Interaction of an S 100 A 9 gene variant with saturated fat and carbohydrates to modulate insulin resistance in 3 populations of different ancestries 1 – 3

Background: S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries. Objectives: We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations. Design: We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155). Results: Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low. Conclusions: The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS). Am J Clin Nutr 2016;104:508–17. 1 Supportedby an Instituto de Salud Carlos III (ISCIII) postdoctoral research contract [Sara Borrell (Spain); to RB-R]. CES is supported by grant K08HL112845 from the National Heart, Lung, and Blood Institute, NIH. The CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention) study was supported by the Ministerio de Economia y Competitividad, Spain (grant AGL2012/39615; to JL-M) and the Ministerio de Ciencia e Innovacion, Spain [grants PIE14/00005 (to JL-M) and PI13/00023 (to JD-L)] and was also partly supported by a research grant from the European Commission (NUTRITECH European Integrated Project-289511). The CORDIOPREV study was also supported by the Fundacion Patrimonio Comunal Olivarero. Additional funding was received from Centro Tecnológico del Olivar y del Aceite, Centro de Excelencia en Investigación sobre Aceite de Oliva y Salud, Junta de Andalucia (Consejeria de Salud, Consejeria de Agricultura y Pesca, Consejeria de Innovacion, Ciencia y Empresa), the Diputaciones de Jaen y Cordoba, the Centro de Excelencia en Investigacion sobre Aceite de Oliva y Salud and Ministerio de Medio Ambiente, the Medio Rural y Marino, and the Spanish Government. The study was also cofinanced by the Fondo Europeo de Desarrollo Regional. The CIBER Fisiopatologia Obesidad y Nutricion is an initiative of the ISCIII, Madrid, Spain. The Genetics of Lipids Lowering Drugs and Diet Network study was supported by the National Heart, Lung, and Blood Institute (NHLBI) [grants U01HL072524 (Genetic and Environmental Determinants of Triglycerides), NHLBI R01 HL091357 (Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat), HL54776, and HL078885 and by contracts 53-K06-5-10 and 58-1950-9-001 from the USDA, Agriculture Research Service]. The Boston Puerto Rican Health Study was supported by the NIH (grants P01 AG023394 and P50 HL105185). 2 Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply the recommendation or endorsement by the USDA. 3 Supplemental Tables 1–4 are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org. 12 These authors contributed equally to this work. 13 These authors contributed equally to this work. *Towhom correspondence should be addressed. E-mail: jose.ordovas@ tufts.edu (JM Ordovas), jlopezmir@uco.es (J Lopez-Miranda). ReceivedFebruary 9, 2016. Accepted for publication May 19, 2016. First published online July 20, 2016; doi: 10.3945/ajcn.116.130898. 508 Am J Clin Nutr 2016;104:508–17. 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