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PubMed2006

Association of hypertension with single nucleotide polymorphisms in the quantitative trait locus for abdominal obesity-metabolic syndrome on chromosome 17.

Genome scan in Chinese revealed an association of blood pressure with the microsatellite marker D17S1303, which lies in a quantitative trait locus for the abdominal obesity-metabolic syndrome (AOMS2) at 17p12 on chromosome 17. We previously reported that D17S1303 was associated with hypertension and obesity. Therefore, we studied 10 single nucleotide polymorphisms (SNP) within 3 kb of D17S1303. One hundred and eighty hypertensive subjects (91 men, 89 women, age 53+/-12 years) and 180 normotensive matched controls (91 men, 89 women, age 52+/-11) were genotyped using the Sequenom genotyping platform. Allelic frequencies in these Chinese subjects differed from those reported for Caucasians. Three SNPs (rs11656507, rs1357926, rs852319) were homozygous in our subjects. The genotype frequencies of rs852320, rs852321 and rs852322 did not differ between hypertensive and normotensive subjects. However, there were significant differences for rs1525402 (P=0.048), rs2692343 (P=0.022), rs2692344 (P=0.017) and rs2321313 (P=0.028). A four-locus haplotype comprising G at rs1525402, C at rs2692343, C at rs2692344 and G at rs2321313 was associated with lower systolic blood pressure (P=0.023) and normotension (P=0.048). Our results provide further evidence that there is a gene, as yet unidentified, influencing blood pressure in the vicinity of D17S1303 in a quantitative trait locus for abdominal obesity-metabolic syndrome at 17p12.

Chi-Square Distribution↗
PubMed2005

Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event.

Basal cell carcinoma is the most common human cancer with increasing incidence reported worldwide. Despite the aberrant signaling role of the Hedgehog pathway, little is known about the genetic mechanisms underlying basal cell carcinomas. Towards a better understanding of global genetic events, we have employed the Affymetrix Mapping 10K single nucleotide polymorphism (SNP) microarray technique for "fingerprinting" genomewide allelic imbalance in 14 basal cell carcinoma-blood pair samples. This rapid high-resolution SNP genotyping technique has revealed a somatic recombination event-uniparental disomy, leading to a loss of heterozygosity (LOH), as a key alternative genetic mechanism to allelic imbalances in basal cell carcinomas. A highly conserved LOH region at 9q21-q31 was found in 13 of 14 (93%) basal cell carcinomas. Further statistical and fluorescence in situ hybridization analyses confirmed that the 9q LOH was a result of uniparental disomy in 5 of 13 (38%) basal cell carcinomas. De novo mutations in the Patched 1 gene (PTCH) were found in 9 of 13 (69%) basal cell carcinomas with 9q LOH. A second important locus, containing LOH at 6q23-q27 was found in 5 of 14 (36%) basal cell carcinomas, suggesting that the presence of an additional putative tumor suppressor gene may be contributing to basal cell carcinoma development. This study shows that the rate of 9q LOH in basal cell carcinomas has been previously underestimated. Furthermore, we provide the first evidence that uniparental disomy due to somatic recombination constitutes one of the mechanisms of LOH in basal cell carcinoma tumorigenesis.

Aged↗
PubMed2003

Rapid detection of aneuploidy (trisomy 21) by allele quantification combined with melting curves analysis of single-nucleotide polymorphism loci.

BACKGROUND: Molecular approaches for the detection of chromosomal abnormalities will allow the development of rapid, cost-effective screening strategies. We present here a molecular alternative for the detection of aneuploidies and, more specifically, trisomy 21. METHODS: We used the quantitative value of melting curve analysis of heterozygous genetic loci to establish a relative allelic count. The two alleles of a given single-nucleotide polymorphism (SNP) were differentiated by thermodynamic stability with a fluorescently labeled hybridization probe and were quantified by relative areas of derivative melting curves detected after fluorescence resonance energy transfer. Heterozygous SNPs provided internal controls for the assay. RESULTS: We selected six SNPs, heterozygous in at least 30% of a random population, to form a panel of informative loci in the majority of a random population. After normalization to a heterozygous control, samples segregated into three categories; nontrisomic samples had mean allele ratios of 0.96-1.09, whereas trisomic samples had mean ratios of 1.84-2.09 or 0.46-0.61, depending on which allele was duplicated. Within-run mean CVs of ratios were 6.5-27%, and between-assay mean CVs were 13-24%. CONCLUSIONS: The use of melting curve analysis of multiple SNPs is an alternative to the use of small tandem repeats for the detection of trisomies. Because of the high density of SNPs, the approach may be specifically useful for very fine mapping of the regions of chromosome 21 that are critical for Down syndrome; it is also applicable to aneuploidies other than trisomy 21 and to specimens that are not amenable to cytogenetic analysis.

