98-17.47 P=0.001) than in males (HR 2.99; 95% CI 1.54-5.83, P=0.001). In males the CD14 variant allele (HR 1.50; 95% CI 1.05-2.15 P=0.027) and carriage of homozygosity compared to wild type (HR 2.18; 95% CI 1.05-4.52 P=0.037) were significantly associated with AC development. In females, no significant association was found between either the CD14 variant allele (HR 0.63; 95% CI 0.32-1.26 P=0.195) or carriage of homozygosity compared to wild type (HR 0.43; 95% CI 0.12-1.49 P=0.179). Conclusions. There are gender differences in the role played by PNPLA3 I148M and CD14 C-159T polymorphisms as risk factors for AC development. The effect of the PNPLA3 variant is more pronounced in females than in males, while the CD14 variant is a risk factor for AC development only in males.