Laminopathies are rare monogenic diseases, some of them exhibiting features of the metabolic syndrome. These diseases are mainly due to mutations in LMNA, encoding A-type lamins. The LMNA_rs4641 polymorphism has been associated with the metabolic syndrome, but results have been controversial. We therefore investigated the effect of single nucleotide polymorphisms (SNPs) in the LMNA gene in combination with four other genes encoding enzymes influencing lamin post-translational maturation on risk of metabolic syndrome (MetS).
Twenty-three tagging SNPs characterizing the haplotypic variability of 5 genes (LMNA, ICMT, ZMPSTE24, FNTA, FNTB) were genotyped in 3916 French men and women who took part in the prospective DESIR study.
LMNA_rs4641 was found to interact with ZMPSTE24_rs2284447 to influence the risk of MetS (P=0.006). Among carriers of the ZMPSTE24_rs2284447 minor T allele, those also carrying the minor T allele for LMNA_rs4641 had a decreased risk of MetS (OR=0.53 [0.31-0.90], p=0.01). The effect of LMNA_rs4641 on MetS was also found to be modulated by the FNTA_rs10958736 (P=0.001). Among carriers of the A allele for the FNTA_rs10958736 SNP, those also carrying the minor T allele at LMNA_rs4641 had an increased risk of MetS (OR=1.68 [1.20-2.36], P=0.002).
We observed that the effect of the LMNA_rs4641 polymorphism on risk of MetS was modulated by other polymorphisms in genes influencing lamin A post-translational maturation. Our findings emphasize the need to examine the complex interplay between genes influencing a given biological system.Le texte complet de cet article est disponible en PDF.