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PubMed2005

Linkage analysis of complex diseases using microsatellites and single-nucleotide polymorphisms: application to alcoholism.

The efficacy of linkage studies using microsatellites and single-nucleotide polymorphisms (SNPs) was evaluated. Analyzed data were supplied by the Collaborative Study on the Genetics of Alcoholism (COGA). Alcoholism was analyzed together with a simulated trait caused by a gene of known position, through a nonparametric linkage test (NPL). For the alcoholism trait, four densities of SNPs (1 SNP per 0.2 cM, 0.5 cM, 1 cM and 2 cM) showed higher peaks of NPL z scores and smaller significant p-values than the usual 10-cM density of microsatellites. However, the two highest densities of SNPs had unstable z score signals, and therefore were difficult to interpret. Analyzing a simulated trait with the same markers in the same pedigrees, we confirmed the higher power of all four densities of SNPs compared to the 10-cM microsatellites panel, although the existence of other confounding peaks was confirmed for maps that are denser than 1 SNP/cM. We further showed that estimating the gene position using SNPs is far less biased than using the usual panel of microsatellites (biases of 0-2 cM for SNPs vs. 8.9 cM for microsatellites). We conclude that using dense maps of SNPs in linkage analysis is more powerful and less biased than using the 10-cM maps of microsatellites. However, linkage signals can be unstable and difficult to interpret when several SNPs are genotyped per centimorgan. The power and accuracy of 1 SNP/cM or 1 SNP/2 cM may be sufficient in a genome-wide linkage scan while denser maps may be most useful in fine-gene mapping studies exploiting linkage disequilibrium.

Alcoholism↗
PubMed2005

Comparison of single-nucleotide polymorphisms and microsatellites in inference of population structure.

Single-nucleotide polymorphisms (SNPs) are a class of attractive genetic markers for population genetic studies and for identifying genetic variations underlying complex traits. However, the usefulness and efficiency of SNPs in comparison to microsatellites in different scientific contexts, e.g., population structure inference or association analysis, still must be systematically evaluated through large empirical studies. In this article, we use the Collaborative Studies on Genetics of Alcoholism (COGA) data from Genetic Analysis Workshop 14 (GAW14) to compare the performance of microsatellites and SNPs in the whole human genome in the context of population structure inference. A total of 328 microsatellites and 15,840 SNPs are used to infer population structure in 236 unrelated individuals. We find that, on average, the informativeness of random microsatellites is four to twelve times that of random SNPs for various population comparisons, which is consistent with previous studies. Our results also indicate that for the combined set of microsatellites and SNPs, SNPs constitute the majority among the most informative markers and the use of these SNPs leads to better inference of population structure than the use of microsatellites. We also find that the inclusion of less informative markers may add noise and worsen the results.

Genetic Loci↗
PubMed2002

SNP analysis of the inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP) gene by a fluorescence-adapted SSCP method.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) are considered to be useful polymorphic markers for genetic studies of polygenic traits. Single-stranded conformational polymorphism (SSCP) analysis has been widely applied to detect SNPs, including point mutations in cancer and congenital diseases. In this study, we describe an application of the fluorescent labeling of PCR fragments using a fluorescent-adapted primer for SSCP analysis as a novel method. METHODS: Single-nucleotide polymorphisms (SNPs) of the inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP) gene were analyzed using a fluorescence-adapted SSCP method. The method was constructed from two procedures: 1) a fluorescent labeling reaction of PCR fragments using fluorescence-adapted primers in a single tube, and 2) electrophoresis on a non-denaturing polyacrylamide gel. RESULTS: This method was more economical and convenient than the single-stranded conformational polymorphism (SSCP) methods previously reported in the detection of the labeled fragments obtained. In this study, eight SNPs of the IHRP gene were detected by the fluorescence-adapted SSCP. One of the SNPs was a new SNP resulting in an amino acid substitution, while the other SNPs have already been reported in the public databases. Six SNPs of the IHRP were associated with two haplotypes. CONCLUSIONS: The fluorescence-adapted SSCP was useful for detecting and genotyping SNPs.

