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PubMed2003

Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.

Common genetic polymorphisms may explain a portion of the heritable risk for common diseases. Within candidate genes, the number of common polymorphisms is finite, but direct assay of all existing common polymorphism is inefficient, because genotypes at many of these sites are strongly correlated. Thus, it is not necessary to assay all common variants if the patterns of allelic association between common variants can be described. We have developed an algorithm to select the maximally informative set of common single-nucleotide polymorphisms (tagSNPs) to assay in candidate-gene association studies, such that all known common polymorphisms either are directly assayed or exceed a threshold level of association with a tagSNP. The algorithm is based on the r(2) linkage disequilibrium (LD) statistic, because r(2) is directly related to statistical power to detect disease associations with unassayed sites. We show that, at a relatively stringent r(2) threshold (r2>0.8), the LD-selected tagSNPs resolve >80% of all haplotypes across a set of 100 candidate genes, regardless of recombination, and tag specific haplotypes and clades of related haplotypes in nonrecombinant regions. Thus, if the patterns of common variation are described for a candidate gene, analysis of the tagSNP set can comprehensively interrogate for main effects from common functional variation. We demonstrate that, although common variation tends to be shared between populations, tagSNPs should be selected separately for populations with different ancestries.

Algorithms↗

PubMed2002

Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study.

Variants in mitochondrial DNA (mtDNA) could be associated with type 2 diabetes because ATP plays a critical role in the production and release of insulin. Diabetes can be precipitated both by mtDNA mutations and by exposure to mitochondrial poisons. The risk of inheriting diabetes from an affected mother is greater than that from an affected father, but this is not explained by maternally inherited diabetes and/or deafness (MIDD) caused by the 3243G : C mtDNA point mutation, which accounts for less than 0.5% of cases of diabetes. A common mtDNA variant (the 16189 variant) is positively correlated with blood fasting insulin, but there are no definitive studies demonstrating that it is associated with diabetes. We demonstrated a significant association between the 16189 variant and type 2 diabetes in a population-based case-control study in Cambridgeshire, UK (n=932, odds ratio=1.61 (1.0-2.7, P=0.048), which was greatly magnified in individuals with a family history of diabetes from the father's side (odds ratio=infinity; P<0.001).

Aged↗

PubMed2001

Personality disorders as extreme variants of common personality dimensions: can the Five-Factor Model adequately represent psychopathy?

The present study examined Widiger and Lynam's (1998) hypothesis that psychopathy can be represented using the Five-Factor Model (FFM) of personality. Participants in the study consisted of 481 21-22-year-old men and women who are part of an ongoing longitudinal study. Psychopathy was assessed by the degree of similarity between an individual's NEO-PI-R and an expert-generated FFM psychopathy prototype. The expert-based prototype supported the account of Widiger and Lynam (1998), as did the correlations between the NEO-PI-R Psychopathy Resemblance Index (PRI) and the individual personality dimensions. The PRI was also related in predicted ways to measures of antisocial behavior, drug use, and psychopathology. The results support the contention that psychopathy can be understood as an extreme variant of common dimensions of personality, and underscore the utility of a dimensional model of personality disorders.

Adult↗

PubMed2005

The 625G>A SCAD gene variant is common but not associated with increased C4-carnitine in newborn blood spots.

The 625G>A variant of the short-chain acyl-CoA dehydrogenase (SCAD) gene is considered to confer susceptibility for developing 'clinical SCAD deficiency' and appears to be common in the general population. To determine the frequency of the 625G>A variant in The Netherlands, we analysed 1036 screening cards of 5- to 8-day-old newborns and found 5.5% homozygous and 31.3% heterozygous for the 625G>A variant. An increased blood/plasma C4-carnitine concentration is considered to be one of the biochemical characteristics of SCAD deficiency. To explore the correlation of C4-carnitine levels with the 625G>A variant, we determined the C4-carnitine concentration, as well as the ratio of C4- to free carnitine, in blood spots from newborns, who were detected as homozygous, heterozygous or noncarriers for the gene variant. No significant differences were found between these groups. Our study demonstrates a high frequency of the 625G>A SCAD gene variant in the Dutch population, but no correlation to significantly increased C4-carnitine levels in blood spots taken between the 5th and 8th days of life. This latter observation might be the result of the relatively late timing of neonatal screening in our country, implying that fatty acid oxidation disorders may be missed at that stage. If the 625G>A variant is associated with clinical SCAD deficiency, the high frequency of the variant suggests a possible involvement of SCAD deficiency in the pathogenesis of common disorders, probably in relation to other genetic and/or environmental factors. However, homozygosity for the 625G>A variant might be only a biochemical phenomenon, representing a 'nondisease'.

