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ABSTRACT: Mutations in the type IV collagen alpha 1 gene (COL4A1) cause dominantly inherited cerebrovascular disease. We seek to determine the extent to which COL4A1 mutations contribute to sporadic, nonfamilial, intracerebral hemorrhages (ICHs).
We sequenced COL4A1 in 96 patients with sporadic ICH. The presence of putative mutations was tested in 145 ICH-free controls. The effects of rare coding variants on COL4A1 biosynthesis were compared to previously validated mutations that cause porencephaly, small vessel disease, and hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC) syndrome.
We identified 2 rare nonsynonymous variants in ICH patients that were not detected in controls, 2 rare nonsynonymous variants in controls that were not detected in patients, and 2 common nonsynonymous variants that were detected in patients and controls. No variant found in controls affected COL4A1 biosynthesis. Both variants (COL4A1(P352L) and COL4A1(R538G)) found only in patients changed conserved amino acids and impaired COL4A1 secretion much like mutations that cause familial cerebrovascular disease.
This is the first assessment of the broader role for COL4A1 mutations in the etiology of ICH beyond a contribution to rare and severe familial cases and the first functional evaluation of the biosynthetic consequences of an allelic series of COL4A1 mutations that cause cerebrovascular disease. We identified 2 putative mutations in 96 patients with sporadic ICH and showed that these and other previously validated mutations inhibit secretion of COL4A1. Our data support the hypothesis that increased intracellular accumulation of COL4A1, decreased extracellular COL4A1, or both, contribute to sporadic cerebrovascular disease and ICH.
Annals of Neurology 04/2012; 71(4):470-7. · 11.09 Impact Factor
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Alessandro Biffi, Akshata Sonni,
Christopher D Anderson,
Brett Kissela,
Jeremiasz M Jagiella,
Helena Schmidt,
Jordi Jimenez-Conde,
Björn M Hansen,
Israel Fernandez-Cadenas,
Lynelle Cortellini, [......],
James F Meschia,
Joan Montaner,
Arne Lindgren,
Jaume Roquer,
Reinhold Schmidt,
Steven M Greenberg,
Agnieszka Slowik,
Joseph P Broderick,
Daniel Woo,
Jonathan Rosand
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ABSTRACT: Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied.
We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification.
Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 × 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 × 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 × 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes.
APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied.
Annals of Neurology 11/2010; 68(6):934-43. · 11.09 Impact Factor
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Moritz F Sinner,
Steven A Lubitz,
Arne Pfeufer,
Seiko Makino,
Britt-Maria Beckmann,
Kathryn L Lunetta,
Gerhard Steinbeck,
Siegfried Perz,
Rosanna Rahman, Akshata Sonni,
Steven M Greenberg,
Karen L Furie,
H-Erich Wichmann,
Thomas Meitinger,
Annette Peters,
Emelia J Benjamin,
Jonathan Rosand,
Patrick T Ellinor,
Stefan Kääb
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ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia and has a substantial heritable component. Numerous associations between single nucleotide polymorphisms (SNPs) and AF have been described, but few have been replicated.
We sought to systematically replicate SNPs that are reported to be associated with AF in two large study samples of European descent.
We searched PubMed for studies reporting associations between SNPs and AF published before July 1, 2007. SNPs were genotyped in two independent case-control samples from Germany and the United States. Associations between SNPs and AF were assessed using logistic regression models adjusting for age, sex, and hypertension. A meta-analysis of the results from the two studies was performed.
We identified 21 SNPs and the angiotensin-converting enzyme insertion/deletion polymorphism that were reported to be associated with AF in the literature. Nine of these genetic variants were not represented on common genome-wide SNP arrays. We successfully genotyped 21 of these 22 variants in 2,145 cases with AF from the German Competence Network for Atrial Fibrillation and 4,073 controls from the KORA S4 study and 16 variants in 790 cases and 1,330 controls from the Massachusetts General Hospital. None of the SNPs replicated in independent populations with AF.
Our results suggest that previously reported associations to AF were likely false positives and highlight the need for systematic replication of genetic associations in large, independent cohorts to accurately detect variants associated with disease.
