The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study

Abstract

Chronic kidney disease (CKD) is an important public health problem in American Indian populations. Recent research has identified associations of polymorphisms in the myosin heavy chain type II isoform A (MYH9) gene with hypertensive CKD in African-Americans. Whether these associations are also present among American Indian individuals is unknown. To evaluate the role of genetic polymorphisms in the MYH9 gene on kidney disease in American Indians, we genotyped 25 SNPs in the MYH9 gene region in 1,119 comparatively unrelated individuals. Four SNPs failed, and one SNP was monomorphic. We inferred haplotypes using seven SNPs within the region of the previously described E haplotype using Phase v2.1. We studied the association between 20 MYH9 SNPs with kidney function (estimated glomerular filtration rate, eGFR) and CKD (eGFR < 60 ml/min/1.73 m2 or renal replacement therapy or kidney transplant) using age-, sex- and center-adjusted models and measured genotyped within the variance component models. MYH9 SNPs were not significantly associated with kidney traits in additive or recessive genetic adjusted models. MYH9 haplotypes were also not significantly associated with kidney outcomes. In conclusion, common variants in MYH9 polymorphisms may not confer an increased risk of CKD in American Indian populations. Identification of the actual functional genetic variation responsible for the associations seen in African-Americans will likely help to clarify the lack of replication of this gene in our population of American Indians.

A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9

“…Recent studies [25,26] based on variants genotyped in Hapmap failed at defining a clear candidate for causal association. If it is in fact true that one single variant can explain the association between this locus and FSGS, then it is likely that it is one of the variants which are highly polymorphic exclusively among Africans, but rare or non-existent in non-Africans, which would explain the lack of replication of association of this locus in other large studies in different populations [27]. The small level of associations observed in Europeans by others [14] could also be explained by low levels of African ancestry in the cases considered or even by the fact that Southern European populations have a 1–3% level of African ancestry due to migrations which took place 50–70 generations ago (private communication with Nick Patterson).…”

The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus

“…These genetic associations were evident in African Americans, 90,91 and possibly in Europeans as well, 92 but not in American Indians (Table 1). 93 However, as kidney biopsies were lacking in some of these studies, whether the etiologic label was accurate is difficult to know. In the case of diabetic nephropathy in particular, researchers suggested that the apparent association with the MYH9 locus might actually reflect the presence of nondiabetic kidney disease incorrectly labeled as diabetic nephropathy.…”

African origins and chronic kidney disease susceptibility in the human immunodeficiency virus era

“…The high frequency of the MYH9 associated haplotypes in African populations led to speculations of selection in Africa ( Figure 2) [42] . The ethnic specificity of the association was explored with different phenotypes and different populations ( Table 2) and subsequent studies provided evidence for a contribution of MYH9 variants in early stages of CKD as well as diabetic and hypertensive-related CKD in both African Americans and Europeans, but not in Native Americans [43][44][45] . However, biopsy-proven forms of CKD were lacking in some of these studies and therefore, as in the case of diabetic and hypertensive nephropathies, researchers suggested that the association with MYH9 could also reflect the presence of non-diabetic and non-hypertensive CKD.…”