Common genetic variants of surfactant protein-D (SP-D) are associated with type 2 diabetes

Abstract

Context: Surfactant 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 methods: We evaluated a common genetic variant located in the SP-D coding region (rs721917, Met(31)Thr) 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).

Results: We 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.

Figure 1. Genotypes for rs721917 and measures of impaired glucose tolerance and circulating SP-D.

Mean and 95% confidence interval for fasting glucose (Fig. 1a) and glycated hemoglobin (Fig. 1b) for the whole cohort (n = 2,711), and for circulating SP-D concentration (Fig. 1c), fasting glucose (Fig. 1d) and glycated hemoglobin (Fig. 1d) in a subpopulation of subjects (n = 1,062) according to the genotypes for rs721917. Men: black bars, women: grey bars. *p<0.05 and #p<0.0001 for comparisons with AA-genotype.

Figure 2. Regional association plot of chr.10.

Regional association plot of the chromosome 10 region for fasting insulin and HOMA-IR in MAGIC GWA.

Figure 3. Genotypes for rs10887344 and measures of impaired glucose tolerance.

Mean and 95% confidence interval for fasting glucose (Fig. 3a), fasting insulin (Fig. 3b), HOMA-IR (Fig. 3c), and glycated hemoglobin (Fig. 3d) according to the genotypes for rs10887344. Men: black bars, women: grey bars. *p<0.05 for comparisons with GG-genotype.