Alleles↗
PubMed2002

Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms: resolution of genetic relationships among closely related microbial strains.

Several human pathogens (e.g., Bacillus anthracis, Yersinia pestis, Bordetella pertussis, Plasmodium falciparum, and Mycobacterium tuberculosis) have very restricted unselected allelic variation in structural genes, which hinders study of the genetic relationships among strains and strain-trait correlations. To address this problem in a representative pathogen, 432 M. tuberculosis complex strains from global sources were genotyped on the basis of 230 synonymous (silent) single nucleotide polymorphisms (sSNPs) identified by comparison of four genome sequences. Eight major clusters of related genotypes were identified in M. tuberculosis sensu stricto, including a single cluster representing organisms responsible for several large outbreaks in the United States and Asia. All M. tuberculosis sensu stricto isolates of previously unknown phylogenetic position could be rapidly and unambiguously assigned to one of the eight major clusters, thus providing a facile strategy for identifying organisms that are clonally related by descent. Common clones of M. tuberculosis sensu stricto and M. bovis are distinct, deeply branching genotypic complexes whose extant members did not emerge directly from one another in the recent past. sSNP genotyping rapidly delineates relationships among closely related strains of pathogenic microbes and allows construction of genetic frameworks for examining the distribution of biomedically relevant traits such as virulence, transmissibility, and host range.

Alleles↗
PubMed2005

CYP2J2*7 single nucleotide polymorphism in a Chinese population.

BACKGROUND: Human cytochrome P450 2J2 (CYP2J2) is the major arachidonic acid epoxygenase that plays important roles in the pathogenesis of a variety of diseases such as cardiovascular disorders and cancers, this P450 also plays a role in the metabolism of some antihistamine drugs. Variability of CYP2J2 gene is highly constrained except for at its proximal promoter a relatively common and functionally relevant single nucleotide polymorphism, namely CYP2J2*7, with allele frequency being 17%, 5.49%, 13%, and 4.23% in African, White, Asian, and Korean, respectively. Since this genetic variation differs strikingly between ethnic groups, we characterized the CYP2J2*7polymorphism in Chinese. METHODS: Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) assays were used to genotype CYP2J2*7 in a sample of 384 healthy Chinese Han subjects. RESULTS: In this Chinese population, 20 (5.21%) heterozygotes and no homozygote for CYP2J2*7 allele were observed, and the allelic frequency was 2.60%. CONCLUSION: The CYP2J2*7 variant represents a relatively rare polymorphism in Chinese, with the allele frequency being comparable to that of Korean, but significantly lower than those of African and White groups. This data may be informative to design population-based association study of genetic predisposition to CYP2J2 related diseases and treatments.

Alleles↗
PubMed2003

Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse.

The nature and organization of polymorphisms, or differences, between genomes of individuals are of great interest, because these variations can be associated with or even underlie phenotypic traits, including disease susceptibility. To gain insight into the genetic and evolutionary factors influencing such biological variation, we have examined the arrangement (haplotype) of single-nucleotide polymorphisms across the genomes of eight inbred strains of mice. These analyses define blocks of high or low diversity, often extending across tens of megabases that are delineated by abrupt transitions. These observations provide a striking contrast to the haplotype structure of the human genome.

Animals↗
PubMed2006

Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2?

Predisposition to type 1 diabetes and juvenile obesity is influenced by the susceptibility locus IDDM2 that includes the insulin gene (INS). Although the risk conferred by IDDM2 has been attributed to a minisatellite upstream of INS, intragenic variants have not been ruled out. We examined whether INS polymorphisms affect pre-mRNA splicing and proinsulin secretion using minigene reporter assays. We show that IVS1-6A/T (-23HphI+/-) is a key INS variant that influences alternative splicing of intron 1 through differential recognition of its 3' splice site. The A allele resulted in an increased production of mature transcripts with a long 5' leader in several cell lines, and the extended mRNAs generated more proinsulin in culture supernatants than natural transcripts. The longer mRNAs were significantly overrepresented among beta-cell-expressed sequenced tags containing the A allele as compared with those with T alleles. In addition, we show that a rare insertion/deletion polymorphism IVS1+5insTTGC (IVS-69), which is exclusively present in Africans, activated a downstream cryptic 5' splice site, extending the 5' leader by 30 bp. These results indicate that -23HphI and IVS-69 are the most important INS variants affecting pre-mRNA splicing and suggest that -23HphI+/- is a common functional single nucleotide polymorphism at IDDM2.

