Common Genetic Variants of Surfactant Protein-D (SP-D) Are Associated with Type 2 Diabetes

Neus Pueyo,Manuel Serrano-Ríos,José M Moreno-Navarrete,Josep M Mercader,Sílvia Bonàs,David Torrents,Francisco J Ortega,Monica Sabater,José M Fernández-Real,Patricia Botas,Wifredo Ricart,Elías Delgado,María T Martinez-Larrad,Massimo Federici

doi:10.1371/journal.pone.0060468

Abstract

ContextSurfactant protein-D (SP-D) is a primordial component of the innate immune system intrinsically linked to metabolic pathways. We aimed to study the association of single nucleotide polymorphisms (SNPs) affecting SP-D with insulin resistance and type 2 diabetes (T2D).Research Design and MethodsWe evaluated a common genetic variant located in the SP-D coding region (rs721917, Met31Thr) in a sample of T2D patients and non-diabetic controls (n = 2,711). In a subset of subjects (n = 1,062), this SNP was analyzed in association with circulating SP-D concentrations, insulin resistance, and T2D. This SNP and others were also screened in the publicly available Genome Wide Association (GWA) database of the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC).ResultsWe found the significant association of rs721917 with circulating SP-D, parameters of insulin resistance and T2D. Indeed, G carriers showed decreased circulating SP-D (p = 0.004), decreased fasting glucose (p = 0.0002), glycated hemoglobin (p = 0.0005), and 33% (p = 0.002) lower prevalence of T2D, estimated under a dominant model, especially among women. Interestingly, these differences remained significant after controlling for origin, age, gender, and circulating SP-D. Moreover, this SNP and others within the SP-D genomic region (i.e. rs10887344) were significantly associated with quantitative measures of glucose homeostasis, insulin sensitivity, and T2D, according to GWAS datasets from MAGIC.Conclusions SP-D gene polymorphisms are associated with insulin resistance and T2D. These associations are independent of circulating SP-D concentrations.

Highlights

Over nutrition and sedentary activities, in combination with repeated exposure to infectious agents and external injuries, could compromise the homeostasis of the innate immune system, leading to chronic subclinical inflammation, which is intrinsic to the metabolic syndrome [1]
We found the significant association of rs721917 with circulating Surfactant protein-D (SP-D), parameters of insulin resistance and type 2 diabetes (T2D)
In order to replicate the associations found in our population, we evaluated the SP-D gene polymorphism rs721917 (NC_000010.10: g.81706324A.G) and screened for other associations within the SP-D genome region in data from publicly available datasets from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Summary

Introduction

Over nutrition and sedentary activities, in combination with repeated exposure to infectious agents and external injuries, could compromise the homeostasis of the innate immune system, leading to chronic subclinical inflammation, which is intrinsic to the metabolic syndrome [1]. Insulin resistance seems to be central to the pathophysiology of these alterations [2] Approaches to this hypothesis have been made through the study of acute phase and innate immune proteins in association with insulin resistance and type 2 diabetes (T2D) [3]. The SP-D single nucleotide polymorphism (SNP) rs721917 (NC_000010.10: g.81706324A.G) is a missense substitution which leads the replacement in position 31 of an ancestral metionine by a threonine (Met31Thr) [10]. This polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and circulating concentrations [11], leading to decreased immunologic capacity against bacteria [10]. Subjects carrying AA-genotype (Met/Met) have increased concentrations of SP-D in plasma [12], and show multimers, dodecamers, and monomers of subunits, whereas GGcarriers (Thr/Thr) produce almost exclusively monomers [11]

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