Our study shows that carriers of the rare allele of TCF7L2 rs7903146 have a disrupted lipid metabolism, which is seen in different ways depending on age and baseline conditions. Healthy young men have a lower HDL and Apo A1 response to a saturated fatty acid-rich meal, while healthy elderly persons show increased postprandial lipemia, with higher totals of plasma cholesterol and Apo B, and a higher accumulation of Apo B, cholesterol and triglycerides in small TRL lipid particles.
Variations in TCF7L2
(particularly rs7903146) are a genetic risk factor for T2DM 
. The alterations caused by these gene variations in the glucose metabolism of diabetic persons have been largely explained by altered insulin secretion (caused by a failure in the fusion and release of the insulin-containing granules in the pancreatic beta cells) 
. We previously showed that this beta-cell dysfunction is also present in MetS patients, affecting the dynamic markers of glucose metabolism 
. However, the TCF7L2 pathway has also been involved in several other biological processes, like the differentiation of adipocytes and the regulation of adipokines, among others 
, and the presence of the minor allele of rs7903146 gene variation has been linked to other diseases apart from diabetes, such as the incidence of cancer 
, or the severity of coronary disease 
Despite the fact that lipid metabolism may be a link between TCF7L2
, adipocyte metabolism and coronary disease, few studies have evaluated fasting lipids, and the influence of gene variations on this gene and on postprandial lipids remains an unexplored field. A single previous report found that rs7903146 was linked to altered postprandial lipid metabolism only in the presence of a high PUFA intake in a sample of Caucasian origin with subjects ranging from 17 to 92 years old mostly recruited from a 3-generational pedigree database 
. The authors identified beta-cell dysfunction as the main underlying cause, although the significance for differences in the HOMA-B index in the full cohort was nominal (p
0.041). To further understand the significance of rs7903146 in human metabolism, we evaluated its effects in three different settings: healthy young men, middle-aged persons with MetS and healthy elderly persons, with the last two cohorts being examined after different dietary models.
The objective in choosing the first cohort (healthy young men) was to observe the possible effects of this SNP on a healthy background, where alterations in the carbohydrate metabolism were not present and the functional status of the pancreas was, in theory, optimal. In this setting, we found that the carrier status of a single minor allele for TCF7L2 rs7903146 was not related to altered postprandial response, requiring the existence of two altered alleles (homozygote for the rare alleles) to produce altered postprandial lipids, consisting of lower HDL and Apo A1 levels during the postprandial test, which would account for the diminished donor capacity of Apo CIII, an important feature of HDL during the postprandial state.
The second cohort model (MetS) was chosen on the basis of our previous research and published data into the influence of TCF7L2 on glucose metabolism and beta-cell function 
. In our sample, we could find no influence of these gene variations on postprandial lipemia in this population. What at first sight seemed a disappointing result may be put down to the fact that TCF7L2
SNPs do not exert the observed effects in the presence of MetS. Nevertheless, data from a previous comparison of the three cohorts resulted in the notion that, once homogenized, these MetS patients showed altered postprandial lipemia, when compared not only to young men, but also to healthy elderly persons (unpublished data, J D-L). In this context, it is possible that the deleterious effects of rs7903146 were not evident in the MetS cohort because all the participants, even those who did not carry the “harmful” allele, may have disrupted postprandial lipemia via other physiopathological pathways.
Our final test model was a cohort of healthy elderly persons. In this cohort, the carriers of the rare allele of rs7903146 showed altered postprandial lipemia, with higher total cholesterol and Apo B, and a higher content of cholesterol, triglycerides and Apo B in small-TRL particles, accounting for a disrupted clearance of postprandial particles - which may be related to the greater severity of cardiovascular events reported for the carriers of rs7903146 
. We also noted higher fasting total cholesterol, total triglycerides, and high LDL concentration and Apo B molecules in this last cohort. All these features are pro-atherogenic, and may have partly determined the altered postprandial lipemia. We did not find any influence of the type of diet on the results.
When looking for potential underlying mechanisms, we studied two well-known biological properties of TCF7L2 - its influence in beta-cell function, and in the adipocyte differentiation - by measuring the main adipokines present in mature adipocytes (adiponectin, leptin and resistin). Although it was non-significant in the case of the young men, both the elderly and the young men who are carriers of the minor alleles shared an increase in resistin levels, a hormone which has been related to obesity, or an increase in insulin resistance 
. As regards adiponectin, the T allele was related to a lower concentration in the young men’s cohort. Adiponectin participates in lipid clearance and glucose metabolism (decreasing gluconeogenesis and increasing glucose uptake) 
, and is inversely correlated to the harmful features of the postprandial state 
. The fact that the young men with the T allele showed higher adiponectin levels, while the elderly persons did not, may partially explain the features observed in lipid clearance in the latter (and absent in the young men), which implies that young men could somehow boost their lipid clearance by increasing their adiponectin levels. Moreover, we found higher levels of leptin (an adipokine that increases in response to obesity, inhibiting appetite at brain level 
) in the elderly persons who were homozygote for the common allele, which may be related to the higher BMI found in these persons in our sample.
Beta-cell dysfunction has been identified as the main cause by which TCF7L2
variants may exert their effects on glucose metabolism 
, and rs7903146 may impair the ability of hyperglycemia to suppress glucagon 
. In our study, HOMA-B measures did not differ in any case between carriers and non-carriers of the minor alleles of the SNPs, in the two populations in which the SNPs influenced the postprandial lipids, which may suggest that, despite the well-established effects of rs7903146 on beta-cell function, there could be additional pathways underlying the effects of rs7903146 on postprandial lipids. At this point, a combination of the direct effects of rs7903146 on insulin secretion with those derived from the crosstalk with other regulators of the energy metabolism via
adipokines cannot be discarded, and is something that, in our opinion, may be looked into further in in vitro
We must be cautious therefore when extrapolating our results, because our study presents some limitations. The possibility of epistasis should be considered between the rs7903146 SNP and postprandial lipemia response in terms of possible linkage disequilibrium in the vicinity of other related genes. On the other hand, oral fat loads have still not been satisfactorily categorized, as this has mainly been studied with different oral fat loads and different timing of blood sampling. In this study, we used different methodology in order to explore the determinants and the pathophysiological aspects of exaggerated/delayed postprandial lipemia in humans. This limitation regarding the different experimental designs is a factor to be considered.
Another point to be taken into account is that, while the effects of rs7903146 in our study are circumscribed to the postprandial measurements in the young men, they are also evident in the fasting state in the aged cohort, and, hence, it may be possible that some of the effects found in this latter cohort are due to the fasting figures. Nevertheless, the postprandial lipid metabolism involves many important clearance pathways and actors, such as the lipoprotein lipase or the different apolipoproteins that could limit the extent of the fasting effects in the postprandial state. In that context, our work shows how the modifications exerted by rs7903146 in the fasting state also extend to the fed state.
To sum up, we have shown how the gene variation rs7903146 negatively influences lipid metabolism during postprandial lipemia in healthy subjects (young men and elderly persons), while we did not find any effects in MetS persons. The elderly persons also exhibited altered fasting lipids.