Alternative Splicing↗
PubMed2002

Single nucleotide polymorphism mapping using genome-wide unique sequences.

As more and more genomic DNAs are sequenced to characterize human genetic variations, the demand for a very fast and accurate method to genomically position these DNA sequences is high. We have developed a new mapping method that does not require sequence alignment. In this method, we first identified DNA fragments of 15 bp in length that are unique in the human genome and then used them to position single nucleotide polymorphism (SNP) sequences. By use of four desktop personal computers with AMD K7 (1 GHz) processors, our new method mapped more than 1.6 million SNP sequences in 20 hr and achieved a very good agreement with mapping results from alignment-based methods.

Chromosome Mapping↗
PubMed2001

A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.

BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.

Adult↗
PubMed2001

Lack of association of a functionally relevant single nucleotide polymorphism of matrix metalloproteinase-1 promoter with systemic sclerosis (scleroderma).

Matrix metalloproteinase 1 (MMP-1) is necessary for degradation of interstitial collagen types I, II, and III, which are the major constituents of the extracellular matrix (ECM). Increased expression of MMP-1 has been correlated with invasiveness of certain malignancies and cartilage degradation in rheumatoid arthritis. Increased transcriptional activity of MMP-1 has been reported with a single nucleotide polymorphism (SNP) of the MMP-1 promoter. Systemic sclerosis (SSc) is characterized by increased accumulation and turnover of collagen and other components of ECM. Previous studies have reported increased expression of MMP-1 transcripts in SSc fibroblasts. Therefore, we sought to determine if SSc patients with early disease (< or =5 years) from a multi-ethnic cohort were more or less likely than ethnically-matched normal controls to have an increased frequency of the high promoter activity MMP-1 genotype and whether MMP-1 promoter genotypes correlated with any of the major clinical manifestations of SSc. The results show that the frequency of the high activity promoter genotype in either the heterozygous or homozygous state did not differ significantly between SSc patients and ethnically-matched controls, or between SSc patients with either diffuse or limited scleroderma. Furthermore, MMP-1 promoter genotypes did not significantly correlate with any of the major clinical manifestations of SSc.

Humans↗
PubMed2005

Single nucleotide polymorphisms in the human norepinephrine transporter gene affect expression, trafficking, antidepressant interaction, and protein kinase C regulation.

The role of norepinephrine (NE) in attention, memory, affect, stress, heart rate, and blood pressure implicates NE in psychiatric and cardiovascular disease. The norepinephrine transporter (NET) mediates reuptake of released catecholamines, thus playing a role in the limitation of signaling strength in the central and peripheral nervous systems. Nonsynonymous single nucleotide polymorphisms (SNPs) in the human NET (hNET) gene that influence transporter function can contribute to disease, such as the nonfunctional transporter, A457P, identified in orthostatic intolerance. Here, we examine additional amino acid variants that have been identified but not characterized in populations that include cardiovascular phenotypes. Variant hNETs were expressed in COS-7 cells and were assayed for protein expression and trafficking using cell-surface biotinylation and Western blot analysis, transport of radiolabeled substrate, antagonist interaction, and regulation through protein kinase C (PKC)-linked pathways by the phorbol ester beta-phorbol-12-myristate-13-acetate. We observed functional perturbations in 6 of the 10 mutants studied. Several variants were defective in trafficking and transport, with the most dramatic effect observed for A369P, which was completely devoid of the fully glycosylated form of transporter protein, was retained intracellularly, and lacked any transport activity. Furthermore, A369P and another trafficking variant, N292T, impeded surface expression of hNET when coexpressed. F528C demonstrated increased transport and, remarkably, exhibited both insensitivity to down-regulation by PKC and a decrease in potency for the tricyclic antidepressant desipramine. These findings reveal functional deficits that are likely to compromise NE signaling in SNP carriers in the population and identify key regions of NET contributing to transporter biosynthesis, activity, and regulation.

Animals↗
PubMed2005

Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6).