Journal Article↗
PubMed2005

Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel.

Sequencing of the T-type Ca2+ channel gene CACNA1H revealed 12 nonsynonymous single nucleotide polymorphisms (SNPs) that were found only in childhood absence epilepsy (CAE) patients. One SNP, G773D, was found in two patients. The present study reports the finding of a third patient with this SNP, as well as analysis of their parents. Because of the role of T-channels in determining the intrinsic firing patterns of neurons involved in absence seizures, it was suggested that these SNPs might alter channel function. The goal of the present study was to test this hypothesis by introducing these polymorphisms into a human Ca(v)3.2a cDNA and then study alterations in channel behavior using whole-cell patch-clamp recording. Eleven SNPs altered some aspect of channel gating. Computer simulations predict that seven of the SNPs would increase firing of neurons, with three of them inducing oscillations at similar frequencies, as observed during absence seizures. Three SNPs were predicted to decrease firing. Some CAE-specific SNPs (e.g., G773D) coexist with SNPs also found in controls (R788C); therefore, the effect of these polymorphisms were studied. The R788C SNP altered activity in a manner that would also lead to enhanced burst firing of neurons. The G773D-R788C combination displayed different behavior than either single SNP. Therefore, common polymorphisms can alter the effect of CAE-specific SNPs, highlighting the importance of sequence background. These results suggest that CACNA1H is a susceptibility gene that contributes to the development of polygenic disorders characterized by thalamocortical dysrhythmia, such as CAE.

Calcium Channels, T-Type↗
PubMed2004

Analysis of the vitamin D receptor gene sequence variants in type 1 diabetes.

Vitamin D is known to modulate the immune system, and its administration has been associated with reduced risk of type 1 diabetes. Vitamin D acts via its receptor (VDR). Four single nucleotide polymorphisms (SNPs) of the VDR gene have been commonly studied, and evidence of association with type 1 diabetes has been reported previously. We sequenced the VDR gene region and developed its SNP map. Here we analyzed association of the 98 VDR SNPs in up to 3,763 type 1 diabetic families. First, we genotyped all 98 SNPs in a minimum of 458 U.K. families with two affected offspring. We further tested eight SNPs, including four SNPs associated with P < 0.05 in the first set and the four commonly studied SNPs, in up to 3,305 additional families from the U.K., Finland, Norway, Romania, and U.S. We only found weak evidence of association (P = 0.02-0.05) of the rs4303288, rs12721366, and rs2544043 SNPs. We then tested these three SNPs in an independent set of 1,587 patients and 1,827 control subjects from the U.K. and found no evidence of association. Overall, our results indicate that common sequence variation in the VDR gene has no major effect in type 1 diabetes in the populations tested.

Diabetes Mellitus, Type 1↗
PubMed2002

Single nucleotide polymorphisms in CAPN10 gene of Chinese people and its correlation with type 2 diabetes mellitus in Han people of northern China.

OBJECTIVE: To investigate the distribution of single nucleotide polymorphisms (SNPs) in CAPN10 gene in Chinese population and their relation with type 2 diabetes mellitus in Han people of Northern China. METHODS: CAPN10 gene was sequenced to detect SNPs in different nationalities of China. Five SNPs were chosen to perform case-control study and haplotype analysis in 156 normal Han people of Northern China and 173 type 2 diabetes. One SNP was also analyzed with transmission-disequilibrium test (TDT) and sib transmission-disequilibrium test (STDT) in 68 type 2 diabetes pedigrees (377 people). RESULTS: A total of 40 SNPs were identified in length of 8,936 bp, with an average of 1 in every 223 bp. The SNPs in CAPN10 gene did not distribute evenly and the SNPs in Chinese were different from those reported in Mexican American. There was no significantly statistical difference in the allele frequency of the 5 SNPs between case and control, and the haplotype frequencies in the two groups were not significantly different. No positive results was found in TDT and STDT analysis. CONCLUSIONS: The SNP distribution of CAPN10 gene differs in different nationalities. The studied SNPs in CAPN10 gene may not be the major susceptibility ones of type 2 diabetes mellitus in Han people of Northern China.

