Juan C. Lopez-Alvarenga 1 , * , Geetha Chittoor 2 , Solomon F. D. Paul 3 , Sobha Puppala 4 , Vidya S. Farook 1 , Sharon P. Fowler 5 , Roy G. Resendez 1 , Joselin Hernandez-Ruiz 6 , Alvaro Diaz-Badillo 1 , David Salazar 7 , Doreen D. Garza 7 , Donna M. Lehman 5 , Srinivas Mummidi 1 , Rector Arya 1 , Christopher P. Jenkinson 1 , Jane L. Lynch 8 , Ralph A. DeFronzo 5 , John Blangero 1 , Daniel E. Hale 9 , Ravindranath Duggirala 1
15 October 2020
Acanthosis nigricans (AN) is a strong correlate of obesity and is considered a marker of insulin resistance (IR). AN is associated with various other cardiometabolic risk factors (CMRFs). However, the direct causal relationship of IR with AN in obesity has been debated. Therefore, we aimed to examine the complex causal relationships among the troika of AN, obesity, and IR in Mexican Americans (MAs).
We used data from 670 non-diabetic MA children, aged 6–17 years (49% girls). AN (prevalence 33%) severity scores (range 0–5) were used as a quasi-quantitative trait (AN-q) for analysis. We used the program SOLAR for determining phenotypic, genetic, and environmental correlations between AN-q and CMRFs (e.g., BMI, HOMA-IR, lipids, blood pressure, hs-C-reactive protein (CRP), and Harvard physical fitness score (PFS)). The genetic and environmental correlations were subsequently used in mediation analysis (AMOS program). Model comparisons were made using goodness-of-fit indexes.
Heritability of AN-q was 0.75 (p<0.0001). It was positively/significantly (p<0.05) correlated with traits such as BMI, HOMA-IR, and CRP, and negatively with HDL-C and PFS. Of the models tested, indirect mediation analysis of BMI→HOMA-IR→AN-q yielded lower goodness-of-fit than a partial mediation model where BMI explained the relationship with both HOMA-IR and AN-q simultaneously. Using complex models, BMI was associated with AN-q and IR mediating most of the CMRFs; but no relationship between IR and AN-q.