**1. Introduction**

4

Excessive gestational weight gain (GWG) affects half of pregnancies worldwide [1] and nearly 40% of pregnancies in Brazil [2]. In women with pregestational diabetes mellitus (DM), excessive GWG is associated with a higher risk of preterm delivery, cesarean section, large-for-gestational-age newborn, macrosomia, neonatal distress, and neonatal malformations [3,4]. In addition to increasing the immediate risk of perinatal complications, excessive GWG is associated with short- and long-term metabolic consequences for mothers and children and probably plays a key role in the metabolic programming of chronic diseases in the offspring [5].

The GWG recommendations [6,7] are based on the pre-pregnancy body mass index (BMI), but genetics, dietetics, and environmental factors appear to be involved in significant interindividual variation in weight gain during pregnancy [8,9]. The fat mass

**Citation:** Santos, K.d.; Rosado, E.L.; da Fonseca, A.C.P.; Belfort, G.P.; da Silva, L.B.G.; Ribeiro-Alves, M.; Zembrzuski, V.M.; Martínez, J.A.; Saunders, C. FTO and ADRB2 Genetic Polymorphisms Are Risk Factors for Earlier Excessive Gestational Weight Gain in Pregnant Women with Pregestational Diabetes Mellitus: Results of a Randomized Nutrigenetic Trial. *Nutrients* **2022**, *14*, 1050. https://doi.org/10.3390/ nu14051050

Academic Editors: Daniel-Antonio de Luis Roman and Ana B. Crujeiras

Received: 18 January 2022 Accepted: 23 February 2022 Published: 1 March 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

and obesity-associated (FTO) gene is located on chromosome 16, and common polymorphisms in the first intron are strongly associated with obesity. FTO encodes a protein with demethylase function and is highly expressed in the hypothalamus, particularly in the arcuate nucleus, suggesting that this gene plays an essential role in energy balance and body weight control [10].

The polymorphisms rs9939609 (T/A) and rs17817449 (T/G) in FTO are associated with body weight, BMI, and extreme obesity in the Brazilian population [11]. The A allele of the polymorphism rs9939609 is associated with higher GWG in North America [12,13] and Spanish women [14] but not with excessive GWG in Brazilian women [15]. Despite the association of rs17817449 (GG) with higher maternal BMI in pregnan<sup>t</sup> Iraqi women [16], its relationship with GWG has not ye<sup>t</sup> been explored in the literature.

The adrenoceptor beta 2 (ADRB2) gene is located on chromosome 5, and some polymorphisms in this gene have been consistently associated with a predisposition to obesity due to its expression in adipose tissue and its role in lipolysis and energy balance [17]. Two common polymorphisms in ADRB2 are the most studied, rs1042713 (G/A) and rs1042714 (C/G), although the results are quite divergent, with only rs1042714 (CG/GG) associated with obesity in a meta-analysis [18]. The relationship between ADRB2 polymorphisms and GWG has not ye<sup>t</sup> been explored.

Interventions that focus on a healthy diet have been found to be effective in optimizing GWG [5] and should start as early as possible, even during the periconceptional period [19]. The adherence to an "Western" dietary pattern—characterized by unhealthy and energydense foods with high intake of red meat, fries, dipping sauces, salty snacks, and alcoholic drinks—was associated with increased GWG, especially among obese women, in a cohort of women from Southern Europe [19].

Pregnant women with DM especially benefit from nutritional guidance to prevent excessive GWG and related adverse outcomes, which are more common in high-risk pregnancies [20]. The Dietary Approach to Stop Hypertension (DASH) diet encourages the consumption of fruits, vegetables, fat-free/low-fat dairy, whole grains, nuts, and legumes as well as limits the intake of saturated fat, cholesterol, refined sugar, sodium, red, and processed meats [21]. The DASH diet was originally proposed to control hypertension; however, in recent years, it has been recommended for pregnan<sup>t</sup> women with DM, obesity, and hypertension to reduce the risk of obstetric and perinatal complications [22,23].

However, the effects of diet on body physiology vary greatly among individuals, which may be partially explained by nutrigenetic interactions. The association between FTO and ADRB2 genetic polymorphisms and obesity phenotypes appears to be modified by diet composition [24–26]. Personalized nutrition may benefit individuals genetically predisposed to have a higher BMI using a dietary pattern that minimizes risk [27]. Studies are needed to elucidate the association between genetic variants, diet, and GWG, especially for high-risk pregnancies, such as in mothers with pregestational DM.

The aim of this study was to investigate the FTO genetic polymorphisms (rs9939609, rs17817449) and the ADRB2 genetic polymorphisms (rs1042713, rs1042714) as candidate genetic risk factors for excessive GWG in pregnan<sup>t</sup> women with pregestational DM using two different types of diets, a traditional diet and the DASH diet, as well as to ascertain nutrigenetic interactions associated to the genetic make-up.

### **2. Materials and Methods**
