HLA-G14bp ins/del polymorphism and post-transplant weight gain in kidney transplantation: potential implications beyond tolerance

Abstract

Background: Human leukocyte antigen (HLA)-G is a non-classical HLA molecule with immunomodulant and immunosuppressive functions, involved in transplantation tolerance. HLA-G14bp ins/del polymorphism in exon 8 has been associated with allograft rejection and kidney transplant outcome, with controversial results. We investigated associations of HLA-G14bp ins/del polymorphism on onset of some of the main post-transplant risk factors, like excess body weight, lipid abnormalities, increased fasting plasma glucose. Polymorphisms of cytokines with both immunosuppressive and metabolic effects were also assessed for comparisons and associated analysis.

Methods: The present study involved kidney transplant recipients (n = 173) in which body mass index, cholesterol, triglycerides, fasting plasma glucose were registered in the first years after transplantation and analyzed in association with genotypes. Presence of hypertension and smoking habits, demographic, transplant-related and therapeutic data of patients were also recorded. Polymerase chain reaction, sequence-specific primer amplification and Taqman allelic discrimination techniques were used for genotyping of HLA-G14bp ins/del, interleukin (IL)-10(-1082G > A,-819 T > C,-592A > C), transforming growth factor-β(+ 869 T > C,+915C > G), IL-6(-174G > C), tumor necrosis factor-α(-308G > A) and IL-18(-137G > C,-607C > A). Effects of genotypes on clinical markers at each time point (pre-transplant and 1 to 5 years after transplant) were analyzed using a repeated-measures general linear model analysis; adjustment for potential confounders was performed.

Results: Results showed that HLA-G14bp ins/ins was significantly associated with obesity, in particular after transplantation (3 years, p = 0.002, OR = 4.48, 95% CI:1.76-11.41). Post-transplant body mass index was significantly increased in HLA-G14bp ins/ins carriers (3 and 4 years, p = 0.033 and p = 0.044); effects of HLA-G14bp genotypes on post-transplant BMI were confirmed by using repeated-measures analysis and after controlling for confounding variables. Cytokine genotypes did not associate with the examined factors.

Conclusions: The study of transplanted patients allowed to evidence a potential relationship between post-transplant weight gain and HLA-G14bp ins/del polymorphism, previously involved in rejection for its immunosuppressive/tolerogenic activity. This novel association could widen the knowledge of the role and functions of HLA-G molecules in diseases and transplantation.

Keywords: Gene polymorphism; HLA-G; Immunogenetics; Kidney transplant; Obesity.

Fig. 1

Variations of pre-post transplant triglycerides, total cholesterol, fasting plasma glucose, BMI and blood creatinine. a blood triglycerides in recipients with or w/o post-transplant treatment with omega-3 fatty acids (total patients, 2 yrs., p = 0.001; 3 yrs., p = 0.005; 4 yrs., p = 0.005, 5 yrs., p = 0.001, compared with pre-transplant triglycerides); b total cholesterol in recipients with or w/o post-transplant treatment with statins (total patients, 1 yr, p < 0.001, 2 yrs., p = 0.003, 3 yrs., p = 0.022, 4 yrs., p = 0.03, compared with pre-transplant cholesterol); c fasting plasma glucose in patients with or w/o diabetes (pre-transplant or NODAT); d BMI in recipients with or w/o dyslipidemia or T2DM (total patients, 1-5 yrs., p < 0.001, compared with pre-transplant BMI); e creatinine (1-5 yrs., p < 0.001, compared with pre-transplant creatinine)

Fig. 2

a Overweight/obesity in Italian population [23]; b Overweight/obesity in pre-transplant recipients (present study)

Fig. 3

Pre/post-transplant measurements of BMI (kg/m²) and HLA-G14bp ins/del genotypes in kidney transplant recipients: a and b: total recipients; b recessive model: significantly increased BMI in HLA-G14bp ins/ins, as compared with ins/del + del/del recipients, at 3 and 4 years (p = 0.033 and 0.044, respectively); using repeated-measures ANOVA, it was observed a significant main effect of HLA-G14bp genotypes on BMI (p = 0.049), with no significant interaction between BMI and HLA-G14bp genotypes; c and d: pre-post transplant BMI when pre-transplant obese patients (BMI > 30) were excluded from the analysis (n = 154); d recessive model: significant pre-post transplant weight gain in both ins/ins and ins/del + del/del carriers (p < 0.005) and significant interaction between BMI and HLA-G14bp genotypes (F = 4.45, p = 0.007); after transplantation, only carriers of ins/ins genotype had significantly increased BMI between 1 to 2 (p = 0.01), 3 (p = 0.001), 4 (p = 0.008) and 5 (p < 0.001) years after transplant. Pre-tx = pre-transplant

Fig. 4

HLA-G14bp genotypes and pre/post-transplant variation of a) creatinine, b) total cholesterol, c) triglycerides and d) fasting plasma glucose in kidney transplant recipients (p = ns)

Fig. 5

Estimated marginal means of BMI and HLA-G14bp genotypes (recessive model), with gender and age at transplant as covariates; a total recipients: effect of HLA-G14bp ins/ins genotype (p = 0.029) and age at transplant (p = 0.001) on BMI (pre-transplant, 1 to 5 years after transplant), with no interaction between HLA-G14bp genotypes and BMI over time (BMI was significantly increased between pre- to post-transplant in both ins/ins and ins/del + del/del carriers); b when pre-transplant obese recipients were excluded from the analysis, a significant interaction between HLA-G14bp genotypes and BMI over time was found (p = 0.009)