No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects

Abstract

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

Figure 1. Association of environmental factors with fibrinogen concentration (in g/L), adjusted for age and sex.

A) Forest plot for smoking status. The beta estimate with 95% confidence intervals indicates the change in mean fibrinogen concentration (in g/L) by smoking status for each study and across all studies (“overall”, estimated by meta-analysis). B) Forest plot for alcohol consumption. The beta estimate with 95% confidence intervals indicates the change in mean fibrinogen concentration (in g/L) by alcohol consumption for each study and across all studies (“overall”, estimated by meta-analysis). Alcohol consumption was assessed only in 20 studies. C) Forest plot for BMI. The beta estimate with 95% confidence intervals indicates the change in mean fibrinogen concentration (in g/L) by BMI for each study and across all studies (“overall”, estimated by meta-analysis).

Figure 2. Interaction of gene variants and environmental factors on fibrinogen concentration (in g/L), adjusted for age and sex.

A) Manhattan plot for smoking status. The horizontal axis denotes chromosome and position of each gene variant and the vertical axis gives the negative log10 of the p value for interaction of each gene variant and smoking status on fibrinogen concentration (in g/L), estimated by meta-analyses. The dotted line denotes genome-wide significance (5.0×10⁻⁸). B) Manhattan plot for alcohol consumption. The horizontal axis denotes chromosome and position of each gene variant and the vertical axis gives the negative log10 of the p value for interaction of each gene variant and alcohol consumption on fibrinogen concentration (in g/L), estimated by meta-analyses. The dotted line denotes genome-wide significance (5.0×10⁻⁸). Alcohol consumption was assessed only in 20 studies. C) Manhattan plot for BMI. The horizontal axis denotes chromosome and position of each gene variant and the vertical axis gives the negative log10 of the p value for interaction of each gene variant and BMI on fibrinogen concentration (in g/L), estimated by meta-analyses. The dotted line denotes genome-wide significance (5.0×10⁻⁸).