Diabetic nephropathy (DN) is a devastating complication of type 1 and type 2 diabetes and leads to increased morbidity and premature mortality. Susceptibility to DN has an inherent genetic basis as evidenced by familial aggregation and ethnic-specific prevalence rates. Progress in identifying the underlying genetic architecture has been arduous with the realization that a single locus of large effect does not exist, unlike in predisposition to non-diabetic nephropathy in individuals with African ancestry. Numerous risk variants have been identified, each with a nominal effect, and they collectively contribute to disease. These results have identified loci targeting novel pathways for disease susceptibility. With continued technological advances and development of new analytic methods, additional genetic variants and mechanisms (e.g., epigenetic variation) will be identified and help to elucidate the pathogenesis of DN. These advances will lead to early detection and development of novel therapeutic strategies to decrease the incidence of disease.
Nephropathy; Type 2 diabetes; Albuminuria; Kidney; Genetics; Association
Chronic kidney disease remains as one of the major complications for individuals with diabetes and contributes to considerable morbidity. Individuals subjected to dialysis therapy, half of whom are diabetic, experience a mortality of ∼20% per year. Understanding factors related to mortality remains a priority. Outside of dialysis units, A1C is unquestioned as the “gold standard” for glycemic control. In the recent past, however, there is evidence in large cohorts of diabetic dialysis patients that A1C at both the higher and lower levels was associated with mortality. Given the unique conditions associated with the metabolic dysregulation in dialysis patients, there is a critical need to identify accurate assays to monitor glycemic control to relate to cardiovascular endpoints. In this two-part point-counterpoint narrative, Drs. Freedman and Kalantar-Zadeh take opposing views on the utility of A1C in relation to cardiovascular disease and survival and as to consideration of use of other short-term markers in glycemia. In the narrative below, Dr. Freedman suggests that glycated albumin may be the preferred glycemic marker in dialysis subjects. In the counterpoint narrative following Dr. Freedman’s contribution, Dr. Kalantar-Zadeh defends the use of A1C as the unquestioned gold standard for glycemic management in dialysis subjects.
—William T. Cefalu, MD Editor in Chief, Diabetes Care
Hypertension (HTN) affects ~30% of adults in industrialized countries and is the major risk factor for cardiovascular disease.
We sought to study the genetic effect of coding and conserved non-coding variants in syndromic HTN genes on systolic (SBP) and diastolic (DBP) blood pressure to assess their overall impact on essential hypertension (EH).
Methods and Results
We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1 and WNK4) in 560 European (EA) and African (AA) ancestry GenNet participants with extreme SBP. We investigated genetic associations of 2,535 variants with BP in 19,997 EAs and 6,069 AAs in three types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9,747 EA and 3,207 AA ARIC subjects. Lastly, we genotyped 37 missense and common noncoding variants in 6,591 EAs and 6,521 individuals (3,659 EA/2,862 AA) from the CLUE and FBPP studies. None of the variants individually reached significant false-discovery rates (FDR≤0.05) for SBP and DBP. However, upon pooling all coding and non-coding variants we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G and WNK1), with higher association at evolutionary conserved sites.
Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units) and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.
essential hypertension; blood pressure; population genetics; sequencing; genotype
African American; APOL1; end-stage renal disease; FSGS; hypertensive nephrosclerosis
Apolipoprotein L1 (APOL1) gene association studies and results of the African American Study of Kidney Disease and Hypertension are disproving the longstanding concept that mild to moderate essential hypertension contributes substantially to end-stage renal disease susceptibility in African Americans. APOL1 coding variants underlie a spectrum of kidney diseases, including that attributed to hypertension (labeled arteriolar or hypertensive nephrosclerosis), focal segmental glomerulosclerosis, and HIV-associated nephropathy. APOL1 nephropathy risk variants persist because of protection afforded by the parasite that causes African sleeping sickness. This breakthrough will lead to novel treatments for hypertensive African Americans with low-level proteinuria, for whom effective therapies are lacking. Furthermore, APOL1 nephropathy risk variants contribute to racially variable allograft survival rates after kidney transplantation and assist in detecting nondiabetic forms of nephropathy in African Americans with diabetes. Discovery of APOL1-associated nephropathy was a major success of the genetics revolution, demonstrating that secondary hypertension is typically present in nondiabetic African Americans with nephropathy.