Calpain↗
PubMed2002

[Single nucleotide polymorphisms in CAPN10 gene of Chinese population and its correlation with type 2 diabetes mellitus in Han people of northern China].

OBJECTIVE: To investigate the distribution of the single nucleotide polymorphisms (SNPs) in CAPN10 gene in Chinese population and their relation with type 2 diabetes mellitus in Han people of Northern China. METHODS: CAPN10 gene was sequenced to detect SNPs in 27 samples of different nationalities in China. 5 SNPs were genotyped with single-base extension (SBE) method to perform case-control study in 156 normal Han people of Northern China and 173 type 2 diabetes and the 3 positive loci reported in the article were performed haplotype analysis. One positive locus was also analyzed with transmission-disequilibrium test (TDT) and sib transmission-disequilibrium test (STDT) in 68 type 2 diabetes pedigrees (377 cases). RESULTS: A total of 40 SNPs were identified in length of 8,936 bp, with an average of 1 in every 223 bp; The SNPs in CAPN10 gene did not distribute evenly and the SNPs in Chinese was different from that reported in American Mexicans. There was no significantly statistical difference in the allele frequency of the 5 SNPs between case and control (P > 0.05), and the haplotype frequencies in the two groups were not much different (P > 0.05). There was no positive results in TDT and STDT analysis (P > 0.05). CONCLUSIONS: The SNP distribution of CAPN10 gene varies with different nationalities. The studied SNPs in CAPN10 gene may not be the major susceptibility ones of type 2 diabetes mellitus in Han people of Northern China.

Alleles↗
PubMed2004

[Single nucleotide polymorphism in SCN5A and the distribution in Chinese Han ethnic group].

Mutations in voltage-gated sodium channel type (SCN5A) may evoke severe, life-threatening disturbances in cardiac rhythm, including long QT syndrome, idiopathic ventricular fibrillation (Brugada Syndrome), and isolated cardiac conduction disease. There is increasing awareness of the role of common polymorphisms in altering gene function and in susceptibility to diseases. The aim of the present study was to investigate single nucleotide polymorphism (SNP) in SCN5A gene and the distribution of these identified SNPs in Chinese Han nationality. SCN5A gene was sequenced by fluorescent labeling automatic sequencing method in 120 unrelated samples from Han nationality in South China. Allele frequency distribution was tested by Hardy-Weinberg equilibrium. The results showed that a total of 5 SNPs were identified in SCN5A gene, including three SNPs in code region, one SNP in regulatory region and the other in intron 23 adjacent to donor splicing site. The distribution of the SNPs in SCN5A gene was uneven. These allele frequencies in Han population of South China were as follows: G87A (A29A) 27.5%, A1673G (H588R) 10.4%, 4245+82A>G 32.8%, C5457T (D1819D) 41.3% and G6174A 44.9% respectively. The SNPs G87A (A29A), 4245+82A>G and G6174A were reported for the first time. There was no significant difference in the allele frequency of A1673G (H558R) within different ethical populations (P>0.05). C5457T (D1819D) allele frequency of Han population in South China was similar to that observed in Japanese (P>0.5), but higher than that in American (p<0.005). There was no significant difference in the distribution of the SNPs between male group and female group (all p>0.05). S1102Y and other 10 SNPs identified in other ethnic populations have not been detected in Chinese Han population. The allele distribution of SNPs was in good unity with the Hardy-Weinberg equilibrium. It is suggested that the SNP distribution of SCN5A gene varies within different nationalities. These data will be of use for genetic association studies of acquired arrythmias and investigation of sensitivity to drug therapy.

Arrhythmias, Cardiac↗
PubMed2006

In silico discrimination of single nucleotide polymorphisms and pathological mutations in human gene promoter regions by means of local DNA sequence context and regularity.

