Evaluation of a SNP map of 6q24–27 confirms diabetic nephropathy loci and identifies novel associations in type 2 diabetes patients with nephropathy from an African-American population

Abstract

Previously we performed a genome scan for type 2 diabetes (T2DM) using 638 African-American (AA) affected sibling pairs from 247 families; non-parametric linkage analysis suggested evidence of linkage at 6q24-27 (LOD 2.26). To comprehensively evaluate this region we performed a 2-stage association study by first constructing a SNP map of 754 SNPs selected from HapMap on the basis of linkage disequilibrium (LD) in 300 AAT2DM-ESRD subjects, 311 AA controls, 43 European American controls and 45 Yoruba Nigerian samples (Set 1). Replication analyses were conducted in an independent population of 283 AA T2DM-ESRD subjects and 282 AA controls (Set 2). In addition, we adjusted for the impact of admixture on association results by using ancestry informative markers (AIMs). In Stage 1, 137 (18.2%) SNPs showed nominal evidence of association (P<0.05) in one or more of tests of association: allelic (n=33), dominant (n=36), additive (n=29), or recessive (n=34) genotypic models, and 2-(n=47) and 3-SNP (n=43) haplotypic analyses. These SNPs were selected for follow-up genotyping. Stage 2 analyses confirmed association with a predicted 2-SNP "risk" haplotype in the PARK2 gene. Also, two intergenic SNPs showed consistent genotypic association with T2DM-ESRD: rs12197043 and rs4897081. Combined analysis of all subjects from both stages revealed nominal associations with 17 SNPs within genes; including suggestive associations in ESR1 and PARK2. This study confirms known diabetic nephropathy loci and identifies potentially novel susceptibility variants located within 6q24-27 in AA.

Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells

“…Additionally, although mutations in Parkin are strongly associated with the development of premature PD (1,41), the links between Parkin and either lipid disorders or metabolic syndromes are more tenuous. It is interesting to note, however, that the risk of developing diabetic nephropathy is associated with polymorphisms in PARK2 (42). Also, an association between fat metabolism and a binding partner of Parkin, i.e., Pink1, has similarly been found (43), and whether this reflects a broader role of Parkin and its interacting partners in lipid metabolism is an emerging concept for future studies.…”

The histidine triad nucleotide-binding protein 1 supports mu-opioid receptor–glutamate NMDA receptor cross-regulation

“…HINT1-mediated coupling of RGSZ2 proteins to MOR C terminus is particularly interesting. It is noteworthy that the human and murine RGSZ2 genes are found close to their respective MOR gene, suggesting that they may be coordinately expressed [49,50]. Moreover, the MOR and RGSZ2 genes are implicated in voluntary oral morphine consumption and/or preference in the morphine-quinine two-bottle choice paradigm [51].…”

Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus : A North Indian study

“…[1][2][3][4][5][6][7][8][9] An association study of candidate genes, viz., fatty acid binding protein 2 (FABP2), uncoupling protein type 1 gene (UCP1), protein phosphatase type 1 (PP1G), β3 adrenergic receptor (β3AR), VDR, was carried out on T2DM patients in a migrant Indian population as well by Boullus-Sanchis et al [10] Genome-wide association studies have led to the identiÞ cation of several single nucleotide polymorphisms in genes such as CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1. [11] Several genes were studied but only a handful showed conÞ rmed association, such as resistin, alpha-endosulfine, calpain10, peroxisome proliferators-activated receptor-gamma 2 (PPARγ-2), abundant transcript 1 gene (apM1), TCF7L2, insulin-like growth factor-binding protein 5 (IGFBP5), to name a few.…”