Alleles↗

PubMed2006

Further investigations of glucose-6-phosphate dehydrogenase variants in Flores Island, eastern Indonesia.

We conducted field surveys for malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency in the eastern part of Flores Island, East Nusa Tenggara Province, Indonesia. A total of 1,108 volunteers (642 males and 466 females) belonging to three ethnic groups (Sikka, Ende and Bajo) were examined, and 55 G6PD-deficient individuals (38 males and 17 females) were detected. Among them, 50 samples were analyzed molecularly, in addition to three deficient cases in a Bajo family. In the Sikka population, G6PD Kaiping (1388G>A), one of the two common variants in the Chinese population, was unexpectedly found as the most dominant variant (11/22, 50.0%), followed by G6PD Chatham (1003G>A, 36.4%), G6PD Coimbra (592C>T, 9.1%) and G6PD Vanua Lava (383T>C, 4.5%). Frequency of G6PD Kaiping in the Sikka might be the highest among non-Chinese populations reported so far. In the Ende population, G6PD Vanua Lava (9/14, 64.3%) was the highest, followed by G6PD Kaiping (14.3%), G6PD Chinese-5 (1024C>T, 14.3%) and G6PD Chatham (7.1%). In the Bajo population, a total of 18 deficient cases were analyzed, and a novel mutation (844G>T) in exon 8 with a predicted amino acid change of 282 Asp>Tyr was found in a 7-year-old boy at a Bajo village near Maumere. This new Class II (mild type) variant was also confirmed in his mother and sister, and designated as G6PD Bajo Maumere. The missense mutation at the same nucleotide 844 has been known as G6PD Seattle/Lodi/Modena/Ferrara II, but this mutation is caused by a G>C substitution (282 Asp>His). In the Bajo population, G6PD Viangchan (871G>A, IVS 11 nt93 T>C, 1311C>T), the most common variant in continental Southeast Asian populations, was found to be the dominant (11/18, 61.1%), followed by G6PD Vanua Lava and the new variant (each 16.7%), and G6PD Coimbra (5.6%). These results strongly suggest that the Bajo peoples may have different ancestors from those for Sikka and Ende, and may be much closer to continental Southeast Asian populations. It is interesting that G6PD Canton (1376G>T), another common variant in Chinese, was not seen in the Flores population.

DNA Mutational Analysis↗

PubMed2005

The D allele of the ACE I/D common gene variant is associated with Type 2 diabetes mellitus in Caucasian subjects.

The deletion D allele of the angiotensin-I converting enzyme (ACE) I/D gene variant is associated with higher ACE activity in Caucasians and previous studies in non-Caucasian samples have suggested an association between the D allele and type 2 diabetes (Type 2DM). The aim of this study was to compare the genotype distribution between Caucasian subjects with Type 2DM and non-diabetic Caucasian men. Genotype distribution was compared between 574 Caucasian subjects with Type 2DM, recruited from the UCL Diabetes and Cardiovascular Disease Study and 2413 non-diabetic Caucasian men, recruited from the second Northwick Park Heart Study. Within both samples, genotype distributions were in Hardy-Weinberg equilibrium. The genotype distributions in those with Type 2DM compared to the non-diabetic men (II/ID/DD) was 18%/50%/32% vs. 23%/49%/27%, p=0.004. In accordance with this, the frequency of the D allele was higher in those with Type 2DM (0.574 [0.55-0.60] vs. 0.519 [0.50-0.53], p=0.001). On combining the two samples, the odds ratio (OR) for Type 2DM was significantly higher in D allele carriers compared to II subjects (OR=1.55, p=0.02, after adjustment for age, sex, BMI, blood pressure, and lipids). In those with diabetes, there was a significant association between genotype and a family history of diabetes. The odds ratio for a family history of diabetes in DD compared to II subjects was 1.52 [0.89-2.60], p=0.03. This study clearly shows an association between the ACE I/D common gene variant and Type 2DM.

