CKD affects minorities disproportionally, who also progress more often to end-stage renal disease (ESRD) than individuals of European ancestry. 8, 9
American Indians have a high prevalence of obesity and T2D, which contribute to the large burden of cardiovascular and kidney diseases in this population. 7-9, 30
We investigated the genetic contribution of recently discovered T2D genetic variants to kidney function and markers of kidney damage in American Indians. The selected SNPs were initially identified in European and Asian ancestry studies and some of these variants have also been replicated for T2D associations in American Indian participants of the SHS (Haiman et al., Diabetes, under review). Several loci (FTO
, KCNJ11, TCF7L2
) were associated with eGFR and a SNP in WFS1
was associated with albuminuria. WFS1
product is a transmembrane protein localized to the endoplasmic reticulum (ER) 31
which is involved in ER stress signaling pathways. 32
SNP T2D risk allele was associated with increased albuminuria and eGFR, with a large effect on eGFR in American Indians younger than 45 years-old compared to those 45 to 59 years or older than 60 years, for whom the SNP effect was greatly attenuated. In analyses adjusted for both BMI and T2D, the association with eGFR was slightly changed in the younger age category but was no longer significant for UACR. These are interesting findings as American Indians develop diabetic nephropathy at earlier ages than individuals of other ancestry. 33
Early stages in the pathogenesis of the diabetic nephropathy are characterized by microalbuminuria and hyperfiltration. Our findings of increasing eGFR and albuminuria for WFS1
, although modest, are consistent with the early development of nephropathy and suggest that the genetic effect is partially mediated by diabetes. Our findings will require further confirmation in American Indians and other populations, and in studies using direct measures of kidney function to detect higher ranges of GFR.
In contrast, the alleles associated with T2D risk for FTO
, KCNJ11, TCF7L2
were associated with reduced eGFR in American Indians and were not associated with albuminuria. FTO
is known to confer risk for T2D through its association with obesity 34
in both children and adults. 34, 35
Variants in this gene have been recently reported to be associated with end-stage renal disease in two case-control studies 36
. Of interest, the associations with low eGFR in American Indians occurred in models adjusting for BMI suggesting an effect independent of body size, although the mean BMI in American Indians in our study was high and in the range of overweight to obese. The KCNJ11
gene was identified in T2D associations in individuals of European and Asian ancestry. 37-39
It impairs glucose-induced insulin release and it has also been associated with increased BMI 40, 41
. It is intriguing that variants in both these loci are associated with lower eGFR in the context of obesity, which is a risk factor for CKD. 42
However, for both loci, the associations seem to be mediated by diabetes as they are no longer significant in analyses adjusted for T2D.
has shown consistent associations with T2D across ancestry groups 43, 44
and, in American Indians, it has been associated with glucose homeostasis traits (unpublished data). TCF7L2 is a key component of the Wnt
signaling pathway involved in the regulation of pancreatic beta-cell proliferation, differentiation and insulin secretion 45
but also important in kidney embryogenesis and disease. 46
The rs7903146 T allele was significantly associated with lower eGFR in American Indians but not with incident CKD in contrast to a previous report in a population-based study of middle-aged individuals. 28
Interestingly, a recent large study of T2D showed association of the rs7903146 T allele with diabetic nephropathy, with larger effect in individuals with early onset T2D.27
In our study, this genetic variant shows no evidence of heterogeneity across age categories. In addition, the association was slightly attenuated when adjusting for diabetes. Therefore, our findings suggest that at least four T2D loci are associated with kidney traits in American Indians of which two may have effects that are partially independent of diabetes. These findings may have important implications in prevention efforts for CKD in this population.
Our prospective associations with incident CKD and new onset-albuminuria were restricted to the SHS cohort study which has long-term longitudinal data. Although we noted significant associations for the FTO rs9939609 A allele in the Dakotas, our samples were limited. In addition, we did not identify associations with new-onset albuminuria for tested SNPs.
This study used kidney function estimates from an equation derived from CKD individuals. Calibrated serum creatinine concentrations are currently not available in the SHS. The SNPs investigated were identified in individuals of European ancestry. However, the FTO, WFS1 and TCF7L2 SNPs associations have replicated in American Indians for T2D or glycemic traits.
In summary, we identified four T2D loci associated with kidney function in American Indians including two previously reported associations with kidney traits in individuals of European ancestry. The WFS1 variant was associated with increased albuminuria and eGFR and it showed age-specific effects on eGFR. These findings suggest shared genetic risk factors for T2D and its kidney complications in this population.