Adequate use of allele frequencies in Hispanics--a problem elucidated in nephrotic syndrome

Abstract

Previous studies in children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) in the USA have revealed inter-ethnic differences in their clinical presentation and outcome. However, ethnicity was based on self-identification rather than on molecular genetic data. Here, we show that genetic heterogeneity exists in self-identified Hispanic (Spanish-American) patients with steroid-resistant nephrotic syndrome (SRNS), as patients may be either of Caucasian or Mesoamerican (Native-American) genetic background. Twenty-one self-identified Hispanic patients with SRNS from 18 families were initially evaluated for mutations in the NPHS2 and WT1 genes. All patients resided and were cared for in the USA. We performed a total genome search for linkage in all Hispanic patients using 250K single nucleotide polymorphism microarrays, comparing Caucasian with Mesoamerican allele frequencies to determine regions of homozygosity by descent and to establish the correct allele frequency for each family. We found that only ten families (56%) of the 18 self-identified Hispanic families are genetically of Mesoamerican descent, whereas the other eight families (44%) are of Caucasian descent. Due to the small number of families examined, we were unable to draw any conclusion on the prevalence of NPHS2 and WT1 in this ethnic group, but the data do suggest that self-identification of ethnicity in Hispanic-American patients is not an adequate basis for genetic studies, as this cohort may represent not only patients of Mesoamerican origin but also patients of Caucasian origin. Thus, one needs to critically review previous studies of FSGS/SRNS patients that involved Hispanic patients as a group. Future larger studies may employ a total genome search for linkage to test self-identified Hispanic ethnicity for true Mesoamerican versus Caucasian ethnicity in order to generate valid genetic data.

Fig. 1

Total genome search for linkage using the 250K Affymetrix SNP DNA microarray presented in MAKESCAN format for patient A1934, who is of Mesoamerican descent and carries a homozygous Y162X mutation in NPHS2. a Calculation using Caucasian allele frequencies, b calculation using Mesoamerican (Native-American) allele frequencies [14, 15]. The X-axis represents genetic distance in centiMorgans, with the corresponding chromosome number written above the panel. Chromosomes are concatenated from p-ter to q-ter from left to right along the X-axis. The Y-axis represents the non-parametric (ZLR) LOD score. The NPHS2 gene is located at the position of the arrow on Chr1q peak of homozygosity, detected using both allele frequencies. Multiple background peaks seen in a were not persistent when calculations were carried out under the three conditions of minor allele frequency (>0.2, >0.3, >0.4). Their absence from b indicates that the adequate allele frequencies for the calculation in this patient is the Mesoamerican and that the patient is predominantly of Mesoamerican descent