Acanthosis nigricans (AN) is highly prevalent in Mexican Americans (MAs). It is a strong correlate of obesity, and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMF). However, the direct causal relationship of IR with AN in obesity has been recently questioned. Therefore, we aimed to assess its genetic and environmental correlations with CMFs and examine the complex causal relationships among the troika of AN, obesity, and IR in MA, using a mediation analysis. As part of our SAFARI Study, we obtained data from 670 nondiabetic MA children, aged 6-17 years (49% girls), BMI percentile median 87 (IQR 60, 97). AN (prevalence 33%) severity scores (range 0-5) were used as a quasi-quantitative trait for analysis. We used the program SOLAR for partitioning phenotypic correlations between AN and CMFs (BMI, HOMA-IR, lipids, blood pressure, hs-C-Reactive Protein (hs-CRP), and Harvard physical fitness score (PFS)). The matrices of genetic and environmental correlations were subsequently used in mediation (direct, indirect and partial) analysis using AMOS program. We computed standardized beta values for effect measurement and goodness-of-fit indices (AIC and BCC) for model comparisons. Heritability of AN was 0.75 (p<0.0001), and it was positively and significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and hs-CRP, and negatively correlated with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI -> HOMA-IR -> AN yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN simultaneously. Using complex models, BMI was associated with AN and IR mediating most of the CMFs; but no relationship between IR and AN.
In conclusion, our models suggest that obesity explains the presence of AN and IR, but no causal relationship between IR and AN in Mexican American children.
J.C. Lopez-Alvarenga: None. R. Arya: None. G. Chittoor: None. S.F. Paul: None. S.R. Puppala: None. V.S. Farook: None. S.P. Fowler: None. R.G. Resendez: None. A. Diaz-Badillo: None. D. Lehman: None. S. Mummidi: None. C. Jenkinson: None. J.L. Lynch: Board Member; Self; American Academy of Pediatrics. Consultant; Self; Novo Nordisk Inc. Research Support; Self; Daiichi Sankyo Company, Limited, National Institutes of Health, Novo Nordisk Inc., Pediatric Diabetes Consortium. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. J. Blangero: None. D.E. Hale: None. R. Duggirala: None.
National Institutes of Health (R01HD049051, HD041111, DK053889, DK042273, K01DK064867, P01HL045522, DK047482, MH059490, M01-RR-01346)