African American; African sleeping sickness; Arteriolar nephrosclerosis; APOL1; Chronic kidney disease; Dialysis; End-stage renal disease; ESRD: Focal segmental glomerulosclerosis; Genetics; Glomerulosclerosis; Hypertension; Hypertensive nephrosclerosis; Kidney disease; Kidney donors; MYH9; Nondiabetic nephropathy; Racial differences; Trypanosoma brucei rhodesiense; Transplantation
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
African Americans (AAs) are predisposed to non-diabetic (non-DM) end-stage renal disease (ESRD) and studies have shown a genetic component to this risk. Rare mutations in ACTN4 (α-actinin-4) an actin binding protein expressed in podocytes cause familial focal segmental glomerulosclerosis.
We assessed the contribution of coding variants in ACTN4 to non-DM ESRD risk in AAs. Nineteen exons, 2800 bases of the promoter and 392 bases of the 3’ untranslated region of ACTN4 were sequenced in 96 AA non-DM ESRD cases and 96 non-nephropathy controls (384 chromosomes). Sixty-seven single nucleotide polymorphisms (SNPs) including 51 novel SNPs were identified. The SNPs comprised 33 intronic, 21 promoter, 12 exonic, and 1 3’ variant. Sixty-two of the SNPs were genotyped in 296 AA non-DM ESRD cases and 358 non-nephropathy controls.
One SNP, rs10404257, was associated with non-DM ESRD (p<1.0E-4, odds ratio (OR)=0.76, confidence interval (CI)=0.59–0.98; additive model). Forty-seven SNPs had minor allele frequencies less than 5%. These SNPs were segregated into risk and protective SNPs and each category was collapsed into a single marker, designated by the presence or absence of any rare allele. The presence of any rare allele at a risk SNP was significantly associated with non-DM ESRD (p = 0.001, dominant model). The SNPs with the strongest evidence for association (n = 20) were genotyped in an independent set of 467 non-DM ESRD cases and 279 controls. Although, rs10404257 was not associated in this replication sample, when the samples were combined rs10404257 was modestly associated (p=0.032, OR=0.78, CI=0.63–0.98; dominant model). SNPs were tested for interaction with markers in the APOL1 gene, previously associated with non-DM ESRD in AAs and rs10404257 was modestly associated (p = 0.0261, additive model).
This detailed evaluation of ACTN4 variation revealed limited evidence of association with non-DM ESRD in AAs.
ACTN4; non-diabetic ESRD; FSGS; kidney; hypertensive nephrosclerosis; African Americans
Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate related genes biological candidates for disease susceptibility. This study analyzed variation in reactive intermediate genes for association with SLE in two populations with African ancestry.
A total of 244 SNPs from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls) and. Single-marker, haplotype, and two-locus interaction tests were computed for these populations.
The glutathione reductase gene GSR (rs2253409, P=0.0014, OR [95% CI]=1.26 [1.09–1.44]) was the most significant single-SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575, P=0.0065, OR [95%CI]=2.10 [1.23–3.59]) and nitric oxide synthase gene NOS1 (rs561712, P=0.0072, OR [95%CI]=0.62 [0.44–0.88]) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409, P=0.00072, OR [95%CI]=1.26 [1.10–1.44]). Haplotype and two-locus interaction analyses also uncovered different loci in each population.
