Linkage Analysis of Albuminuria

Mottl, Amy K.; Vupputuri, Suma; Cole, Shelley A.; Almasy, Laura; Göring, Harald H.H.; Diego, Vincent P.; Laston, Sandra; Shara, Nawar; Lee, Elisa T.; Best, Lyle G.; Fabsitz, Richard R.; MacCluer, Jean W.; Umans, Jason G.; North, Kari E.

doi:10.1681/asn.2008080895

Cited by 22 publications

(23 citation statements)

References 65 publications

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“…This possibility is supported by several linkage studies pointing to the 3q27 region (i.e. the same as the ADIPOQ locus) as a candidate region for albuminuria [33,[45][46][47]. Finally, we cannot rule out the possibility that the positive association between serum HMW adiponectin and ACR levels, even in this normal range of albuminuria, may be due, at least partly, to a homeostatic protective mechanism aimed at counteracting renal and cardiovascular damage.…”

Section: Discussionmentioning

confidence: 79%

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

et al. 2011

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Aims/hypothesis Insulin resistance is associated with reduced serum adiponectin and increased albuminuria levels. Thus, one would anticipate an inverse relationship between circulating adiponectin and albuminuria. However, several studies have described a 'paradoxical' elevation of serum adiponectin in patients with elevated albuminuria. These findings may have been confounded by the presence of diseases and related treatments known to affect circulating adiponectin and albuminuria. We therefore studied the relationship between circulating adiponectin and albuminuria in the absence of such confounders. Methods To this purpose, the relationship between adiponectin isoforms and albumin:creatinine ratio (ACR) was investigated in a family-based sample of 634 non-diabetic untreated white individuals with normal kidney function. We also investigated whether the two variables share a common genetic background and addressed the specific role of the gene encoding adiponectin on that background by genotyping several ADIPOQ single nucleotide polymorphisms (SNPs). Results ACR was directly associated with high molecular weight (HMW) adiponectin isoform (p=0.024). The two variables shared some genetic correlation (ρ g = 0.38, p=0.04). ADIPOQ promoter SNP rs17300539 was associated with HMW adiponectin (p=4.8×10 −5 ) and ACR (p=0.0027). The genetic correlation between HMW adiponectin and ACR was no longer significant when SNP rs17300539 was added to the model, thus reinforcing the role of this SNP in determining both traits.Conclusions/interpretation Our study shows a positive, independent correlation between HWM adiponectin and ACR. ADIPOQ variability is associated with HMW adiponectin and ACR, and explains some of the common genetic background shared by these traits, thus suggesting that ADIPOQ and HMW adiponectin modulate albuminuria levels.

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Section: Discussionmentioning

confidence: 79%

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

et al. 2011

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“…Nevertheless, given their phenotypic characteristics the panel of rat models summarized here represents an important tool in our armamentarium to explore the genetics of the most prevalent forms of complex CKD to which both arterial hypertension and type-2 diabetes mellitus are major contributors. [1][2][3][4][5]9 In this regard, this panel is a valuable experimental and data resource in which numerous QTLs associated with renal (disease) phenotypes have been identified on all rat chromosomes (Tables 4 and 5). Moreover, several important findings obtained from studies in these models have already contributed to our knowledge on the genetic determination of complex renal disease phenotypes.…”

Section: Resultsmentioning

confidence: 99%

“…[1][2][3][4][5] Both arterial hypertension and type-2 diabetes mellitus are major contributors to complex CKD, which has a high prevalence in the general human population worldwide affecting B11-15% of individuals in Europe and United States. [6][7][8][9] CKD represents as expected a major risk factor for the progression to end-stage renal disease but associates also with an increased risk of cardiovascular morbidity and mortality.…”

Section: Introductionmentioning

confidence: 99%

Mapping genetic determinants of kidney damage in rat models

Schulz

Kreutz

2012

Hypertens Res

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During the last two decades, significant progress in our understanding of the development of kidney diseases has been achieved by unravelling the mechanisms underlying rare familial forms of human kidney diseases. Due to the genetic heterogeneity in human populations and the complex multifactorial pathogenesis of the disease phenotypes, the dissection of the genetic basis of common chronic kidney diseases (CKD) remains a difficult task. In this regard, several inbred rat models provide valuable complementary tools to uncover the genetic basis of complex renal disease phenotypes that are related to common forms of CKD. In this review, data obtained in nine experimental rat models, including the Buffalo (BUF), Dahl salt-sensitive (SS), Fawn-hooded hypertensive (FHH), Goto-Kakizaki (GK), Lyon hypertensive (LH), Munich Wistar Frömter (MWF), Sabra hypertension-prone (SBH), spontaneously hypertensive rat (SHR) and stroke-prone spontaneously hypertensive rat (SHRSP) inbred strains, that contributed to the genetic dissection of renal disease phenotypes are presented. In this panel of inbred strains, a large number of quantitative trait loci (QTL) linked to albuminuria/proteinuria and other functional or structural kidney abnormalities could be identified by QTL mapping analysis and follow-up studies including consomic and congenic rat lines. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is suitable for making a significant contribution to the development of an integrated approach to the systems genetics of common CKD. INTRODUCTIONCommon forms of chronic kidney diseases (CKD) represent complex disease phenotypes that are influenced by both environmental and genetic factors. [1][2][3][4][5] Both arterial hypertension and type-2 diabetes mellitus are major contributors to complex CKD, which has a high prevalence in the general human population worldwide affecting B11-15% of individuals in Europe and United States. 6-9 CKD represents as expected a major risk factor for the progression to end-stage renal disease but associates also with an increased risk of cardiovascular morbidity and mortality. 10,11 In addition to the assessment of impaired renal function or glomerular filtration rate, urinary albumin excretion rate (albuminuria) represents another important clinical marker for the evaluation of CKD and cardiovascular risk of patients. [10][11][12][13][14][15] These renal disease phenotypes are also inherited in several inbred rat strains many of which are hypertensive. 16 During the last decades, genetic mapping studies by genome-wide linkage analysis followed by fine mapping of selected quantitative trait loci (QTL) for renal disease phenotypes were reported. Subsequently, studies in consomic and congenic rats were performed to further unravel the genetics of kidney injury in inbred rat strains. For QTL confirmation, consomic strains were generated by transfer of an entire chromosome carrying a QTL from a donor strain into the disease backgro...

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“…8 Heritability of albuminuria ranges from 0.16 to 0.49 in families enriched with hypertension or diabetes. 9,10 Rare genetic variants are known to cause monogenic diseases featuring severe, nephrotic range proteinuria. 11 However, linkage or candidate gene studies have not reproducibly identified common genetic variants in association with lower levels of albuminuria.…”

mentioning

confidence: 99%

CUBN Is a Gene Locus for Albuminuria

Böger¹,

Chen²,

Tin³

et al. 2011

Journal of the American Society of Nephrology

214

210

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Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P ϭ 1.1 ϫ 10 Ϫ11) and microalbuminuria (P ϭ 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

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Linkage Analysis of Albuminuria

Cited by 22 publications

References 65 publications

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

Mapping genetic determinants of kidney damage in rat models

CUBN Is a Gene Locus for Albuminuria

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