Biomedical subjects

Mark J Rieder

Publications and source records attributed to Mark J Rieder.

At least 19 recordsLinked to original sources

PubMed2006

TagSNP evaluation for the association of 42 inflammation loci and vascular disease: evidence of IL6, FGB, ALOX5, NFKBIA, and IL4R loci effects.

Inflammatory markers have consistently been associated with vascular disease. Evidence of genetic polymorphisms in inflammatory loci that predict severe carotid artery disease (CAAD) would suggest that this relationship is not secondary to other correlated factors, but related to inflammation itself. We examined the full common genetic variation in 42 inflammatory loci for prediction of severe CAAD versus ultrasound proven controls using a tagSNP approach. For selected loci, monocyte RNA levels were contrasted in subjects with and without CAAD. We confirm the association of IL6(-174), FGB (-455), and ALOX5 with CAAD and show that multiple ALOX5 SNPs independently predict CAAD. We provide evidence for previously unreported associations of SNPs in IL4R, NFKBIA, and PLG with CAAD, and weaker evidence for associations with CSF3, IL10RA, and VCAM1. The NFKBIA and IL10RA expression levels significantly differed between subjects with CAAD and controls. These results support a role for genetic variation related to inflammation in CAAD and a causal role for specific gene products.

Aged↗

PubMed2006

Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey.

BACKGROUND: Increased serum C-reactive protein (CRP) is an independent risk factor for cardiovascular disease. Previous studies have suggested that genetic variation within the CRP gene is associated with serum CRP. METHODS AND RESULTS: We genotyped CRP genetic variants in 7159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is American population-based sample linked to hundreds of phenotypes, including CRP; however, the CRP assay used in this survey is not a high-sensitivity CRP assay, and 65% of participants (n=4679) had CRP measurements at or below the level of detection. Despite these limitations, we identified specific CRP single-nucleotide polymorphisms (SNPs) and haplotypes associated with serum CRP levels in the general population. Two variants were associated with increased levels of serum CRP: SNP rs3093058 (in linkage disequilibrium with a CRP promoter SNP rs3093062) in the non-Hispanic black sample and the triallelic promoter SNP rs3091244 in the non-Hispanic black and Mexican American samples. Two other SNPs were associated with decreased levels of serum CRP in either the non-Hispanic black (rs1205 and rs2808630) or Mexican American (rs1205) samples. Three haplotypes inferred from 7 SNPs (ATTGCGA, TTAGCGA, and AAAGAGA) were associated (P < or = 0.01) with increased levels of serum CRP in the non-Hispanic black sample; 2 haplotypes (ATTGCGA and AAAGCGA) were associated (P < 0.05) with increased levels in the Mexican American sample; and 1 haplotype (AAAGCGA) was associated (P < 0.03) with increased levels in the non-Hispanic white sample. Post hoc analysis suggests that the AA genotype of the triallelic SNP rs3091244, after adjustment for covariates, was associated with prevalent coronary heart disease in the non-Hispanic white population sample. CONCLUSIONS: Genetic variation within CRP is associated with serum CRP levels in the general population and may be associated with prevalent coronary heart disease.

Adult↗

PubMed2006

Allele frequency matching between SNPs reveals an excess of linkage disequilibrium in genic regions of the human genome.

Significant interest has emerged in mapping genetic susceptibility for complex traits through whole-genome association studies. These studies rely on the extent of association, i.e., linkage disequilibrium (LD), between single nucleotide polymorphisms (SNPs) across the human genome. LD describes the nonrandom association between SNP pairs and can be used as a metric when designing maximally informative panels of SNPs for association studies in human populations. Using data from the 1.58 million SNPs genotyped by Perlegen, we explored the allele frequency dependence of the LD statistic r(2) both empirically and theoretically. We show that average r(2) values between SNPs unmatched for allele frequency are always limited to much less than 1 (theoretical approximately 0.46 to 0.57 for this dataset). Frequency matching of SNP pairs provides a more sensitive measure for assessing the average decay of LD and generates average r(2) values across nearly the entire informative range (from 0 to 0.89 through 0.95). Additionally, we analyzed the extent of perfect LD (r(2) = 1.0) using frequency-matched SNPs and found significant differences in the extent of LD in genic regions versus intergenic regions. The SNP pairs exhibiting perfect LD showed a significant bias for derived, nonancestral alleles, providing evidence for positive natural selection in the human genome.