These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
systemic lupus erythematosus; African Americans; genetic association studies; oxygen compounds; single nucleotide polymorphism
Racial differences in the etiology, natural history and effects of chronic kidney disease have long been the subject of investigation. Dialysis-dependent kidney failure occurs nearly four times more often in African Americans than European Americans. Despite this observation, studies repeatedly demonstrate that African Americans have a significant survival advantage after initiating dialysis. Although this phenomenon has been attributed to environmental and socioeconomic factors, recent studies demonstrate that inherited factors strongly influence racial differences in development of diverse kidney diseases and may impact the risk for nephropathy-associated cardiovascular disease. Herein we review relevant studies and propose the hypothesis that inherited factors leading to organ-limited kidney diseases and a lower burden of systemic atherosclerosis contribute, in part, to the improved survival rates seen in African American patients on dialysis.
African Americans; chronic kidney disease; dialysis; race; European Americans; genetics; survival
Several related disorders comprise the spectrum of non-muscle myosin heavy chain 9-associated (MYH9) nephropathy. The contribution of variants in this single MYH9 gene to ethnic differences in the incidence rates of end-stage renal disease (ESRD) is now clearly established. The importance of recognizing the role of MYH9 in these inherited kidney disorders goes beyond simple disease association; there may well be effects on clinical outcomes in patients on dialysis and after kidney transplantation. MYH9 may adversely affect treatment outcomes in severe kidney disease and such gene effects are rarely encountered in practice.
African American; dialysis; FSGS; kidney disease; MYH9; outcomes; transplantation
This manuscript reviews the controversial relationship between hypertension and initiation of kidney disease. We focus on ethnic differences in renal histopathology and associated gene variants comprising the spectrum of MYH9-nephropathy.
Purpose of review
Treating mild to moderate essential hypertension in non-diabetic African Americans fails to halt nephropathy progression; while hypertension control slows nephropathy progression in European Americans. The pathogenesis of these disparate renal syndromes is reviewed.
The non-muscle myosin heavy chain 9 gene (MYH9) is associated with a spectrum of kidney diseases in African Americans, including idiopathic focal global glomerulosclerosis historically attributed to hypertension, idiopathic focal segmental glomerulosclerosis, and the collapsing variant of focal segmental glomerulosclerosis (HIV-associated nephropathy). Risk variants in MYH9 likely contribute to the failure of hypertension control to slow progressive kidney disease in non-diabetic African Americans.
Early and intensive hypertension control fails to halt progression of “hypertensive nephropathy” in African Americans. Genetic analyses in patients with essential hypertension and nephropathy attributed to hypertension, FSGS and HIVAN reveal that MYH9 gene polymorphisms are associated with a spectrum of kidney diseases in this ethnic group. Mild to moderate hypertension may cause nephropathy in European Americans with intra-renal vascular disease improved by the treatment of hypertension, hyperlipidemia and smoking cessation.
African Americans; CHGA; focal segmental glomerulosclerosis; genetics; hypertensive nephrosclerosis; MYH9
Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in African Americans. The HIV-1 virus infects podocytes, cells integral to formation of the glomerular filtration barrier, often leading to focal segmental glomerulosclerosis. HIVAN is typically a complication of late-stage HIV infection, associated with low CD4 cell counts and elevated serum HIV RNA levels. Highly active antiretroviral therapy (HAART) is partially protective and has altered the natural history of HIV-associated kidney disease. Nonetheless, HIVAN remains an important public health concern among HIV-infected African Americans. Although polymorphisms in the MYH9 gene on chromosome 22 are strongly associated with HIVAN, as well as with idiopathic focal segmental glomerulosclerosis and global glomerulosclerosis (historically labeled "hypertensive nephrosclerosis"), the majority of HIV-infected patients who are genetically at risk from MYH9 do not appear to develop severe kidney disease. Therefore, we postulate that additional environmental exposures and/or inherited factors are necessary to initiate human HIVAN. Gene-environment interactions have also been proposed as necessary for initiation of HIVAN in murine models. It is important that these novel risk factors be identified, as prevention of environmental exposures and targeting of additional gene products may reduce the risk for HIVAN, even among those harboring two risk alleles in MYH9.
