A Military Community Cohort Study Reveals Single Nucleotide Polymorphisms in Inflammation Mediator Genes That Associate With Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder characterized by hyperglycemia of varying degrees. Genetic and lifestyle variations are known to influence the onset and severity of T2DM. Among the genetic variations reported to confer susceptibility to the disease are certain single nucleotide polymorphisms (SNPs). Here, we report the analysis of 18 such SNPs in a military community cohort of 716 subjects, comprising 477 diabetic and 239 control subjects. The population studied included active-duty military personnel, veterans, and their families. The SNPs analyzed in this work occur in nine different genes, comprising six interleukin (IL) genes (IL1A, IL1B, IL4, IL6, IL10, and IL18), fatty acid amide hydrolase (FAAH) gene, and cannabinoid receptors 1 and 2 genes (CNR1, CNR2). The products of these genes are players in different conditions, including inflammation, a process linked with diabetes. The T2DM and control (no diabetes) DNA samples were acquired from an archived sample repository (Center for Advanced Molecular Detection, 59th Medical Wing, U.S. Air Force, Joint Base San Antonio [JBSA]-Lackland, TX). The blood samples had been previously collected from gender- and race-mixed cohorts under a protocol approved by the 59th Medical Wing Institutional Review Board. Single nucleotide polymorphism (SNP) genotyping was done by real-time Polymerase Chain Reaction (PCR) using TaqMan assay reagents. The statistical analysis software 9.3 (SAS 9.3) was used for statistical analyses to reveal associations between the SNP genotypes and T2DM. Out of the 18 SNPs analyzed, six showed statistically significant association with T2DM in the overall cohort (P < .05). The odds ratio for these associations varied from 1.57 to 3.16. The rs16944 T/T homozygous genotype (IL1B) showed the strongest association with T2DM, with P = .005. In the White cohort, five of these six SNPs and one other, rs806368 (cannabinoid receptor 1), associate with T2DM. However, the gender-specific analysis of the White cohort revealed only two SNP associations with T2DM in the female cohort, rs16944 (IL1B) and rs2295632 (FAAH), both also showing association in the overall mixed cohort. Likewise, four SNPs showed T2DM association in the White male cohort, with rs187238 (IL18) being uniquely significant in this group. The IL1B SNP rs16944 showed consistent statistically significant association with T2DM and therefore is likely a promising biomarker for T2DM. We note, however, that this association in a generic sense may be with the inflammatory process that accompanies T2DM and not per se with T2DM.