Animals↗

PubMed2006

A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9.

AIMS: To determine the cause of a genotype-phenotype discordancy for acenocoumarol sensitivity. Methods A patient, highly sensitive to acenocoumarol, and previously determined to carry only a single CYP2C9*3 allele, was genotyped for additional functionally defective alleles in the CYP2C9 and VKORC1 genes. Family members were also analyzed to trace the pedigree. Results The acenocoumarol-sensitive patient was found to possess, in addition to CYP2C9*3 allele, a CYP2C9*11 allele and the VKORC1 AA diplotype which were all traced back through the parental lines. Conclusions Acenocoumarol sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the CYP2C9 and VKORC1 genes. The study provides additional data in support of diminished CYP2C9 activity due to the presence of the rare *11 allele.

Acenocoumarol↗

PubMed2006

Efficient selection of tagging single-nucleotide polymorphisms in multiple populations.

Common genetic polymorphism may explain a portion of the heritable risk for common diseases, so considerable effort has been devoted to finding and typing common single-nucleotide polymorphisms (SNPs) in the human genome. Many SNPs show correlated genotypes, or linkage disequilibrium (LD), suggesting that only a subset of all SNPs (known as tagging SNPs, or tagSNPs) need to be genotyped for disease association studies. Based on the genetic differences that exist among human populations, most tagSNP sets are defined in a single population and applied only in populations that are closely related. To improve the efficiency of multi-population analyses, we have developed an algorithm called MultiPop-TagSelect that finds a near-minimal union of population-specific tagSNP sets across an arbitrary number of populations. We present this approach as an extension of LD-select, a tagSNP selection method that uses a greedy algorithm to group SNPs into bins based on their pairwise association patterns, although the MultiPop-TagSelect algorithm could be used with any SNP tagging approach that allows choices between nearly equivalent SNPs. We evaluate the algorithm by considering tagSNP selection in candidate-gene resequencing data and lower density whole-chromosome data. Our analysis reveals that an exhaustive search is often intractable, while the developed algorithm can quickly and reliably find near-optimal solutions even for difficult tagSNP selection problems. Using populations of African, Asian, and European ancestry, we also show that an optimal multi-population set of tagSNPs can be substantially smaller (up to 44%) than a typical set obtained through independent or sequential selection.

Algorithms↗

PubMed2006

Direct detection of null alleles in SNP genotyping data.

Pinpointing genetic associations in the human genome relies heavily on the accuracy of the underlying genotype data. Null alleles can generate significant inaccuracies in genotype data and can negatively affect the statistical power of a study. Existing quality control (QC) tests, including tests of Hardy-Weinberg equilibrium, are not sensitive enough to detect the presence of even moderately frequent null alleles in the data. We show that direct analysis of raw data from a quantitative genotyping platform can detect up to 75% of null alleles, even at frequencies below the sensitivity of more traditional methods. Detecting unexpected null alleles not only has benefits in QC of genotype data but may also be valuable in detecting rare, functional null alleles that would otherwise be missed.

Alleles↗

PubMed2006

Allelic spectrum of the natural variation in CRP.

With the recent completion of the International HapMap Project, many tools are in hand for genetic association studies seeking to test the common variant/common disease hypothesis. In contrast, very few tools and resources are in place for genotype-phenotype studies hypothesizing that rare variation has a large impact on the phenotype of interest. To create these tools for rare variant/common disease studies, much interest is being generated towards investing in re-sequencing either large sample sizes of random chromosomes or smaller sample sizes of patients with extreme phenotypes. As a case study for rare variant discovery in random chromosomes, we have re-sequenced approximately 1,000 chromosomes representing diverse populations for the gene C-reactive protein (CRP). CRP is an important gene in the fields of cardiovascular and inflammation genetics, and its size (approximately 2 kb) makes it particularly amenable medical or deep re-sequencing. With these data, we explore several issues related to the present-day candidate gene association study including the benefits of complete SNP discovery, the effects of tagSNP selection across diverse populations, and completeness of dbSNP for CRP. Also, we show that while deep re-sequencing uncovers potentially medically relevant coding SNPs, these SNPs are fleetingly rare when genotyped in a population-based survey of 7,000 Americans (NHANES III). Collectively, these data suggest that several different types re-sequencing and genotyping approaches may be required to fully understand the complete spectrum of alleles that impact human phenotypes.