African Americans; FSGS; HIV-associated nephropathy; kidney disease; MYH9
Purpose of review
This manuscript reviews recent efforts to identify genetic variants conferring risk for chronic kidney disease (CKD). A brief overview of methods for identifying gene variants is provided, along with genetic associations and new avenues under exploration.
The role of renal failure susceptibility genes including MYH9, ELMO1, UMOD and ACTN4 has become clearer over the last 18 months. The spectrum of MYH9-associated kidney disease including focal segmental glomerulosclerosis (FSGS), global glomerulosclerosis and collapsing glomerulopathy, related entities contributing to approximately 43% of end-stage renal disease in African Americans, has come to light.
MYH9 will re-categorize FSGS and related disorders, and has clarified the relationship between hypertension and kidney disease. MYH9 polymorphisms account for much of the excess risk of HIV-associated nephropathy and non-diabetic kidney disease in African Americans. Kidney disease associations with ELMO1 and UMOD have been replicated and applications of genome-wide association studies based on expression data are providing novel insights on renal protein expression. These breakthroughs will alter our approach to kidney disease surveillance and lead to new therapeutic options.
diabetes mellitus; ELMO1; focal segmental glomerulosclerosis; genetics; kidney disease; MYH9
Despite intensive anti-hypertensive therapy there was a high incidence of renal end-points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the non-muscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dL during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.
Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval.
We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index.
Within KCNQ1 there was weak evidence for association between the minor allele of IVS12+14T>C and increased QTc (p=0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (p=0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (p=0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation.
We found weak evidence of association between three previously-reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remains to be determined.
QT interval; diabetes; association study; genetics; ion channels
Pre-eclampsia is the second leading cause of maternal morbidity and mortality in the United States. Infants born to affected mothers face a five-fold increase in death rate [Lain and Roberts 2002; National Heart Lung and Blood Institute 2001]. Although pre-eclampsia has been recognized by physicians for millennia, relatively little is known about its pathogenesis or prevention. Predicting its development is often extremely difficult, perhaps leading the Greeks to use the name ’eklampsis’ meaning lightening. Recent studies provide novel insights into the role of the placenta in the development of pre-eclampsia and demonstrate novel markers to assist in predicting the onset of disease and potential therapeutic targets. Following an introduction which highlights the classification of hypertensive disorders of pregnancy and defines incidence and adverse outcomes of pre-eclampsia, this manuscript will discuss the role of the placenta in the pathophysiology of pre-eclampsia and recent markers that may predict its onset.
hypertension; pre-eclampsia; pregnancy; vascular endothelial growth factor (VEGF); placental growth factor (PlGF); soluble fms-like tyrosine kinase 1 (sFlt1); endoglin (Eng); placental protein 13 (PP13); long pentraxin 3 (PTX3)
Polymorphisms in the non-muscle myosin IIA gene (MYH9) are associated with focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease (ESRD) in African Americans and FSGS in European Americans. We tested for association of single nucleotide polymorphisms (SNPs) in MYH9 with T2DM–ESRD in European Americans; additionally, three APOL1 gene variants were evaluated.
Fifteen MYH9 SNPs and two APOL1 SNPs plus a 6-bp deletion were genotyped in 1963 European Americans, 536 cases with T2DM–ESRD and 1427 non-nephropathy controls (467 with T2DM and 960 without diabetes).
Comparing T2DM–ESRD cases with the 467 T2DM non-nephropathy controls, single variant associations trending toward significance were detected with SNPs rs4821480, rs2032487 and rs4281481 comprising part of the major MYH9 E1 risk haplotype [P-values 0.053–0.055 recessive, odds ratio (OR) 6.08–6.14]. Comparing T2DM–ESRD cases to all 1427 non-nephropathy controls, we confirmed evidence of association in these three SNPs as well as in the fourth E1 SNP (rs3752462) (P-values 0.017–0.035, OR 1.41–3.72). APOL1 G1/G2 nephropathy risk variants were rare in individuals of European American heritage, present in 0.28% of chromosomes in T2DM–ESRD cases and 0.32% of controls.
