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At least 631 records · Page 35Linked to original sources
PubMed2005

Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population.

OBJECTIVE: To identify rheumatoid arthritis (RA) susceptibility genes in a Japanese population by conducting a large-scale case-control association analysis and linkage disequilibrium (LD) mapping on chromosome 7q31-34, a candidate susceptibility locus identified in a preliminary genome-wide scan in 53 Japanese families, using single-nucleotide polymorphisms (SNPs). METHODS: We prepared 728 dense, evenly spaced SNPs with a minor allele frequency >0.15 in each gene locus on chromosome 7q31-34. Using these SNPs, a 2-stage case-control analysis was performed on 760 RA patients (157 men and 603 women) and 806 non-RA controls (189 men and 617 women). Haplotypes and LD mapping results were assessed based on SNP genotypes in 380 controls. RESULTS: Forty-eight SNPs showed allele associations (P < 0.05) in the first set of DNA samples (380 RA cases and 380 non-RA controls; first-stage analysis). For 4 of the SNPs in the SEC8L1 gene, the association was replicated (P < 0.05) in the second, independent set of DNA samples (an additional 380 RA cases and 380 non-RA controls; second-stage analysis). When data from the 2 groups were combined, the most significant allele association was observed with SNP 441, an intronic SNP of the SEC8L1 gene (P = 0.000059). The SEC8L1 SNPs with significant allele associations were all located in a single conserved LD block (block 4). Haplotype analysis revealed the disease-risk (P = 0.0015) and disease-protective (P = 0.0000062) haplotypes. Resequencing of coding exons within block 4 did not identify any nonsynonymous SNPs. Real-time quantitative polymerase chain reaction revealed that SEC8L1 was expressed ubiquitously in human tissues, including fibroblast-like synoviocytes from RA patients. CONCLUSION: Our locus-wide association and LD analyses identified intronic SNPs and haplotypes in the SEC8L1 gene that are strongly associated with RA. We propose that SEC8L1, which encodes a component of the exocyst complex, is a candidate susceptibility gene for RA in the Japanese population.

Adult↗
PubMed2003

Improved use of SNP information to detect the role of genes.

A topical question in genetic association studies is the optimal use of the information provided by genotyped single-nucleotide polymorphisms (SNPs) in order to detect the role of a candidate gene in a multifactorial disease. We propose a strategy called "combination test" that tests the association between a quantitative trait and all possible phased combinations of various numbers of SNPs. We compare this strategy to two alternative strategies: the association test that considers each SNP separately, and a multilocus genotype-based test that considers the phased combination of all SNPs together. To compare these three tests, a quantitative trait was simulated under different models of correspondence between phenotype and genotype, including the extreme case when two SNPs interact with no marginal effects of each SNP. The genotypes were taken from a sample of 290 independent individuals genotyped for three genes with various number of SNPs (from 5-8 SNPs). The results show that the "combination test" is the only one able to detect the association when the two SNPs involved in disease susceptibility interact with no marginal effects. Interestingly, even in the case of a single etiological SNP, the "combination test" performed well. We apply the three tests to Genetic Analysis Workshop 12 (Almasy et al. [2001] Genet. Epidemiol. 21:332-338) simulated data, and show that although there was no interactions between the etiological SNPs, the "combination test" was preferable to the two other compared methods to detect the role of the candidate gene.

Genotype↗
PubMed2005

Genotyping errors, pedigree errors, and missing data.

Our group studied the effects of genotyping errors, pedigree errors, and missing data on a wide range of techniques, with a focus on the role of single-nucleotide polymorphisms (SNPs). Half of our group used simulated data, and half of our group used data from the Collaborative Study on the Genetics of Alcoholism (COGA). The simulated data had no missing genotypes and no genotyping errors, so our group, as a whole, removed data and introduced artificial errors to study the robustness of various techniques. Our teams showed that genotyping errors are less detectable and may have a greater impact on SNPs than on microsatellites, but recently developed methods that account for genotyping errors help reduce false positives, and the assumptions of these methods appear to be supported by observations from repeated genotyping. The ability to detect linkage disequilibrium (LD) was also substantially reduced by missing data; this in turn could affect tagging SNPs chosen to generate haplotypes. In the COGA sample, genotyping measurements were repeated in three ways. First, full-genome screens were performed on three sets of markers: 328 microsatellites, 11,560 SNPs from the Affymetrix GeneChip Mapping 10 K Array marker set, and 4,720 SNPs from the Illumina Linkage III panel. Second, the entire Affymetrix marker set was typed on the same 184 individuals by two different laboratories. Finally, the Affymetrix and Illumina marker panels had 94 SNPs in common. Our teams showed that both SNPs and microsatellites can be readily used to identify pedigree errors, and that SNPs have fewer genotyping errors and a low inconsistency rate. However, a fairly high rate of no-calls, especially for the Affymetrix platform, suggests that the inconsistency rate may be higher than observed.