DNA sequence features were sought that could be used for the in silico ascertainment of the likely functional consequences of single nucleotide changes in human gene promoter regions. To identify relevant features of the local DNA sequence context, we transformed into consensus tables the nucleotide composition of sequences flanking 101 promoter SNPs of type C<-->T or A<-->G, defined empirically as being either 'functional' or 'non-functional' on the basis of a standardised reporter gene assay. The similarity of a given sequence to these consensus tables was then measured by means of the Shapiro-Senapathy score. A decision rule with the potential to discriminate between empirically ascertained functional and non-functional SNPs was proposed that potentiated discrimination between functional and non-functional SNPs with a sensitivity of 80% and a specificity of 20%. Two further datasets (viz. disease-associated SNPs of types A<-->G and C<-->T (N = 75) and pathological promoter mutations (transitions, N = 114)) were retrieved from the Human Gene Mutation Database (HGMD; http://www.hgmd.org/) and analyzed using consensus tables derived from the functional and non-functional promoter SNPs; approximately 70% were correctly recognized as being of probable functional significance. Complexity analysis was also used to quantify the regularity of the local DNA sequence environment. Functional SNPs/mutations of type C<-->T were found to occur in DNA regions characterized by lower average sequence complexity as measured with respect to symmetric elements; complexity values increased gradually from functional SNPs and pathological mutations to functional disease-associated SNPs and non-functional SNPs. This may reflect the internal axial symmetry that frequently characterizes transcription factor binding sites.

Algorithms↗
PubMed2006

[Single nucleotide polymorphism (SNP) and its application in rice].

Single nucleotide polymorphisms (SNPs) distribute numerously and high-density throughout rice (Oryza sativa L.) genome. A total of 80,127 SNP sites were identified in rice genome, and one SNP every 154 bp was found between two rice subspecies indica and japonica. The SNP rate is 0.65%. SNPs also are very considerable among within-subspecies cultivars, even it can be found between closely related cultivars, in which it has been difficult to find polymorphic sites by conventional methods. The frequency of SNPs in rice genome varied between chromosomes, moreover it showed uneven distribution of polymorphism-rich and -poor regions along each chromosome. Several routes have been used for identification of SNP in rice, such as sequencing PCR products of DNA samples, screening SNPs in SSR fragments, and searching for SNPs through the rice genome sequences and EST database. A number of genotyping systems have been developed to identify SNPs in rice genome. High automation in SNPs identification has become a very convenient operation by the automatized systems. SNPs can be converted to CAPS (cleaved amplified polymorphic sequence) or dCAPS (derived-CAPS), and allele-specific PCR markers. SNP has shown huge potential in establishing rice genetic maps, genes cloning and functional genomics, MAS (marker assisted selection) in rice breeding, and studying on classification and evolution of germplasm.

Breeding↗
PubMed2006

[Establishing the linkage disequilibrium pattern for the all-trans-retinol dehydrogenase (RDH8) gene].

OBJECTIVE: As part of an on-going effort to map genes involved in complex eye diseases, myopia in particular, single nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) pattern were used to identified the gene within and around the All-trans-retinol dehydrogenase (RDH8). METHODS: Denaturing high-performance liquid chromatography (DHPLC) was used to screen SNPs in 4 DNA pools each consisting of DNA from five individuals, and genotypes identified SNPs coupled with DNA pooling strategy were performed in 150 Chinese subjects from Hong Kong. The identified common SNPs were included in LD and haplotype analysis using the Haploview2.05 and EH programs. RESULTS: Fifteen SNPs were identified: 7 were common with the minor allele frequency > 0.05, and 10 were novel. Four SNPs in the 3' region exhibited significant LD (/|D'/ > 0.75 and its confidence interval suggesting strong LD, r2 > 0.33, P < 0.031) and formed a haplotype block while 3 common SNPs in the 5' region did not exhibit obvious LD. CONCLUSION: The block-like LD pattern existed around the RDH8 gene region suggest that one SNP (RDH8E5a probably) in the 3' region and at least 2 SNPs in the 5' region (RDH851 particularly) were needed in association studies involving RDH8.

Alcohol Oxidoreductases↗
PubMed2001

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.

Age of Onset↗
PubMed2006

A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans.