Heart rhythm: the official journal of the Heart Rhythm Society 11/2010; 8(3):403-9. · 4.56 Impact Factor
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Steven A Lubitz,
Moritz F Sinner,
Kathryn L Lunetta,
Seiko Makino,
Arne Pfeufer,
Rosanna Rahman,
Caroline E Veltman,
John Barnard,
Joshua C Bis,
Stephan P Danik, [......],
Jacqueline Witteman,
Jonathan D Smith,
Mina K Chung,
Susan R Heckbert,
Emelia J Benjamin,
Jonathan Rosand,
Dan E Arking,
Alvaro Alonso,
Stefan Kääb,
Patrick T Ellinor
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ABSTRACT: Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.
Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) at the 4q25 locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital and tested for association with AF. We replicated SNPs associated with AF after adjustment for the most significantly associated SNP in 5066 case and 30 661 referent subjects from the German Competence Network for Atrial Fibrillation, Atherosclerosis Risk In Communities Study, Cleveland Clinic Lone AF Study, Cardiovascular Health Study, and Rotterdam Study. All subjects were of European ancestry. A multimarker risk score composed of SNPs that tagged distinct AF susceptibility signals was constructed and tested for association with AF, and all results were subjected to meta-analysis. The previously reported SNP, rs2200733, was most significantly associated with AF (minor allele odds ratio 1.80, 95% confidence interval 1.50 to 2.15, P=1.2 x 10(-20)) in the discovery sample. Adjustment for rs2200733 genotype revealed 2 additional susceptibility signals marked by rs17570669 and rs3853445. A graded risk of AF was observed with an increasing number of AF risk alleles at SNPs that tagged these 3 susceptibility signals.
We identified 2 novel AF susceptibility signals on chromosome 4q25. Consideration of multiple susceptibility signals at chromosome 4q25 identifies individuals with an increased risk of AF and may localize regulatory elements at the locus with biological relevance in the pathogenesis of AF.
Circulation 09/2010; 122(10):976-84. · 14.74 Impact Factor
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Alessandro Biffi,
Christopher D Anderson,
Michael A Nalls,
Rosanna Rahman, Akshata Sonni,
Lynelle Cortellini,
Natalia S Rost,
Mar Matarin,
Dena G Hernandez,
Anna Plourde,
Paul I W de Bakker,
Owen A Ross,
Steven M Greenberg,
Karen L Furie,
James F Meschia,
Andrew B Singleton,
Richa Saxena,
Jonathan Rosand
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ABSTRACT: Although inherited mitochondrial genetic variation can cause human disease, no validated methods exist for control of confounding due to mitochondrial population stratification (PS). We sought to identify a reliable method for PS assessment in mitochondrial medical genetics. We analyzed mitochondrial SNP data from 1513 European American individuals concomitantly genotyped with the use of a previously validated panel of 144 mitochondrial markers as well as the Affymetrix 6.0 (n = 432), Illumina 610-Quad (n = 458), or Illumina 660 (n = 623) platforms. Additional analyses were performed in 938 participants in the Human Genome Diversity Panel (HGDP) (Illumina 650). We compared the following methods for controlling for PS: haplogroup-stratified analyses, mitochondrial principal-component analysis (PCA), and combined autosomal-mitochondrial PCA. We computed mitochondrial genomic inflation factors (mtGIFs) and test statistics for simulated case-control and continuous phenotypes (10,000 simulations each) with varying degrees of correlation with mitochondrial ancestry. Results were then compared across adjustment methods. We also calculated power for discovery of true associations under each method, using a simulation approach. Mitochondrial PCA recapitulated haplogroup information, but haplogroup-stratified analyses were inferior to mitochondrial PCA in controlling for PS. Correlation between nuclear and mitochondrial principal components (PCs) was very limited. Adjustment for nuclear PCs had no effect on mitochondrial analysis of simulated phenotypes. Mitochondrial PCA performed with the use of data from commercially available genome-wide arrays correlated strongly with PCA performed with the use of an exhaustive mitochondrial marker panel. Finally, we demonstrate, through simulation, no loss in power for detection of true associations with the use of mitochondrial PCA.
The American Journal of Human Genetics 06/2010; 86(6):904-17. · 10.60 Impact Factor