MYH9 SNPs rs4821480, rs2032487, rs4281481 and rs3752462 are associated with T2DM–ESRD susceptibility in European Americans. The APOL1 risk variants are not present at appreciable frequency in this cohort with T2DM–ESRD. Therefore, polymorphisms in MYH9 appear to influence nephropathy risk in this sample.
APOL1; diabetic nephropathy; end-stage renal disease; MYH9; type 2 diabetes mellitus
Familial aggregation of non-diabetic end stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2 percent of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared to one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated GFR (MDRD equation) and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.
African American; APOL1; end-stage renal disease; FSGS; kidney; screening
Haptoglobin (HP) is an acute phase protein that binds to freely circulating hemoglobin. HP exists as two distinct forms, HP1 and HP2. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM).
This study examined the association of HP genotypes with subclinical CVD, T2DM risk, and associated risk factors in a T2DM-enriched sample. Haptoglobin genotypes were determined in 1208 European Americans (EA) from 473 Diabetes Heart Study (DHS) families via PCR. Three promoter SNPs (rs5467, rs5470, and rs5471) were also genotyped.
Analyses revealed association between HP2-2 duplication and increased carotid intima-media thickness (IMT; p = 0.001). No association between HP and measures of calcified arterial plaque were observed, but the HP polymorphism was associated with triglyceride concentrations (p = 0.005) and CVD mortality (p = 0.04). We found that the HP2-2 genotype was associated with increased T2DM risk with an odds ratio (OR) of 1.49 (95% CI 1.18-1.86, p = 6.59x10-4). Promoter SNPs were not associated with any traits.
This study suggests association between the HP duplication and IMT, triglycerides, CVD mortality, and T2DM in an EA population enriched for T2DM. Lack of association with atherosclerotic calcified plaque likely reflect differences in the pathogenesis of these CVD phenotypes. HP variation may contribute to the heritable risk for CVD complications in T2DM.
Haptoglobin; Genetic polymorphism; Cardiovascular disease; Type 2 diabetes
Multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) susceptibility have been identified in predominantly European-derived populations. These SNPs have not been extensively investigated for individual and cumulative effects on T2D risk in African Americans.
RESEARCH DESIGN AND METHODS
Seventeen index T2D risk variants were genotyped in 2,652 African American case subjects with T2D and 1,393 nondiabetic control subjects. Individual SNPs and cumulative risk allele loads were assessed for association with risk for T2D. Cumulative risk was assessed by counting risk alleles and evaluating the difference in cumulative risk scores between case subjects and control subjects. A second analysis weighted risk scores (ln [OR]) based on previously reported European-derived effect sizes.
Frequencies of risk alleles ranged from 8.6 to 99.9%. Eleven SNPs had ORs >1, and 5 from ADAMTS9, WFS1, CDKAL1, JAZF1, and TCF7L2 trended or had nominally significant evidence of T2D association (P < 0.05). Individuals carried between 13 and 29 risk alleles. Association was observed between T2D and increase in risk allele load (unweighted OR 1.04 [95% CI 1.01–1.08], P = 0.010; weighted 1.06 [1.03–1.10], P = 8.10 × 10−5). When TCF7L2 SNP rs7903146 was included as a covariate, the risk score was no longer associated with T2D in either model (unweighted 1.02 [0.98–1.05], P = 0.33; weighted 1.02 [0.98–1.06], P = 0.40).
The trend of increase in risk for T2D with increasing risk allele load is similar to observations in European-derived populations; however, these analyses indicate that T2D genetic risk is primarily mediated through the effect of TCF7L2 in African Americans.
Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance.
We searched PubMed to identify genome linkage analyses of renal function traits in humans, such as estimated glomerular filtration rate (GFR), albuminuria, serum creatinine concentration and creatinine clearance. We contacted authors for numerical data and extracted information from individual studies. We applied the GSMA nonparametric approach to combine results across 14 linkage studies for GFR, 11 linkage studies for albumin creatinine ratio, 11 linkage studies for serum creatinine and 4 linkage studies for creatinine clearance.
No chromosomal region reached genome-wide statistical significance in the main analysis which included all scans under each phenotype; however, regions on Chromosomes 7, 10 and 16 reached suggestive significance for linkage to two or more phenotypes. Subgroup analyses by disease status or ethnicity did not yield additional information.
While heterogeneity across populations, methodologies and study designs likely explain this lack of agreement, it is possible that linkage scan methodologies lack the resolution for investigating complex traits. Combining family-based linkage studies with genome-wide association studies may be a powerful approach to detect private mutations contributing to complex renal phenotypes.
albuminuria; chronic kidney disease; glomerular filtration rate; linkage scans; meta-analysis
The hepatocyte nuclear factor 4-α (HNF4α) gene codes for a transcription factor which is responsible for regulating gene transcription in pancreatic beta cells, in addition to its primary role in hepatic gene regulation. Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), an uncommon, autosomal dominant, non-insulin dependent form of diabetes. Mutations in HNF4α have been found in few individuals, and infrequently have they segregated completely with MODY in families. In addition, due to similarity of phenotypes, it is unclear what proportion of type 2 diabetes (T2DM) in the general population is due to MODY or HNF4α mutations specifically. In this study, 27 documented rare and common variants were genotyped in a European American population of 1270 T2DM cases and 1017 controls from review of databases and literature implicating HNF4α variants in MODY and T2DM. Seventeen variants were found to be monomorphic. Two cases and one control subject had one copy of a 6-bp P2 promoter deletion. The intron 1 variant (rs6103716; MAF = 0.31) was not significantly associated with disease status (p>0.8) and the missense variant Thr130Ile (rs1800961; MAF = 0.027) was also not significantly different between cases and controls (p>0.2), but showed a trend consistent with association with T2DM. Four variants were found to be rare as heterozygotes in small numbers of subjects. Since many variants were infrequent, a pooled chi-squared analysis of rare variants was used to assess the overall burden of variants between cases and controls. This analysis revealed no significant difference (P=0.22). We conclude there is little evidence to suggest that HNF4α variants contribute significantly to risk of T2DM in the general population, but a modest contribution cannot be excluded. In addition, the observation of some mutations in controls suggests they are not highly penetrant MODY-causing variants.
Type 2 Diabetes; HNF4A; Rare variants
Over the past 50 years, increases in dietary n-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid, have been hypothesized to cause or exacerbate chronic inflammatory diseases. This study examines an individual’s innate capacity to synthesize n-6-long chain PUFAs (LC-PUFAs), with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes/metabolic syndrome. Compared to European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7.9±2.1; AfAm 9.8±1.9 % of total fatty acids, mean ± sd; p<2.29×10−9) and the AA to n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5.4±2.2, AfAm 6.9±2.2; p=1.44×10−5). Seven single nucleotide polymorphisms (SNP) mapping to the FADS locus revealed strong association with AA, eicosapentaenoic acid (EPA) and dihomogamma-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT: 6.3±1.0; GG: 8.5±2.1; p=3.0×10−5) and AA/DGLA ratios (TT: 3.4±0.8; GG: 6.5±2.3; p=2.2×10−7) but higher DGLA levels (TT: 1.9±0.4; GG: 1.4±0.4; p=3.3×10−7) compared to those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0.81) compared to EAm (0.46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are likely important differences in the capacity of different populations to synthesize LC-PUFAs. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.
SNP; FADS; arachidonic acid synthesis