Alleles↗

PubMed2006

Distribution of common CARD15 variants in patients with sporadic Crohn's disease: cases from Turkey.

Three common genetic variations, namely, R702W, G908R, and 1007fs, on CARD15 have been shown to increase the risk for Crohn's disease (CD) in Caucasian populations. In this study the frequencies of these CARD15 variants were determined by genotyping in 56 patients with CD and 100 healthy ethnically matched controls from Turkey. Overall frequency of all three variants was 10.7% in CD patients, compared with 1.5% in controls (odds ratio [OR]: 7.9). Among them, the frequency of the G908R variant allele was 8% in CD cases, compared with 0% in controls (OR: 36.8). The allele frequencies of three CD-related CARD15 variants were considerably lower in the control group compared to the reported Caucasian populations. Among the described CARD15 variants, G908R confers an increased susceptibility to CD, whereas the more frequently reported associations in Europeans with R702W and 1007fs are not confirmed in this Turkish population.

Adolescent↗

PubMed1968

Enzymic properties of different types of human erythrocyte glucose-6-phosphate dehydrogenase, with characterization of two new genetic variants.

Enzymic properties have been compared in the following five genetic variants of glucose-6-phosphate dehydrogenase from human erythrocytes: the two common variants with normal activity, A and B; the common variant associated with enzyme deficiency, A-; and two new rare variants, "Ijebu-Ode" and "Ita-Bale."The maximal velocity of the enzyme reaction (V(max)) increases steadily with pH over the entire range explored (from pH 5.5 to 9.5) for all enzyme variants when buffers are used that show no specific ion effects on enzyme activity. Small differences are found among the variants in the pH range 7.5-8.2, where A and B show a "peak and trough," while A-, "Ijebu-Ode," and "Ita-Bale" exhibit a plateau. When the effects of reagents that bind to sulphydryl groups are compared, iodoacetate, bromoacetate, and iodoacetamide are weak inhibitors, while N-ethylmaleimide (NEM) and hydroxymercuribenzoate (HMB) are potent inhibitors. The last two reagents have differential inhibitory action on different variants; one of these, "Ijebu-Ode," is strikingly resistant to HMB and totally resistant to NEM (up to 3 mmoles/liter). The enzyme inactivation as a function of temperature exhibits distinctive profiles for all variants examined. BOTH OF THE NEW VARIANTS DESCRIBED DIFFER SIGNIFICANTLY FROM THE NORMAL B TYPE IN SEVERAL RESPECTS: "Ijebu-Ode" in electrophoretic mobility, thermostability, dependence of V(max) on pH, and resistance to sulphydryl group reagents; "Ita-Bale" in electrophoretic mobility, Michaelis constant (K(m)) for glucose-6-phosphate, and dependence of V(max) on pH. When these data are compared with those available in the literature, both variants are different from all those previously described. The estimated frequencies of the corresponding genes in western Nigeria are between 0.0005 and 0.0025 for "Ijebu-Ode" and less than 0.0005 for "Ita-Bale". The A- variant, compared to A, has a distinctly higher K(m) for 2-deoxyglucose-6-phosphate and is more inhibited by very low concentrations of HMB. These are the first observed differences in kinetic properties between A and A-.

Chemical Phenomena↗

PubMed2026

A Common CD36 Variant and the Genetic Landscape of Dilated Cardiomyopathy in Individuals of African Ancestry.