The human organic anion transporter hOAT1 (SLC22A6) contributes to the uptake of a range of small organic anions across the basolateral membrane of the renal proximal tubule and drives their urinary elimination. The aim of this study was to identify genetic variants of hOAT1 and to investigate potential effects on the functional properties of this transporter. Twenty single nucleotide polymorphisms (SNPs) in hOAT1 were identified in genomic DNA from 92 individuals of African, Asian, and Caucasian origin. Two SNPs encoded changes in amino acid sequence; arginine to histidine (residue 50) and lysine to isoleucine (residue 525). Significantly, these SNPs were only present in the samples of African origin. When expressed in Xenopus oocytes, wild-type R50-hOAT1 and the variants R50H-hOAT1 and K525I-hOAT1 all mediated the probenecid-sensitive uptake of the classic organic anion para-aminohippurate (PAH). Kinetic analysis indicated that the transport affinity (K(m)) for PAH was unchanged in the variants, compared with wild type. Interestingly, the K(m) for the nucleoside phosphonate analogs adefovir, cidofovir, and tenofovir seemed to be decreased in the R50H-hOAT1 variant compared with the wild type, whereas the kinetics of K525I-hOAT1 remained unchanged. In conclusion, this is the first study to identify variation of hOAT1 in a racially diverse sample and to investigate the functional properties of the resulting variants. Since hOAT1 has been suggested as the basis of nephrotoxicity induced by nucleoside phosphonate analogs, this study raises the intriguing possibility that individuals with genetic variation in hOAT1, such as R50H, may display different handling of these drugs.

Adenine↗
PubMedDate not supplied

Genotyping single nucleotide polymorphisms by mass spectrometry.

In the last decade, the demand for high-throughput DNA analysis methods has dramatically increased, mainly due to the advent of the human genome sequencing project that is now nearing completion. Even though mass spectrometry did not contribute to that project, it is clear that it will have an important role in the post-genome sequencing era, in genomics and proteomics. In genomics, mainly matrix-assisted laser desorption/ionization (MALDI) mass spectrometry will contribute to large-scale single nucleotide polymorphism (SNP) genotyping projects. Here, the development and history of DNA analysis by mass spectrometry is reviewed and put into the context with the requirements of genomics. All major contributions to the field and their status and limitations are described in detail.

Alleles↗
PubMed2000

Hypertension and single nucleotide polymorphisms.

Hypertension is a common, complex disease phenotype that has been intensively studied to identify susceptibility loci in humans. Candidate genes continue to be uncovered via genetic analysis in model organisms through linkage analysis with families and/or sib-pairs and through association studies using sequence variants in genes that play a role in key pathways regulating blood pressure in humans, such as the renin-angiotensin system (RAS). Recent studies exploring the sequence diversity in human candidate genes suggest that the distribution and organization of single nucleotide polymorphisms (SNPs) within and among human populations is complex. Issues related to the use of SNPs in analyzing the genetic determinants of hypertension are illustrated using recent studies on the angiotensin-converting enzyme (ACE).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3' untranslated region of the human serotonin transporter gene.

The human serotonin transporter (hSERT) gene is a candidate for involvement in the aetiology of affective disorders. In humans, multiple transcripts of the gene have been detected by northern blot analysis of brain and other tissues. We performed 3' rapid amplification of cDNA ends to identify the common sites of polyadenylation in hSERT mRNA from human JAR cells and whole blood. Two major polyadenylation sites were identified: one 567 bp downstream of the stop codon, consistent with the usage of the polyadenylation signal AATGAA, and a second site 690 bp downstream of the stop codon. The putative polyadenylation signal upstream of this site contained a single nucleotide polymorphism (AG/TTAAC). However, allelic variation at this site did not influence polyadenylation site usage, and there were no significant differences in the abundance of the two alleles of this polymorphism between 329 control subjects, 158 individuals with major depression, and 130 individuals with bipolar affective disorder. This single nucleotide polymorphism in the 3' untranslated region of the hSERT gene should provide a useful genetic marker in the evaluation of hSERT as a candidate gene influencing susceptibility to mood disorders.

3' Untranslated Regions↗
PubMed2006

Single nucleotide polymorphism of the AXIN2 gene is preferentially associated with human lung cancer risk in a Japanese population.

The AXIN2 gene, a negative regulator gene of Wnt/beta-catenin signaling, is a putative tumor suppressor gene on human chromosome 17q24. In the genomic locus on which the AXIN2 gene is located, allelic loss and rearrangement were frequently detected in many cancers. An association between human cancer risk and a single nucleotide polymorphism (SNP) at codon 50 of the AXIN2 gene, encoding either proline (CCT) or serine (TCT), remains undefined. We, therefore, investigated the distribution of the SNP at codon 50 in 110 healthy controls and 160 patients with non-small-cell lung cancer, 113 patients with colorectal cancer, and 63 patients with head and neck cancer. We found that the frequency of the homozygous T/T (Ser/Ser) genotype was significantly less in lung cancer patients (5.0%) than in healthy controls (13.6%) (p=0.005). As compared with the C/C (Pro/Pro) genotype of the controls, lung cancer patients with the T/T genotype showed reduced risk of cancer; the adjusted odds ratio (OR) for patients with the homozygous T/T (Ser/Ser) genotype was 0.31 (95% confidence interval (CI), 0.12-0.79). The association was particularly strong in lung cancer patients with lung adenocarcinoma (LAD) (adjusted OR, 0.24; 95% CI, 0.07-0.81), with well-differentiated grade cancer (adjusted OR, 0.12; 95% CI, 0.01-0.99) and with moderately-differentiated grade cancer (adjusted OR, 0.18; 95% CI, 0.04-0.85). These results suggest that the AXIN2 Pro50Ser SNP is associated with development of lung cancer as a protective SNP, while an association between the AXIN2 SNP and risk of colorectal cancer and of head and neck cancer was not observed. This is the first report to show an association between the AXIN2 SNP and lung cancer risk.

