Genome-Wide Association Study of Inflammatory Cytokines in Southwestern Native Americans Identifies Novel Association between WWOX and Serum TNF-? Levels

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. Supplement_1
• Main Authors: WEDEKIND, LAUREN E., WALTER, MARY, KOBES, SAYUKO, CHEN, PENG, HSUEH, WEN-CHI, NELSON, ROBERT, BAIER, LESLIE, KNOWLER, WILLIAM C., HANSON, ROBERT L.
• Format: Journal Article
• Language: English
• Published: 01.07.2018
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db18-1713-P

Inflammatory processes may contribute to type 2 diabetes (T2D), but there is limited information about genetic associations with circulating levels of inflammatory cytokines. We performed a genome-wide association study (GWAS) of cytokines in 1061 nondiabetic Southwestern Native Americans (500 women; 561 men). Fasting serum concentrations of interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor-α (TNF-α) were measured using EMD Millipore assays. Genotypic data on 496,190 single-nucleotide polymorphisms (SNPs) with minor allele frequency >1% were derived from an Affymetrix Axiom array designed to capture common variation in Pima Indians. Data were normalized and analyzed for associations using a mixed model accounting for familial relationships, adjusted for age, sex and genetic principal components 1-5. The strongest associations were on chromosome 3 near A4GNT with IL-6 levels (rs2724711 p=4.2×10-6), and on chromosome 7 with PAI-1 levels (rs1608488 (p=8.3×10-7). An association of genome-wide statistical significance (rs1862840; p=1.2×10-8) was observed on chromosome 16 near WWOX with TNF-α levels. Each copy of the G allele (frequency=0.12) confers a 0.41-SD increase in TNF-α levels. In a larger cohort of Southwestern Native Americans, rs1862840 was not associated with T2D (N=7,659; p=0.17). Among 3,983 nondiabetic subjects it did associate with 2 hour corrected insulin response (β=0.06-SD decrease per G allele copy, p=0.011). Among 300 normal glucose tolerant subjects it associated with the acute insulin response to intravenous glucose (β=20% decrease per G allele copy, p=0.045). This study identified a novel association for TNF-α levels at WWOX (a gene previously implicated in T2D and insulin secretion in Han Chinese study populations) and suggests potential genetic links between inflammation and insulin secretion.