IMPORTANCE: Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in CD36 that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown. OBJECTIVE: To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic (P/LP) variants in other established DCM genes. DESIGN SETTING AND PARTICIPANTS: Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study. EXPOSURE: Carrier status for TTN truncating variants, P/LP variants in 11 high confidence DCM genes, and the CD36 nonsense variant (Y325*; 0, 1, or 2 copies). MAIN OUTCOMES AND MEASURES: Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM. RESULTS: Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM. CD36 Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and CD36 Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds. TTN truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were CD36 homozygotes, second only to TTN truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous CD36 Y325* carriers, the population-attributable fraction for CD36 (9.0%) surpassed that of TTN truncating variants (3.6%). CONCLUSIONS AND RELEVANCE: An ancestry-specific CD36 variant contributes more to DCM burden in AFR ancestry than established DCM genes, including TTN truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.

Journal Article↗

PubMed2005

Aging syndrome genes and premature coronary artery disease.

BACKGROUND: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. METHODS: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. RESULTS: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. CONCLUSION: Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO.

Aging, Premature↗

PubMed2001

A common genetic variant of luteinizing hormone; relation to normal and aberrant pituitary-gonadal function.

Mutations of the luteinizing hormone (LH) subunit genes are extremely rare. Only one polymorphic LHbeta gene variant makes an exception. In 1992, an immunologically anomalous form of LH was found in a healthy woman, and it was subsequently found to be caused by two point mutations leading to two amino acid substitutions in the LHbeta subunit. Of the two point mutations, Trp(8)Arg and Ile(15)Thr, the first one is mainly responsible for the altered immunoreactivity and the latter one introduces an extra glycosylation site into Asn(13) of the mutated LHbeta peptide. The frequency of this variant LHbeta allele differs widely between ethnic groups, being most common in aboriginal Australians (carrier frequency >50%; allelic frequency 28.3%) and totally lacking from Kotas of Southern India. Functional differences have been detected when wild-type LH and variant LH have been compared. Variant LH possesses increased in vitro bioactivity, whereas its half-life in circulation is shorter in comparison to wild-type LH. Also the regulation of the variant LHbeta gene differs due to additional changes in its promoter sequence. Correlations of occurrence of variant LH with various clinical conditions involving LH function suggest that it represents a biologically less active form of LH and may be related to borderline suppression of gonadal function, including subfertility. In this article, we will review the current information about the differences observed in structure and functions between the wild-type and variant LH, as well as their possible pathophysiological correlations.

Animals↗

PubMed1995

Common genetic variants of lipoprotein lipase that relate to lipid transport in patients with premature coronary artery disease.

Two common coding sequence mutations of lipoprotein lipase (serine447-ter, producing a carboxy terminal truncation; and asp9-asn variants) were studied in 329 Caucasian subjects, of whom 243 had angiographic features of premature atheroscelerosis (220 with coronary artery disease; 23 with coronary and peripheral artery disease). As expected, the mean levels of cholesterol, triglycerides, LDL-cholesterol, ApoB and Lp(a) were significantly higher in the arterial disease group than in the controls. HDL levels were lower in the patient group. With regard to the common mutations, plasma triglycerides and VLDL-triglycerides were lower in subjects possessing the Serine447-Ter mutation (p = 0.06 and < 0.05, respectively). When the lipid distributions were analysed by tertiles, the Ser447-Ter mutation was significantly less frequent in the highest tertiles for triglycerides (p < 0.02), and VLDL (p < 0.04). The Asp9-Asn substitution was significantly more frequent in the lowest tertiles for ApoAI (p = 0.05). Case-control analyses of genotypic distributions between the two groups with or without arterial disease did not show any significant differences. The possible functional effects of these common mutants of lipoprotein lipase are discussed.

Asparagine↗

PubMed2006

Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants.