Alleles↗

PubMed2006

High-throughput genotyping of intermediate-size structural variation.

The contribution of large-scale and intermediate-size structural variation (ISV) to human genetic disease and disease susceptibility is only beginning to be understood. The development of high-throughput genotyping technologies is one of the most critical aspects for future studies of linkage disequilibrium (LD) and disease association. Using a simple PCR-based method designed to assay the junctions of the breakpoints, we genotyped seven simple insertion and deletion polymorphisms ranging in size from 6.3 to 24.7 kb among 90 CEPH individuals. We then extended this analysis to a larger collection of samples (n=460) by application of an oligonucleotide extension-ligation genotyping assay. The analysis showed a high level of concordance ( approximately 99%) when compared with PCR/sequence-validated genotypes. Using the available HapMap data, we observed significant LD (r2=0.74-0.95) between each ISV and flanking single nucleotide polymorphisms, but this observation is likely to hold only for similar simple insertion/deletion events. The approach we describe may be used to characterize a large number of individuals in a cost-effective manner once the sequence organization of ISVs is known.

Cohort Studies↗

PubMed2006

Common genetic variation in the prothrombin gene, hormone therapy, and incident nonfatal myocardial infarction in postmenopausal women.

Genetic variants in coagulation factors are associated with myocardial infarction and may modify the association between hormone therapy and cardiovascular disease risk. This study assessed whether common variation in the prothrombin gene was associated with incident nonfatal myocardial infarction in postmenopausal women and whether this association differed according to current estrogen use. Eight variants representing 98% of common prothrombin variants were selected using publicly available genomic variation data. These variants and the functional G20210A variant were genotyped and used to infer haplotypes in a population-based Washington State case-control study of postmenopausal Caucasian women (1995-1999; 273 cases and 788 controls). Women carrying a nonsynonymous polymorphism in exon 6 (C5467T) had an increased risk of myocardial infarction (for each additional copy, relative to women with one fewer copy, odds ratio = 1.4, 95% confidence interval: 1.0, 1.8). Prothrombin haplotypes were also associated with myocardial infarction (with minimal adjustment, global p = 0.056; with full adjustment, p = 0.034). Associations between haplotypes and myocardial infarction were similar among users of hormone therapy and nonusers (global p = 0.61), though statistical power was limited. These preliminary results suggest that common genetic variants in the prothrombin gene or other variants in linkage disequilibrium are associated with myocardial infarction in postmenopausal women.

Aged↗

PubMed2005

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

Anticoagulants↗

PubMed2005

CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes.

OBJECTIVE: The goal of this study was to define the haplotype structure of the cytochrome P450 (CYP) 2C9 gene in a European American population and evaluate associations between CYP2C9 haplotypes and anticoagulation-related outcomes. METHODS: Genomic deoxyribonucleic acid from 192 European American patients stabilized on warfarin therapy was resequenced across 60 kilobases of the CYP2C9 genomic region, including all exons, dense sampling of introns, approximately 10 kilobases of the 5'-flanking region, and approximately 1.7 kilobases of the 3'-untranslated region. RESULTS: A total of 132 single nucleotide polymorphisms (SNPs) were detected, of which 47 were present in the 5'-flanking promoter region, 11 in the exonic coding region, and 74 in the intron regions. Nine nonsynonymous SNPs in the coding region consisted of CYP2C9*2 , *3 , *9 , *11 , and *12 ; R125H; and 3 new structural variants. Sixty SNPs were present at a minor allele frequency of greater than 5%, and from this subpopulation, 23 haplotypes were inferred. Clustering analysis identified 6 major groups of related haplotypes that were further designated 1A, 1B, 1C, 1D, 2, or 3. The *2 and *3 SNPs appeared exclusively in groups 2 and 3, and these groups combined were associated with significantly reduced warfarin maintenance doses, longer time to stable dosing, and increased risk of bleeding. In contrast, combinations of haplotypes 1A, 1B, 1C, and 1D were not associated with differences in any of these outcomes. CONCLUSION: These data establish a whole-gene, high-resolution haplotype structure for CYP2C9 in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for warfarin sensitivity associated with CYP2C9 variants in this population.

Alleles↗

PubMed2005

In-vitro and in-vivo effects of the CYP2C9*11 polymorphism on warfarin metabolism and dose.