OBJECTIVE: Anticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single-nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability of PADI4 messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in the PADI4 gene with RA in a Korean population. METHODS: Four exonic SNPs of the PADI4 gene (padi4_89, padi4_90, padi4_92, and padi4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi-square test and multivariate logistic regression analyses. RESULTS: Increased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P = 2.3 x 10(-5)), padi4_90 (P = 2.3 x 10(-5)), padi4_92 (P = 2.1 x 10(-5)), and padi4_104 (P = 1.1 x 10(-3)) and the haplotype carrying the 4 minor alleles (P = 1.0 x 10(-4)). Genotypes carrying the minor alleles and HLA-DRB1 shared epitope (SE) alleles (P = 9.4 x 10(-21)) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of padi4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles. CONCLUSION: The PADI4 SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association of PADI4 with RA may depend on genetic heterogeneity between Asians and Europeans.

Arthritis, Rheumatoid↗
PubMed2004

Principal component analysis for selection of optimal SNP-sets that capture intragenic genetic variation.

Candidate gene association studies often utilize one single nucleotide polymorphism (SNP) for analysis, with an initial report typically not being replicated by subsequent studies. The failure to replicate may result from incomplete or poor identification of disease-related variants or haplotypes, possibly due to naive SNP selection. A method for identification of linkage disequilibrium (LD) groups and selection of SNPs that capture sufficient intra-genic genetic diversity is described. We assume all SNPs with minor allele frequency above a pre-determined frequency have been identified. Principal component analysis (PCA) is applied to evaluate multivariate SNP correlations to infer groups of SNPs in LD (LD-groups) and to establish an optimal set of group-tagging SNPs (gtSNPs) that provide the most comprehensive coverage of intra-genic diversity while minimizing the resources necessary to perform an informative association analysis. This PCA method differs from haplotype block (HB) and haplotype-tagging SNP (htSNP) methods, in that an LD-group of SNPs need not be a contiguous DNA fragment. Results of the PCA method compared well with existing htSNP methods while also providing advantages over those methods, including an indication of the optimal number of SNPs needed. Further, evaluation of the method over multiple replicates of simulated data indicated PCA to be a robust method for SNP selection. Our findings suggest that PCA may be a powerful tool for establishing an optimal SNP set that maximizes the amount of genetic variation captured for a candidate gene using a minimal number of SNPs.

Adult↗
PubMed2006

SNPSplicer: systematic analysis of SNP-dependent splicing in genotyped cDNAs.

Functional annotation of SNPs (as generated by HapMap (http://www.hapmap.org) for instance) is a major challenge. SNPs that lead to single amino acid substitutions, stop codons, or frameshift mutations can be readily interpreted, but these represent only a fraction of known SNPs. Many SNPs are located in sequences of splicing relevance-the canonical splice site consensus sequences, exonic and intronic splice enhancers or silencers (exonic splice enhancer [ESE], intronic splice enhancer [ISE], exonic splicing silencer [ESS], and intronic splicing silencer [ISS]), and others. We propose using sets of matching DNA and complementary DNA (cDNA) as a screening method to investigate the potential splice effects of SNPs in RT-PCR experiments with tissue material from genotyped sources. We have developed a software solution (SNPSplicer; http://www.ikmb.uni-kiel.de/snpsplicer) that aids in the rapid interpretation of such screening experiments. The utility of the approach is illustrated for SNPs affecting the donor splice sites (rs2076530:A>G, rs3816989:G>A) leading to the use of a cryptic splice site and exon skipping, respectively, and an exonic splice enhancer SNP (rs2274987:C/T), leading to inclusion of a new exon. We anticipate that this methodology may help in the functional annotation of SNPs in a more high-throughput fashion.

Alternative Splicing↗
PubMed2000

A first high-density map of 981 biallelic markers on human chromosome 14.

