Immunoglobulin Locus Associates with Serum IgG Levels and Albuminuria

Herring, Stacy M.; Gokul, Nisha; Monita, Monique; Bell, Rebecca; Boerwinkle, Eric; Wenderfer, Scott E.; Braun, Michael C.; Doris, Peter A.

doi:10.1681/asn.2010111148

Cited by 12 publications

(21 citation statements)

References 35 publications

(31 reference statements)

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“…We have reported extensive functional sequence variation in the Fc region of the immunoglobulin gamma heavy chains of SHR-A3 and its association with renal injury 8 . Our analysis of the whole genome sequences for the two SHR lines reveals that the IgH locus contains extensive variation between the two SHR lines, for SHR-B2 this is the most divergent region of the entire genome 20 .…”

Section: Resultsmentioning

confidence: 99%

“…In SHR lines differing in CKD risk, injury susceptibility may arise within the genes participating in immune responses triggered by disturbed vascular auto-regulation. We have recently reported extensive functional natural allelic variation affecting the immunoglobulin heavy chain locus in this rat model of hypertensive renal disease 2, 8 . This variation results in functional alteration to IgG sequence that is associated with severity of albuminuria.…”

Section: Introductionmentioning

confidence: 99%

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Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Braun

Herring

Gokul

et al. 2014

Circ Cardiovasc Genet

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Background The spontaneously hypertensive rat (SHR) strain exists in lines that contrast strongly in susceptibility to renal injury in hypertension. These inbred lines share common ancestry and only 13% of their genomes arise from different ancestors. Methods and Results We used next gen sequencing to detect natural allelic variation in 5 genes of the immunoreceptor signaling pathway (IgH, Dok3, Src, Syk and JunD) that arise from different ancestors in the injury-prone SHR-A3 and the resistant SHR-B2 lines. We created an intercross between these lines and in the F2 progeny we observed that the inheritance of haplotype blocks containing the SHR-A3 alleles of these 5 genes correlated with increased albuminuria and histological measures of renal injury. To test whether accumulated genetic variation in this pathway may create a therapeutic target in hypertensive renal injury, rats of both lines were treated with the immunosuppressant mycophenolate mofetil (MMF). MMF reduced proteinuria (albumin to creatinine ratio, uACR) from 6.6 to 1.2 mg/mg (p<0.001) in SHR-A3. Glomerular injury scores were reduced in MMF treated SHR-A3 from 1.6 to 1.4 (p<0.002). Tubulo-interstitial injury was reduced in MMF-treated SHR-A3 from 2.62 to 2.0 (p=0.001). MMF treatment also reduced renal fibrosis in SHR-A3, (3.9 vs. 2.0, p<0.001). Conclusions Polygenic susceptibility to renal injury in hypertension arises in association with genetic variation in genes that participate in immune responses and is dramatically improved by reduction of immune system activity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Braun

Herring

Gokul

et al. 2014

Circ Cardiovasc Genet

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“…160,161 In addition, SHR rats develop several other phenotypes including insulin resistance, [162][163][164][165] renal damage such as mild proteinuria and albuminuria, glomerular sclerosis and pathological alterations in small vessels with age. 166,167 Cosegregation and linkage analyses Herring et al 168 investigated whether the IgG/Fc-g receptor pathway in glomeruli is capable of modulating hypertensive glomerular disease such as albuminuria in SHR. In an (SHR-A3 Â SHR-B2)-F2 intercross, the authors identified in male SHR-A3 a QTL on RNO6 linked to IgG subclasses (Tables 1 and 5), which was derived from the IgH gene (immunoglobulin heavy chain complex).…”

Section: Strain Characteristicsmentioning

confidence: 99%

“…In an (SHR-A3 Â SHR-B2)-F2 intercross, the authors identified in male SHR-A3 a QTL on RNO6 linked to IgG subclasses (Tables 1 and 5), which was derived from the IgH gene (immunoglobulin heavy chain complex). 168 Subsequently, single-nucleotide polymorphism genotyping revealed that allelic variation in the IgH haplotype block or neighboring genes may modify the susceptibility to hypertensive renal injury without a BP influence. 168 …”

Section: Strain Characteristicsmentioning

confidence: 99%

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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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Genetic susceptibility to hypertensive renal disease

Doris

2012

Cell. Mol. Life Sci.

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Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared with individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise.

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Immunoglobulin Locus Associates with Serum IgG Levels and Albuminuria

Cited by 12 publications

References 35 publications

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

Mapping genetic determinants of kidney damage in rat models

Genetic susceptibility to hypertensive renal disease

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