Alcoholism↗
PubMed2005

Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C.

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC.

Adult↗
PubMed2000

Estimate of nucleotide diversity in dogs with a pool-and-sequence method.

Nucleotide diversity (pi), the average number of base differences per site for two homologous sequences randomly selected from a population, is an important parameter used to understand the structure and history of populations. It is also important for determining the feasibility of developing a genetic map for a species from single nucleotide polymorphisms (SNPs). Nucleotide diversity has never been estimated for dogs. Segments of twelve canine genes from ten diverse dog breeds were examined for nucleotide variation by using a pool-and-sequence method. We identified three SNPs in the coding regions (2501 bp) and 11 SNPs in the introns (2953 bp). Each of these putative SNPs was tested by restriction enzyme analysis, and all were verified. Six additional SNPs were identified in a single SINE contained in one gene. Using these data, canine sequence diversity across breeds was estimated to be 0.001 and 0.0004 in intronic and coding regions, respectively, with SNPs spaced every 400 bp on average. Discovery of useful SNPs in 7 of the 12 genes suggests that construction of a canine SNP-based map can be accomplished with current technology. Thirteen polymorphic SNPs were also found in 5847 bp in the cat, horse, ox, and pig, by using four of the same genes from which canine nucleotide diversity was estimated. These results suggest that these species may have similar amounts of nucleotide diversity.

Amino Acid Sequence↗
PubMed2005

Meprin beta metalloprotease gene polymorphisms associated with diabetic nephropathy in the Pima Indians.

There is evidence that susceptibility to diabetic nephropathy has a significant genetic component. This investigation tested the hypothesis that variations in the structural or regulatory regions of the MEP1B gene are related to susceptibility to diabetic nephropathy in the Pima Indian population. The structure of the human MEP1B gene on chromosome 18 was determined by polymerase chain reaction (PCR) amplification. Samples from 154 diabetic individuals were analyzed for polymorphisms. These individuals belonged to 65 sibships with at least one sibling pair discordant for diabetic nephropathy. Approximately half of the individuals had diabetic nephropathy. Of the 154 samples, there were 91 discordant sibling pairs. Sequencing revealed 19 single nucleotide polymorphisms (SNPs) in the MEP1B gene. SNPs 1-5 were in the 5' region upstream of the start site for transcription; SNPs 6, 7, 9, 11-15, 17, and 19 were within introns; SNPs 8, 10, 16, and 18 were in exons 4, 9, 12, and 14. SNP 18 was the only one that results in an amino acid change (proline to leucine in the cytoplasmic tail). No overall associations were found for individual SNPs. Within-family association tests found significant results for SNPs 1, 3, 4, 5, 6, 9, 11, 18, and 19 such that the more common allele was more frequently observed in those with nephropathy than in their unaffected siblings. The present study demonstrates significant within-family association for SNPs in MEP1B gene with diabetic nephropathy. These results could be explained by functional effects of one or more of these SNPs or by linkage disequilibrium with a nearby functional locus.

DNA Primers↗
PubMed2005

Approaches to determine clinical significance of genetic variants.

The clinical significance of genetic variants (single nucleotide polymorphisms, SNPs) has implications for risk assessment and also for predicting the outcome of a disease process, especially in response to intervention. Approaches to determine the clinical significance of genetic polymorphisms are now beginning to be developed. The technology tools and procedures currently available have significant potential in identifying and validating polymorphisms associated with environmentally sensitive phenotypes. Numerous concepts can now provide the methodology to selectively identify SNPs with the potential for impacting gene function. These include computational algorithms, biochemical assays, yeast mutagenicity assays, and epidemiological studies, either as a stand-alone screen, or in various combinations depending on the gene of interest. Proof of principle will ultimately depend on large-scale epidemiological and clinical studies, but will require intensive resources. Therefore, the use of the mouse as a preclinical biological model is paramount in helping screen valid SNPs or combinations of SNPs for human studies. But more importantly, mouse modeling will help answer the question of what role gene variants play in sensitivity or resistance to a wide variety of environmental insults ranging from toxic chemicals and carcinogens to more mundane and routine exposure items, such as dietary factors, air quality, over the counter and prescription medications, and ultraviolet light. Our focus on SNPs that result in an amino acid change is a matter of expediency because these variants are more amenable to the prescreening approaches currently available that are expected to help identify SNPs that affect protein function. The mouse models generated to evaluate the environmental relevance of selected SNPs will be extremely valuable biological tools to validate gene variant and environment interaction in a variety of settings. Informative mouse models will also provide the basis of pursuing relevant SNPs in epidemiological and clinical investigations.