Methotrexate (MTX) is used in patients with malignant and autoimmune diseases. This drug is primarily excreted unchanged in the urine, and its net excretion occurs via active secretory and reabsorptive processes. We characterized the interaction of MTX with human organic-anion transporting polypeptide transporter (OATP) 1A2, which is expressed in tissues important for MTX disposition and toxicity, such as the intestine, kidney, liver, and endothelial cells of the blood-brain barrier. In Xenopus laevis oocytes expressing OATP1A2, the uptake of the model substrate, estrone-3-sulfate (ES), was enhanced 30-fold compared with uninjected oocytes. MTX uptake in oocytes expressing OATP1A2 was saturable (Km = 457 +/- 118 microM; Vmax = 17.5 +/- 4.9 pmol/oocyte/60 min) and sensitive to extracellular pH. That is, acidic pHs stimulated MTX uptake by as much as 7-fold. Seven novel protein-altering variants were identified in 270 ethnically diverse DNA samples. Four protein-altering variants in OATP1A2 exhibited altered transport of ES and/or MTX. The common variant, protein reference sequence (p.) Ile13Thr, was hyperfunctional for ES and MTX and showed a 2-fold increase in the V(max) for ES. The common variant, p. Glu172Asp, exhibited reduced maximal transport capacity for ES and MTX. p. Arg168Cys was hypofunctional, and p. Asn277DEL was nonfunctional. Because of its expression on the apical membrane of the distal tubule and in tissues relevant to MTX disposition and toxicity, these findings suggest that OATP1A2 may play a role in active tubular reabsorption of MTX and in MTX-induced toxicities. Furthermore, genetic variation in OATP1A2 may contribute to variation in MTX disposition and response.

Alleles↗

PubMed2004

A common functional variant in the interleukin-6 gene is associated with increased body mass index in subjects with type 2 diabetes mellitus.

Circulating levels of interleukin-6 (IL-6) are raised in insulin resistant states such as obesity, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM). Growing evidence suggests that IL-6 is not only produced by fat cells but is also capable of inducing insulin resistance in these cells. The expected result of this in vivo, would be to increase adipose mass and subsequently body mass index (BMI). The IL-6 -174G > C common functional gene variant has consistently been associated with increased plasma IL-6, insulin resistance, and increased cardiovascular risk. We looked at the association between genotype and BMI in 571 Caucasian subjects with T2DM. There was a significant linear association between genotype and BMI: Median (interquartile range) GG 28.8 kg/m2 (26.0-31.6) vs GC; 29.4 kg/m2 (26.3-32.5) vs CC; 30.4 kg/m2 (26.1-33.0), p=0.05. When the group was divided by the median BMI (29.1 kg/m2), 62% of -174CC subjects were in the higher group compared to 38% in the lower group (p=0.008). By contrast, in 2,652 non-diabetic Caucasian men with a median BMI of 26.1 kg/m2, there was no difference in genotype distribution (p=0.288). The frequency of the -174C allele was lower in type 2 diabetes compared to the non-diabetic men (-174C allele frequency: 0.35[0.33-0.38] vs 0.43[0.42-0.45], p <0.00001; -174CC homozygotes: 12.3 vs 18.3%, respectively). The -174C allele is associated with higher BMI in type 2 diabetes, but not amongst healthy subjects. The increased cardiovascular risk associated with the -174C allele may account for the lower frequency of this allele in those with type 2 diabetes.

Body Mass Index↗

PubMed2005

Mapping common regulatory variants to human haplotypes.

Inter-individual variation in gene expression has proven to be in part governed by genetic determinants, which may be trans- or cis-acting. The underlying cause of cis-acting regulatory variation has been identified in only a handful of the hundreds of genes shown to display differential allelic expression. In this report, we describe a systematic effort to map common cis-acting variants in 64 genes, using association methods in HapMap samples. We identified 16 loci (25%), each of which harbors common haplotypes that affect total expression of a gene, and a further 17 loci (27%) with evidence of haplotypes affecting relative allelic expression in heterozygote samples. Our survey suggests that detailed mapping of allele-specific in vivo expression will provide a rich source of regulatory SNPs or haplotypes that should be given high priority in association studies of human phenotypes.

Chromosome Mapping↗

PubMed2005

Genetic analysis and functional characterization of polymorphisms in the human concentrative nucleoside transporter, CNT2.