Aged↗
PubMed2003

Endothelial nitric oxide synthase T-786C single nucleotide polymorphism: a putative genetic marker differentiating small versus large ruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: Anecdotal evidence exists for at least 2 subpopulations of intracranial saccular aneurysms, namely, those that may form rapidly and rupture when small versus those that enlarge slowly and may rupture particularly when > or =10 mm in diameter. We sought to determine whether the endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), implicated in cardiovascular disease susceptibility, could facilitate differentiation between small (< or =5 mm) versus large (> or =10 mm) ruptured aneurysms. METHODS: In accordance with institutional guidelines, clinical data were recorded prospectively and genomic DNA was isolated from blood samples obtained from 52 aneurysmal subarachnoid hemorrhage (SAH) patients (cases) and 90 randomly selected controls. Samples were assayed for eNOS gene promoter T-786C SNP with the use of gene microarray technology. Statistical analyses included multiple logistic regression. RESULTS: Although there was no difference in genotype distributions between cases and controls, all 13 patients with large aneurysms were (T/C) heterozygous for the polymorphism, while 9 of 22 patients (41%) with small aneurysms were (T/T or C/C) homozygous (P=0.01). The mean (+/-SD) ruptured aneurysm diameter among all heterozygotes (8.5+/-5.2 mm) was significantly greater than that for C/C (6.0+/-2.3 mm) or T/T (4.7+/-1.8 mm) homozygotes (P=0.04). With the use of multivariate analysis, heterozygosity remained significantly associated with aneurysm size > or =10 mm (P=0.03). CONCLUSIONS: The eNOS T-786C SNP distinguishes genetically between small and large ruptured aneurysms. Although not predictive of SAH in the population at large, our data suggest that among persons with known intracranial aneurysms, eNOS T-786C genotype may be a factor influencing the size at which an aneurysm ruptures, a finding that should be taken into consideration along with other anatomic features of the aneurysm.

Age Distribution↗
PubMed1998

Single nucleotide polymorphism spectra in newborns and centenarians: identification of genes coding for rise of mortal disease.

Some single-nucleotide polymorphisms (SNPs) increase the risk of mortal disease. Identifying these SNPs and the genes in which they reside is an important area in human genomics. Such qualitative observations are important in themselves. However, an accurate assessment of the numerical distribution and age-dependent decline of SNPs in the population would permit calculation of the rises represented by each SNP. Such analyses have not been attempted because of a lack of an efficient and cost-effective method to detect multiple SNPs in a large number of individuals and a large number of genes. Here, we suggest the use of an analytical procedure that can scan for SNPs in 100-bp DNA sequences from as many as 10000 donors' blood cell samples, or 20000 alleles, simultaneously. Our suggestion is based on technology developed for studies of somatic mutations in human tissue DNA for point mutations at frequencies equal to or greater than 10(-6). In a simplified version of this technology, any SNP arising at frequencies at or above 5x10(-4) would be identified with useful precision. A gene would be represented by 10 or more sections of 100bp. This strategy includes splice-site mutations that represent a significant fraction of gene inactivating point mutations and would not be observed in strategies using cDNA. To illustrate the logic of the suggested approach, we use American mortality records to calculate the expected decrease in SNPs coding for premature mortality in newborns and centenarians. We consider several elementary cases: SNPs in one gene only, any of several genes, or all of several genes that create a risk of death by pancreatic cancer. The fraction of expressed polymorphisms affecting mortality should be simultaneously increased in probands and decreased in the aged relative to newborns. Silent polymorphisms in the same gene would remain unchanged in all three groups and serve as internal standards. A key point is that scanning a gene, in which loss of gene function creates the risk of mortality is expected to reveal not one, but multiple SNPs, which decline with age, as carriers die earlier in life than non-carriers. Several SNPs in a scanned gene would suggest that the decreasing SNP was genetically linked to a different polymorphism that creates the disease risk.

Age Factors↗