Algorithms↗
PubMed2002

Sequence variation in the human T-cell receptor loci.

Identifying common sequence variations known as single nucleotide polymorphisms (SNPs) in human populations is one of the current objectives of the human genome project. Nearly 3 million SNPs have been identified. Analysis of the relative allele frequency of these markers in human populations and the genetic associations between these markers, known as linkage disequilibrium, is now underway to generate a high-density genetic map. Because of the central role T cells play in immune reactivity, the T-cell receptor (TCR) loci have long been considered important candidates for common disease susceptibility within the immune system (e.g., asthma, atopy and autoimmunity). Over the past two decades, hundreds of SNPs in the TCR loci have been identified. Most studies have focused on defining SNPs in the variable gene segments which are involved in antigenic recognition. On average, the coding sequence of each TCR variable gene segment contains two SNPs, with many more found in the 5', 3' and intronic sequences of these segments. Therefore, a potentially large repertoire of functional variants exists in these loci. Association between SNPs (linkage disequilibrium) extends approximately 30 kb in the TCR loci, although a few larger regions of disequilibrium have been identified. Therefore, the SNPs found in one variable gene segment may or may not be associated with SNPs in other surrounding variable gene segments. This suggests that meaningful association studies in the TCR loci will require the analysis and typing of large marker sets to fully evaluate the role of TCR loci in common disease susceptibility in human populations.

Chromosome Mapping↗
PubMed2004

Assessing hematopoietic chimerism after allogeneic stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles.

Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor-recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor-recipient pairs. Samples from nine of the donor-recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.

Alleles↗
PubMed2004

HapBlock: haplotype block partitioning and tag SNP selection software using a set of dynamic programming algorithms.

UNLABELLED: Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed with regions of low LD. Such LD patterns make it possible to select a set of single nucleotide polymorphism (SNPs; tag SNPs) for genome-wide association studies. We have developed a suite of computer programs to analyze the block-like LD patterns and to select the corresponding tag SNPs. Compared to other programs for haplotype block partitioning and tag SNP selection, our program has several notable features. First, the dynamic programming algorithms implemented are guaranteed to find the block partition with minimum number of tag SNPs for the given criteria of blocks and tag SNPs. Second, both haplotype data and genotype data from unrelated individuals and/or from general pedigrees can be analyzed. Third, several existing measures/criteria for haplotype block partitioning and tag SNP selection have been implemented in the program. Finally, the programs provide flexibility to include specific SNPs (e.g. non-synonymous SNPs) as tag SNPs. AVAILABILITY: The HapBlock program and its supplemental documents can be downloaded from the website http://www.cmb.usc.edu/~msms/HapBlock.

Algorithms↗
PubMed2006

MLR-tagging: informative SNP selection for unphased genotypes based on multiple linear regression.

UNLABELLED: The search for the association between complex diseases and single nucleotide polymorphisms (SNPs) or haplotypes has recently received great attention. For these studies, it is essential to use a small subset of informative SNPs accurately representing the rest of the SNPs. Informative SNP selection can achieve (1) considerable budget savings by genotyping only a limited number of SNPs and computationally inferring all other SNPs or (2) necessary reduction of the huge SNP sets (obtained, e.g. from Affymetrix) for further fine haplotype analysis. A novel informative SNP selection method for unphased genotype data based on multiple linear regression (MLR) is implemented in the software package MLR-tagging. This software can be used for informative SNP (tag) selection and genotype prediction. The stepwise tag selection algorithm (STSA) selects positions of the given number of informative SNPs based on a genotype sample population. The MLR SNP prediction algorithm predicts a complete genotype based on the values of its informative SNPs, their positions among all SNPs, and a sample of complete genotypes. An extensive experimental study on various datasets including 10 regions from HapMap shows that the MLR prediction combined with stepwise tag selection uses fewer tags than the state-of-the-art method of Halperin et al. (2005). AVAILABILITY: MLR-Tagging software package is publicly available at http://alla.cs.gsu.edu/~software/tagging/tagging.html

Algorithms↗
PubMed2005

Human adenosine 2B receptor: SNP discovery and evaluation of expression in patients with cystic fibrosis.