OBJECTIVE: To determine the in-vitro and in-vivo effects of the CYP2C9*11 polymorphism on (S)-warfarin metabolism. METHODS AND RESULTS: The *11 allele that results in mutation of Arg335-->Trp occurred with a frequency of approximately 1% in Caucasian and African-American populations. Four subjects carrying the *1/*11 genotype were identified in a clinical cohort of 192 warfarin patients. Compared to control subjects with the *1/*11 genotype (n=127), the *1/*11 group exhibited a 33% reduction in warfarin maintenance dose, that was independent of study population age or INR. In-vitro studies directed towards understanding the mechanism of reduced in-vivo activity revealed very low levels of holo-CYP2C9.11 expression in insect cells and decreased solubility in the presence of detergent. Membrane preparations of CYP2C9.11 contained inactive P420 and exhibited a shorter half-life for thermally induced conversion of P450 to P420 than CYP2C9.1. Metabolic studies demonstrated that functional CYP2C9.11 possessed similar (S)-warfarin hydroxylation regioselectivity and modestly reduced catalytic efficiency relative to the wild-type enzyme. CONCLUSIONS: In-vivo reduction in CYP2C9 (S)-warfarin activity due to the CYP2C9*11 polymorphism may largely be a consequence of decreased enzyme stability resulting in compromised expression of holo-enzyme. Increased enzyme lability of CYP2C9.11 may be related to improper folding due to the disruption of conserved salt-bridge and hydrogen bonding contacts in the loop region between the J and J' helices of the protein.

Anticoagulants↗

PubMed2005

Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population.

OBJECTIVE: To evaluate the association of VKORC1 genetic variants with warfarin dose requirements in a Hong Kong Chinese patient population. METHODS: A retrospective study of Hong Kong Chinese patients chronically maintained on warfarin was conducted. Single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 were genotyped. Stable warfarin dose data were retrieved from patient medical records. RESULTS: Sixty-nine patients were included in the analysis. VKORC1 haplotypes H1 (group A) and H7 (group B) were most common, accounting for 86% and 13% of all haplotypic variation in this cohort. Patients carrying at least one copy of a VKORC1 group B haplotype (n = 16) required a significantly higher stable warfarin dose (5.17+/-1.53 mg/day) than patients that were homozygous for group A haplotypes (n = 53; 2.93+/-1.22 mg; P < 0.001). In the VKORC1 A/A group, four patients (5.8%) were heterozygous for CYP2C9*3 and had a lower dose requirement (1.94+/-0.43 mg) than patients that exhibited the CYP2C9 *1/*1 genotype (3.01+/-1.23 mg), P = 0.004. In multivariate analysis, VKORC1 and CYP2C9 explained 31% and 7.9% of the variability in warfarin dose, respectively. CONCLUSIONS: VKORC1 genotype is the dominant genetic influence on inter-individual variability in warfarin dose in Hong Kong Chinese. The lower mean dose of warfarin in Chinese, relative to Europeans, appears to be a reflection of their preponderance of the 'low-dose' VKORC1 H1/H1 (homozygous group A) genotype.

Anticoagulants↗

PubMed2005

Genomic regions exhibiting positive selection identified from dense genotype data.

The allele frequency spectrum of polymorphisms in DNA sequences can be used to test for signatures of natural selection that depart from the expected frequency spectrum under the neutral theory. We observed a significant (P = 0.001) correlation between the Tajima's D test statistic in full resequencing data and Tajima's D in a dense, genome-wide data set of genotyped polymorphisms for a set of 179 genes. Based on this, we used a sliding window analysis of Tajima's D across the human genome to identify regions putatively subject to strong, recent, selective sweeps. This survey identified seven Contiguous Regions of Tajima's D Reduction (CRTRs) in an African-descent population (AD), 23 in a European-descent population (ED), and 29 in a Chinese-descent population (XD). Only four CRTRs overlapped between populations: three between ED and XD and one between AD and ED. Full resequencing of eight genes within six CRTRs demonstrated frequency spectra inconsistent with neutral expectations for at least one gene within each CRTR. Identification of the functional polymorphism (and/or haplotype) responsible for the selective sweeps within each CRTR may provide interesting insights into the strongest selective pressures experienced by the human genome over recent evolutionary history.

