Variant in the 3′ Region of the IκBα Gene Associated With Insulin Resistance in Hispanic Americans: The IRAS Family Study |
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| Authors: | Melissa R Miller Weiming Zhang Scott P Sibbel Carl D Langefeld Donald W Bowden Steven M Haffner Richard N Bergman Jill M Norris Tasha E Fingerlin |
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| Institution: | 1. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA;2. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA;3. Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston‐Salem, North Carolina, USA;4. Department of Biochemistry, Wake Forest University Health Sciences, Winston‐Salem, North Carolina, USA;5. Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA;6. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA |
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| Abstract: | The IKKβ/NF‐κB pathway is known to play an important role in inflammatory response and has also recently been implicated in the process of insulin resistance. We hypothesized that one or more variants in the IκBα gene (NFKBIA) or surrounding untranslated regions would be associated with insulin sensitivity (SI) in Hispanic‐American families. We tested for association between 25 single‐nucleotide polymorphisms (SNPs) in and near NFKBIA and SI in 981 individuals in 90 Hispanic‐American families from the Insulin Resistance Atherosclerosis (IRAS) Family Study. SNP rs1951276 in the 3′ flanking region of NFKBIA was associated with SI in the San Antonio (SA) sample after adjusting for age, gender, and admixture (uncorrected P = 1.69 × 10?5; conservative Bonferroni correction P = 3.38 × 10?4). Subjects with at least one A allele for NFKBIA rs1951276 had ～29% lower SI compared to individuals homozygous for the G allele in the SA sample. Although not statistically significant, the effect was in the same direction in the San Luis Valley (SLV) sample alone (P = 0.348) and was significant in the combined SA and SLV samples (P = 5.37 × 10?4; presence of A allele associated with ～20% lower SI). In SA, when adjusted for subcutaneous adipose tissue area (SAT, cm2), the association was modestly attenuated (P = 1.25 × 10?3), but the association remained highly significant after adjustment for visceral adipose tissue area (VAT, cm2; P = 4.41 × 10?6). These results provide corroborating evidence that the NF‐κB/IKKβ pathway may mediate obesity‐induced insulin resistance in humans. |
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