OBJECTIVES AND METHODS: We analyzed the adenosine 2B (A2B) receptor gene, which consists of two exons, for single nucleotide polymorphisms (SNPs) and tested the hypothesis that coding sequence polymorphisms in the gene contribute to disease state in patients with cystic fibrosis (CF). Using PCR and restriction fragment length polymorphism (RFLP) analysis, we assessed 53 American subjects of mixed ethnicity, 64 European Caucasian control subjects and 148 Caucasian patients with CF for A2B SNPs. RESULTS: We identified one SNP in the 5' untranslated region (UTR) and seven SNPs in the open reading frame. One SNP was identified in the coding region of a German patient with CF but in none of the American subjects. No other SNPs were found in CF patients. A nonsynonymous SNP was identified in exon 2 of the German controls with an allelic frequency of 11%. The US subjects were of mixed ethnicity and most frequently (10.4%) had a SNP in the 5'UTR; 7 coding SNPs occurred in <3%. All SNPs other than the Leu96Phe and Gly136Arg variants were found only in African-Americans. Of the 26 African-Americans who were genotyped, 42% were hypertensive but the study group was too small to show an association between blood pressure status and SNP expression. CONCLUSIONS: The data show that SNPs in the A2B receptor gene are much more frequent in African-Americans than in Caucasians and that German Caucasians, but not African-Americans, express Gly136Arg. None of the SNPs identified in A2B receptors are likely to be modifiers in CF.

Adult↗
PubMed2004

Single nucleotide polymorphisms associated with rat expressed sequences.

Single nucleotide polymorphisms (SNPs) are the most common source of genetic variation in populations and are thus most likely to account for the majority of phenotypic and behavioral differences between individuals or strains. Although the rat is extensively studied for the latter, data on naturally occurring polymorphisms are mostly lacking. We have used publicly available sequences consisting of whole-genome shotgun (WGS), expressed sequence tag (EST), and mRNA data as a source for the in silico identification of SNPs in gene-coding regions and have identified a large collection of 33,305 high-quality candidate SNPs. Experimental verification of 471 candidate SNPs using a limited set of rat isolates revealed a confirmation rate of approximately 50%. Although the majority of SNPs were identified between Sprague-Dawley (EST data) and Brown Norway (WGS data) strains, we found that 66% of the verified variations are common among different rat strains. All SNPs were extensively annotated, including chromosomal and genetic map information, and nonsynonymous SNPs were analyzed by SIFT and PolyPhen prediction programs for their potential deleterious effect on protein function. Interestingly, we retrieved three SNPs from the database that result in the introduction of a premature stop codon and that could be confirmed experimentally. Two of these "in silico-identified knockouts" reside in interesting QTL regions. Data are publicly available via a Web interface (http://cascad.niob.knaw.nl), allowing simple and advanced search queries.

Animals↗
PubMed2002

Novel and nondetected human signaling protein polymorphisms.

The frequency of single nucleotide polymorphisms (SNPs) in downstream signaling proteins was determined by combination heteroduplex HPLC and double-stranded sequencing of genomic DNA from 96-144 congestive heart failure (CHF) patients. Analysis of 56 coding exons in 9 signaling genes revealed 17 novel and 8 previously reported synonymous (no change in amino acid) SNPs, as well as one novel nonsynonymous SNP in the Rad small G protein. Because this initial analysis failed to detect numerous SNPs reported in the NCBI and Celera databases, double-strand sequencing of relevant exons from 74-91 CHF patients was used to confirm the absence of 10 previously reported nonsynonymous SNPs. Our results show that synonymous SNPs are frequent in signaling protein genes, whereas nonsynonymous SNPs are rare, suggesting a high degree of evolutionary conservation among these downstream signaling molecules. Comparisons of our results to the NCBI and Celera databases indicates that 56% of their SNP entries are not detected in our cohort. Importantly, while 31% of database SNPs were verified, 69% of SNPs detected in our cohort are not included in these databases. These findings indicate that caution may be warranted in relying exclusively on SNP databases as catalogs for polymorphic signaling protein genes.