The concentrative nucleoside transporter CNT2 (SPNT1; SLC28A2) plays a role in the absorption and disposition of naturally occurring nucleosides, as well as nucleoside analog drugs. The aim of the present study was to characterize genetic variation in SLC28A2, the gene encoding CNT2, and to functionally analyse non-synonymous variants of CNT2, as a first step towards understanding whether genetic variation in this nucleoside transporter contributes to variation in response to nucleoside analogs. As part of a larger study, DNA samples from an ethnically diverse population (100 African-Americans, 100 European-Americans, 30 Asians, 10 Mexicans and seven Pacific Islanders) were screened and 10 coding region variants of CNT2 were identified. The non-synonymous variants were then constructed and characterized in Xenopus laevis oocytes. Six non-synonymous variants were identified, and all were able to transport guanosine. The four common variants (>1% in the sample population) were further characterized with the anti-viral nucleoside analog drug ribavirin. No differences were observed among the four common variants in the uptake kinetics of 3H-ribavirin (Km in microM: 35.6+/-9.27 for CNT2-reference, 40.7+/-6.47 for CNT2-P22L, 31.2+/-15.8 for CNT2-S75R, 26.7+/-6.13 for CNT2-S245T and 49.9+/-14.6 for CNT2-F355S). The variant CNT2-F355S exhibited a change in specificity for the naturally occurring nucleosides, inosine and uridine. All non-synonymous variants of CNT2 took up guanosine, and the four variants examined showed no significant difference in ribavirin kinetics. However, CNT2-F355S (3% allele frequency in the African-American sample) was found to alter specificity for naturally occurring nucleosides, which may have implications for nucleoside homeostasis.

Alleles↗

PubMed2005

Methylenetetrahydrofolate reductase polymorphisms/haplotypes and risk of gastric cancer: a case-control analysis in China.

Studies have suggested that low dietary folate intake is associated with an increased risk of gastric cancer. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and influences DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. We hypothesized that three MTHFR common variants (i.e. C677T, A1298C and G1793A) and their haplotypes are associated with the risk of gastric cancer. To test this hypothesis, we genotyped these polymorphisms in a population-based case-control study of 320 incident gastric adenocarcinoma cases and 313 cancer-free controls in a Chinese population. Consistent with our previous observations, the 677TT genotype was associated with a significantly increased risk for gastric cancer (adjusted OR =1.79, 95% CI =1.02-3.15) compared with the 677CC genotype; the association was more evident for gastric cardia adenocarcinoma (adjusted OR =2.60, 95% CI =1.30-5.21). When we used the haplotype analyses and assumed MTHFR 677T, 1298C and 1793A as risk alleles, individuals with 6 variant alleles had a significantly (4.64-fold) increased risk for gastric cardia adenocarcinoma (OR =4.64, 95% CI =1.34-16.01) compared with those having 0-2 variants. These findings suggest that the MTHFR common variants and their haplotypes may play a role in the etiology of gastric cancer, particularly gastric cardia adenocarcinoma. Future studies using large sample sizes and incorporating detailed data on dietary folate intake and related serological measurements are warranted to confirm our findings.

Adenocarcinoma↗

PubMed2006

CDKN2A-positive breast cancers in young women from Poland.

PURPOSE: To investigate the contribution of CDKN2A A148T common variant to early-onset breast cancer in Poland, and to establish the characteristic features of these cancers. EXPERIMENTAL DESIGN: We studied 3,069 women diagnosed with breast cancer under the age of 51 and 3,493 population controls. CDKN2A variant were detected using RFLP-PCR and confirmed by genomic sequencing. Clinical and pathological features of CDKN2A-positive cases and CDKN2A-negative cases were compared. RESULTS: A148T variant was identified in 157 of 3,069 women with breast cancer (5.1%). Overall, the odds ratio for early-onset breast cancer, given a CDKN2A variant was 1.4 (95% CI 1.075-1.725; P = 0.012). Breast tumors in women with the CDKN2A variant were more commonly intraductal cancers (DCIS) with micro-invasion (14.8% vs. 8.5%; P = 0.035). Carriers and non-carriers were similar with respect to tumor size, laterality, multicentricity, nodal status, family history and estrogen-receptor status. CONCLUSION: The CDKN2A A148T variant seems to contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of A148T variant appear to be similar to those of breast cancers in the population at large.

Adult↗