As the largest set of sequence variants, single-nucleotide polymorphisms (SNPs) constitute powerful assets for mapping genes and mutations related to common diseases and for pharmacogenetic studies. A major goal in human genetics is to establish a high-density map of the genome containing several hundred thousand SNPs. Here we assayed 3.7 Mb (154,397 bp in 24 alleles) of chromosome 14 expressed sequence tags (ESTs) and sequence-tagged sites, for sequence variation in DNA samples from 12 African individuals. We identified and mapped 480 biallelic markers (459 SNPs and 21 small insertions and deletions), equally distributed between EST and non-EST classes. Extensive research in public databases also yielded 604 chromosome 14 SNPs (dbSNPs), 520 of which could be mapped and 19 of which are common between CNG (i.e., identified at the Centre National de Génotypage) and dbSNP polymorphisms. We present a dense map of SNP variation of human chromosome 14 based on 981 nonredundant biallelic markers present among 1345 radiation hybrid mapped sequence objects. Next, bioinformatic tools allowed 945 significant sequence alignments to chromosome 14 contigs, giving the precise chromosome sequence position for 70% of the mapped sequences and SNPs. In addition, these tools also permitted the identification and mapping of 273 SNPs in 159 known genes. The availability of this SNP map will permit a wide range of genetic studies on a complete chromosome. The recognition of 45 genes with multiple SNPs, by allowing the construction of haplotypes, should facilitate pharmacogenetic studies in the corresponding regions.

Alleles↗
PubMed2006

Identification of new single nucleotid polymorphisms (SNP) in alcohol dehydrogenase class IV ADH7 gene within a French population.

Many epidemiological studies have explored the possible link between the susceptibility to alcohol related cancers, such as oesophageal cancers, and genetic variants of alcohol dehydrogenases (ADHs). Alcohol dehydrogenase class IV ADH7 is mainly expressed in the upper aero-digestive tract and is involved in the first pass ethanol metabolism. As far as we know, no study has described single nucleotide polymorphisms (SNPs) within ADH7 exons in the Caucasian population. Therefore, in a pilot study, we used the denaturing high performance liquid chromatography (DHPLC) method to screen 49 oesophageal cancer cases for SNPs in the ADH7 gene. A total of 5 SNPs was observed in this study: one SNP in the 5' non-translated regions of exon 1, two SNPs in introns 3 and 4 and two others SNPs in exons 3 and 4. The SNP located in the exon 1, which has never been described before, occurred in a reverse TATA box whereas the SNP of exon 3 was a non-silent polymorphism. Because these two SNPs could potentially affect the transcription and/or the enzyme activity, their distribution was evaluated in a representative sample of healthy Caucasians (n = 89) recruited in Lower Normandy. Frequencies of heterozygous samples ranged from 11% (exon 3) to 28% (exon 1). No homozygous samples were found. In this pilot study, the DHPLC method was suitable for both SNP screening and genotyping and allowed the detection of five SNPs in the ADH7 gene, two of which have never been described before, among the European population.

Alcohol Dehydrogenase↗
PubMed2006

Screening for polymorphisms in the PXR gene in a Dutch population.

OBJECTIVE: Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of over 50% of all drugs currently in use. However, CYP3A4 expression shows a large inter-individual variation that cannot only be explained by genetic polymorphisms identified in this gene. The pregnane X receptor (PXR) has been identified as a transcriptional regulator of CYP3A4. Single nucleotide polymorphisms (SNPs) in the PXR gene could influence PXR activity and thereby CYP3A4 expression. This study was therefore aimed at determining the frequencies of known SNPs and detecting yet unknown SNPs in the PXR gene in a Dutch population. METHODS: Genomic DNA was isolated from blood samples obtained from 100 healthy volunteers and subjected to PCR amplification, followed by DNA sequencing. The population, of which the ethnicity was 93% Caucasian, consisted of 79 female individuals and 21 males. RESULTS: A total of 24 SNPs were found in the PXR gene, eight of which are previously unknown. The allelic frequencies found in this population varied from 0.5 to 73%. Most of the previously detected SNPs were located in introns. One new SNP, T8555G in exon 8, causes an amino acid change of C379G and is located in the Ligand Binding Domain of PXR. CONCLUSION: Several SNPs were detected in the PXR gene, one of which is located in the ligand binding domain (LBD). These SNPs may influence PXR-mediated CYP3A4 induction.

Cytochrome P-450 CYP3A↗