Age of Onset↗
PubMed2006

Characterization of HPSE gene single nucleotide polymorphisms in Jewish populations of Israel.

Heparanase is a mammalian endoglucuronidase responsible for heparan sulfate (HS) degradation. HS is a major constituent of the extracellular matrix (ECM) and HS-degrading activity plays a decisive role in fundamental biological processes associated with remodeling of the ECM, such as cancer metastasis, angiogenesis and inflammation. There is great interest in the prospect of genome-wide association studies to identify genetic factors underlying complex diseases. It is important to establish a detailed description of the heparanase (HPSE) gene single nucleotide polymorphisms (SNPs). In this study, four Israeli Jewish populations (Ashkenazi, North African, Mediterranean and Near Eastern) were examined for 7 HPSE gene SNPs. Four out of 7 SNPs (rs4693608, db11099592, rs4364254, db6856901) were found to be polymorphic. Population comparisons revealed significant differences in SNPs allele frequency between Near Eastern and each of the other three populations. Genotype and allele frequencies in Jewish populations were different from non-Jewish populations, except for a certain similarity to Caucasians. Although the distance between SNPs is relatively small, the db11099592 SNP was in linkage disequilibrium (LD) only with the proximal SNP rs4693608. LD between distal SNPs rs4364254 and db6856901 was found only in Mediterraneans and North Africans. The current study provides a characterization of the normally occurring HPSE gene SNPs in different populations. This information is obligatory for further studies on the linkage between these SNPs and heparanase expression and function in various pathological processes, primarily cancer progression.

Africa, Northern↗
PubMed2005

Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction.

Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of haplotypes associated with variation in risk of MI. Of the four haplotypes inferred using the FGA -58G>A and FGG 1299 +79T>C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGG-FGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.

Case-Control Studies↗
PubMed2006

The versican gene and the risk of intracranial aneurysms.

BACKGROUND AND PURPOSE: The proteoglycan versican is an excellent candidate gene for intracranial aneurysms (IAs) because it plays an important role in extracellular matrix assembly and is localized in a previously implicated locus for IAs on chromosome 5q. METHODS: We analyzed all the common variations using 16-tag single nucleotide polymorphisms (SNPs) and haplotypes in the versican gene using a 2-stage genotyping approach. For stage 1, 16 SNPs were genotyped in 307 cases and 639 controls. For stage 2, the two SNPs yielding the most significant associations (P<0.01) were genotyped in a second independent cohort of 310 cases for confirmation of the associations. RESULTS: In stage 1, we found several SNPs in strong linkage disequilibrium and haplotypes constituting these SNPs associated with IAs in the Dutch population (strongest SNP association for rs173686 with odds ratio=1.34, 95% CI=1.09 to 1.65, P=0.004). In stage 2, we confirmed association for the 2 SNPs with the most significant associations (strongest SNP association for rs173686 with odds ratio=1.36, 95% CI=1.11 to 1.67, P=0.003). CONCLUSIONS: SNPs in strong linkage disequilibrium and haplotypes constituting these SNPs in the versican gene are associated with IAs suggesting that variation in or near the versican gene plays a role in susceptibility to IAs.

Adult↗
PubMed2005

A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population.

RATIONALE: A disintegrin and metalloprotease 33 (ADAM33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excessive decline of lung function in individuals with asthma. OBJECTIVES: To assess whether SNPs in ADAM33 are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD). METHODS: DNA was collected from subjects of the Vlagtwedde-Vlaardingen cohort participating in the last survey in 1989-1990 after a follow-up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. A total of 1,390 subjects from the cohort was genotyped for the following SNPs in ADAM33: F+1, Q-1, S_1, S_2, T_1, T_2, V_4, and ST+5. Differences in prevalence of SNPs were analyzed with chi(2) tests. Linear mixed effects models were used to analyze FEV(1) decline according to genotype. MEASUREMENTS AND MAIN RESULTS: In the whole population, mean adjusted decline was 18.7 and 12.7 ml/year in females and males, respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q-1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV(1) of, respectively, 4.9, 9.6, and 3.6 ml/year compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2, and T_2 in subjects with COPD. CONCLUSIONS: We demonstrated that SNPs in ADAM33 are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.

ADAM Proteins↗