To our knowledge, our study is the first to report the interaction between MC4R rs17782313 polymorphisms and diet quality indices on cardio-metabolic traits. In the present study, we found that adherence to the HEI modified the effects of MC4R rs17782313 polymorphisms (rs17782313) on levels of LDL-C in women and glucose in men. Among female group, rare allele heterozygotes of rs17782313 had highest mean of LDL-C concentration when placed in second tertile of HEI. Furthermore, in male group, a gene-diet interaction was detected between DQI-I and MC4R rs17782313 on glucose level, SBP and DBP. Statistical adjustment for age, physical activity and WC did not change the statistical significance of these gene–diet interactions in both men and women. Among male homozygous carriers of the risk allele, those with lowest adherence to HEI and DQI-I had highest glucose concentrations. Another novel finding of our study was the inverse association between adherence to the HEI and chance of having CC genotype among female group. In addition, minor homozygote carriers of rs17782313 had lower adjusted means of AgRP levels compared with other genotypes (TT and TC).
Various range of minor allele frequency of rs17782313 polymorphism has been reported in different populations from 14% in Asians to 28% in Europeans. However, current study showed a frequency of 37% in Iranian population. Despite interactions between MC4R genes and dietary factors on obesity and other metabolic traits have been investigated in several studies [
25,
41], significant results have been reported only in limited number of investigations [
42]. In this regard, Ortega-Azorín et al. found that adherence to the Mediterranean dietary pattern (MedDiet) could modify genetic susceptibility to diabetes [
43]. In that study, CC-genotype carriers of the MC4R rs17782313 with low adherence to the MedDiet had a higher risk of Type 2 diabetes. To the best of our knowledge, specific interaction of variant rs17782313 gene with dietary intakes on cardio-metabolic risk factors is unknown. In the present research, among males with susceptible genotypes, individuals with poor adherence to HEI and DQI-I exhibited a higher SBP, DBP and glucose concentration. Our finding in this regard are supported by animal studies in which homozygous mutated mice exposed with high fat diet, exhibited hyperphagia and weight gain compared with wild-type mice [
44]. Moreover, finding of a cohort study confirmed that improving adherence to diet quality represented by higher scores of alternate healthy eating index (AHEI)-2010 and dietary approach to stop hypertension (DASH) could attenuate the genetic association with weight gain particularly in subjects at high genetic risk for obesity [
45]. On the other hand, our data indicated among female group, CT-genotype carriers who placed in the second tertile of HEI had the highest LDL-C concentrations. Gender-dependent differences regard to the association between rs17782313 and obesity-related traits have previously recognized [
46]. The reason for this discrepancy between men and women is unclear but might be related to difference in hormonal status and regional depots of adipose tissue [
47]. There is increasing evidence that polymorphism of rs17782313 (minor C allele) is related to some of cardio-metabolic risk factors such as hypertriglyceridemia [
48], low HDL-cholesterol [
49] and high LDL and total cholesterol [
24]. Likewise, we found the homozygous males for the minor allele (C) had higher adjusted means of serum glucose levels compared with the other genotypes (TT and TC). Our finding in this regard was in line with previous observational studies that SNP rs17782313 was significantly associated with insulin resistance [
50] and enhanced risk of diabetes [
51]. In the present study, HEI score was negatively associated with polymorphism of rs17782313 (CC genotype) among female group. Similarly, there is evidence that indicate rs17782313 SNP of MC4R gene influence on dietary intake parameters [
51]. For example, Qi et al. in a large cohort study indicated that rs17782313 variant was associated with higher intakes of total energy and dietary fat [
51]. Nevertheless, the evidence from other human investigations in this regard is inconsistent [
52]. In the current study, adherence to healthy dietary patterns, which consider the effects of whole diet instead of focusing on single foods and macro- and micronutrients in isolation, were assessed by diet quality scores. Even though the precise mechanisms behind these observed interactions remain unknown, there is considerable evidence that these diet quality indices (HEI and DQI-I) protects against major diet-dependent chronic diseases [
53,
54]. Hence, it is not surprising that lower adherence to these diet quality indices can promote effects of greater genetic susceptibility to cardio-metabolic risk factors. The favorable effects of these indices can be attributed to healthy choice such as vegetables, fruits, whole grains, sea food and plant proteins and more emphasize on polyunsaturated-to saturated fat ratio [
10,
54]. In this regard, emerging researches demonstrated the inverse associations of fruit, vegetables and diet-related chronic diseases [
55].
Although not much is known about the association between α-MSH, AgRP and MC4R polymorphisms, present investigation showed that homozygous male for the minor allele (C) had lower levels of AgRP than other genotypes. Previous human studies that have investigated plasma AgRP and α-MSH concentration have reported equivocal results [
56‐
58]. However, most of these studies have shown that both plasma α-MSH and AgRP levels increase in obese adult subjects [
56,
57]. Evidence had indicated that any alteration in expression of these orexigenic and anorexigenic peptides (α-MSH and AgRP) may play a potential role in energy homeostasis, food intake and development of obesity [
59].
Several limitations of the current study should also be addressed; firstly, due to the cross-sectional nature of this study, causality cannot be inferred. Nevertheless, these results can provide hypothesis for prospective studies to evaluate and confirm true causal relation. Secondly, since small sample size may limit statistical power, the results of present study with relatively small sample size should be interpreted with caution until replicated in large longitudinal studies. Thirdly, under-reporting of dietary intakes that are commonly observed in obese individuals, may lead to potential bias and null results [
60]. However, subjects with extreme dietary intake values were not included in the analysis. On the other hand, current study as the same as other observational studies is prone to residual confounding due to unknown or unmeasured confounders [
61]. Fourthly, we did not have information regarding other modifiable factors such as meal and snacking patterns and dietary habits that may be effective on observed associations. Lastly, this research was carried out in Tabriz, one of the major cities in Iran with a unique culture and dietary intake, so results may not be generalizable to all Iranians and it need to be replicated in other populations. Despite limitations discussed above, this is the first attempt to study the interaction between MC4R rs17782313 polymorphisms and diet quality indices on cardio-metabolic traits, according to our knowledge. Identification of these gene-diet interactions could be crucial in planning appropriate personalized nutritional advice for the prevention and management of obesity and its-related consequences. Another major strengths of present study was use of a reliable [
29] and validated [
28] FFQ to collect dietary information.