Black or African American↗

PubMed2004

Comprehensive identification and characterization of diallelic insertion-deletion polymorphisms in 330 human candidate genes.

Despite being the second most frequent type of polymorphism in the genome, diallelic insertion-deletion polymorphisms (indels) have received far less attention in the study of sequence variation. In this report, we describe an approach that can detect indels in the heterozygous state and can comprehensively identify indels in the target sequence. Using this approach, we identified 2393 indels in a set of 330 candidate genes, i.e. an average of seven indels per gene with about two indels per gene being common (minor allele frequency >or=0.1). We compared the population genetic characteristics of indels with substitutions in this data. Our data supported the findings that deletions occur more frequently in the human genome. 5'-UTR and coding regions of the genes showed a significantly lower diversity for indels compared with other regions, suggesting differences in effects of selection on indels and substitutions. Sequence diversity and pairwise linkage disequilibrium (LD) findings of the different populations were similar to earlier results and included a greater skew towards low-frequency variants and a faster rate of LD decay in the African-descent population compared with the non-African populations. Within populations, the allele frequency spectra and LD-decay profiles for indels were similar to substitutions. Overall, the findings suggest that, although the mechanisms giving rise to indels may be different from those causing substitutions, the evolutionary histories of indels and substitutions are similar, and that indels can play a valuable role in association studies and marker selection strategies.

5' Untranslated Regions↗

PubMed2004

Pattern of sequence variation across 213 environmental response genes.

To promote the clinical and epidemiological studies that improve our understanding of human genetic susceptibility to environmental exposure, the Environmental Genome Project (EGP) has scanned 213 environmental response genes involved in DNA repair, cell cycle regulation, apoptosis, and metabolism for single nucleotide polymorphisms (SNPs). Many of these genes have been implicated by loss-of-function mutations associated with severe diseases attributable to decreased protection of genomic integrity. Therefore, the hypothesis for these studies is that individuals with functionally significant polymorphisms within these genes may be particularly susceptible to genotoxic environmental agents. On average, 20.4 kb of baseline genomic sequence or 86% of each gene, including a substantial amount of introns, all exons, and 1.3 kb upstream and downstream, were scanned for variations in the 90 samples of the Polymorphism Discovery Resource panel. The average nucleotide diversity across the 4.2 MB of these 213 genes is 6.7 x 10(-4), or one SNP every 1500 bp, when two random chromosomes are compared. The average candidate environmental response gene contains 26 PHASE inferred haplotypes, 34 common SNPs, 6.2 coding SNPs (cSNPs), and 2.5 nonsynonymous cSNPs. SIFT and Polyphen analysis of 541 nonsynonymous cSNPs identified 57 potentially deleterious SNPs. An additional eight polymorphisms predict altered protein translation. Because these genes represent 1% of all known human genes, extrapolation from these data predicts the total genomic set of cSNPs, nonsynonymous cSNPs, and potentially deleterious nonsynonymous cSNPs. The implications for the use of these data in direct and indirect association studies of environmentally induced diseases are discussed.

Apoptosis↗

PubMed2004

Population history and natural selection shape patterns of genetic variation in 132 genes.

Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout the genome. We studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. We developed a rigorous computational approach for taking into account multiple hypothesis tests and demographic history and found that while many apparent selective events can instead be explained by demography, there is also strong evidence for positive or balancing selection at eight genes in the European-American population, but none in the African-American population. Our results suggest that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces. In addition, a region containing four contiguous genes on Chromosome 7 showed striking evidence of a recent selective sweep in European-Americans. More generally, our results have important implications for mapping genes underlying complex human diseases.

Black People↗

PubMed2004

Sequence-based linkage analysis.

The rapid decrease in the cost of DNA sequencing will enable its use for novel applications. Here, we investigate the use of DNA sequencing for simultaneous discovery and genotyping of polymorphisms in family linkage studies. In the proposed approach, short contiguous segments of genomic DNA, regularly spaced across the genome, are resequenced in each pedigree member, and all sequence polymorphisms discovered within a pedigree are used as genetic markers. We use computer simulations consistent with observed human sequence diversity to show that segments of 500-1,000 base pairs, spaced at intervals of 1-2 Mb across the genome, provide linkage information that equals or exceeds that of traditional marker-based approaches. We validate these results experimentally by implementing the sequence-based linkage approach for chromosome 19 in CEPH pedigrees.

Chromosome Mapping↗