Our findings show that risk allele frequencies of the included SNPs discovered in populations of European ancestry differed significantly by racial/ethnic group, consistent with the findings of other studies and HapMap estimates (11
). However, despite significant variations in allele frequencies, the patterns of influence of these SNPs on FG levels, HOMA-B, and IFG were generally consistent across racial/ethnic groups. A GRS derived by the combination of these 16 SNPs was weakly, yet significantly, associated with an increase in FG levels, a decrease in HOMA-B, and an increase in risk for IFG in all racial/ethnic groups. Our findings suggest that the genetic variants at these glycemic loci, discovered in the white population of European ancestry, also contribute to the elevated FG and reduced HOMA-B among non-Hispanic blacks and Mexican Americans.
The 16 FG-associated SNPs are located in or near genes involved in multiple biological pathways (10
). Some of these SNPs were also associated with type 2 diabetes (19
), and a few have been replicated in non-European populations (22
). Our study includes the most updated SNPs associated with FG and estimates their frequencies and effects in a nationally representative sample of the U.S. population. Our results suggest that with an adequate sample size (not necessarily as large as for a GWAS), these FG-associated SNPs would likely be replicated among non-Hispanic blacks and Mexican Americans.
Although FG levels seem tightly regulated within a narrow range by a feedback mechanism that targets a particular FG set point for each person (24
), FG levels vary substantially among nondiabetic populations, and an estimated 25–40% of the variation may be explained by genetic factors (7
). Many studies have suggested that elevated FG levels are associated with multiple health conditions, including risk for type 2 diabetes and cardiovascular diseases (1
). These diseases represent a major burden of disease in many populations (25
). Identification of populations at high risk of developing type 2 diabetes has great public health importance. Our findings suggest that a GRS, on the basis of these FG-associated SNPs, is significantly associated with IFG, but it is unclear if these SNPs can improve predictions for risks of type 2 diabetes or cardiovascular disease in the general population. Further studies are also needed to examine the possible associations of these SNPs with type 2 diabetes and cardiovascular diseases in different races and ethnicities.
However, the combined effects of these SNPs explain only a small percentage of the total variations in FG levels and HOMA-B (<3%), suggesting that additional loci exist. These loci may be common genetic variants with small effects, rare variants with larger effects, or variants that strongly interact with each other or with environmental factors (in which the number and effect size remain unknown). These interactions are undoubtedly important but complicated to model; their exploration is beyond the scope of our study.
The major strengths of our study include the availability of FG and HOMA-B measurements from a nationally representative sample of the U.S. population with multiple racial/ethnic groups and the genotyping of the 16 most updated FG-associated SNPs. There are several limitations of our study. First, these FG-associated SNPs were discovered among populations of European ancestry and may be proxies for the causal variants. It is well known that linkage disequilibrium patterns vary significantly by race/ethnicity (17
), and it is unclear if linkage disequilibrium might break down for some of these SNPs in other racial/ethnic groups (online appendix Fig. 3). Additional fine mapping in all three race/ethnic groups is needed. Second, we replicated a limited number of SNPs—even among non-Hispanic whites—that were significantly associated with FG levels or HOMA-B in the NHANES III. As indicated in the power calculation (online appendix), we had limited sample size to detect an effect size of <0.07 mmol/l in FG per allele for each individual SNP. The most likely explanation for the lack of significant association was the limited sample size of fasting individuals from the NHANES III. Since these were GWAS-confirmed, FG-associated SNPs (at least among non-Hispanic whites), we included all SNPs in our analysis. However, using the GRS as a continuous variable, we have adequate power to detect an effect size as low as 0.016 mmol/l per risk allele. When including only the 11 SNPs that showed the expected direction of effects for FG and HOMA-B, the association of the GRS appeared to be stronger, though the patterns remained unchanged (results not shown). At least for non-Hispanic whites, a larger sample size would not likely change the conclusions since the majority of the SNPs' effects are in the expected direction, consistent with studies in European populations (10
). Third, we calculated the weighted GRS for the three racial/ethnic groups on the basis of the published β-coefficients from populations of European ancestry because of a lack of estimates for other racial/ethnic groups (10
). These β-coefficients might not be appropriate for other populations. However, the consistent effects of the GRS on FG, HOMA-B, and IFG across racial/ethnic groups suggest that the weighting was not totally inappropriate in these populations. In addition, the pattern of association between weighted and unweighted GRS on FG, HOMA-B, and IFG were consistent (online appendix Tables 4 and 5).
In summary, our results suggest that the allele frequencies of FG-associated SNPs varied significantly by race/ethnicity. However, the patterns of combined effects of these SNPs on FG levels and HOMA-B were consistent across the different racial/ethnic groups. A GRS that was based on 16 SNPs was significantly associated with risk of IFG among all racial/ethnic groups, which may make it useful for the identification of people who are at high risk for developing diabetes.