Yoshiko Ishida

Serum Folate and Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Adjusted for Folate Intake

Background Serum folate concentration is lower in individuals with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype than in those with the MTHFR 677CC or 677CT genotypes. Since studies considering folate intake are limited, we examined the association between folate intake and serum folate levels, according to the genotype. Methods The subjects comprised 170 Japanese persons (74 males and 96 females) aged 20-75 years who visited a clinic to test for Helicobacter pylori infection. Folate intake was estimated using a semiquantitative food-frequency questionnaire, and serum folate was measured in the residual fasting blood samples of the subjects. MTHFR C677T was genotyped using polymerase chain reaction. Results The geometric means of serum folate level were 6.19, 6.20, and 5.17 ng/mL among the 60 participants with the 677CC genotype, 90 participants with the 677CT genotype, and 20 participants with the 677TT genotype, respectively. No difference was noted in the mean folate intake estimated using the food-frequency questionnaire. Regression analysis showed that loge(serum folate) adjusted for age, sex, and loge(folate intake) was significantly lower among those with the 677TT genotype than among those with the 677CT or 677CC genotypes (p = 0.01). The adjusted reduction in serum folate was 20.2% (95% confidence interval, 5.4-32.6%) in the case of the 677TT genotype relative to the levels in the case of the 677CC/677CT genotypes. When folate intake was adjusted for total energy intake, using the residual method, the slope of the regression line for 677TT was smaller than those of the regression lines for 677CC and 677CT. Conclusion Individuals with the 677TT genotype may need to consume more folate to maintain serum folate levels similar to those found in individuals with the 677CC/677CT genotypes.

Smoking and serum CA19-9 levels according to Lewis and secretor genotypes.

CA19‐9, a marker for cancers of biliary tract, pancreas and colorectum, is not synthesized in those with no enzyme activity genotype (le/le) of Lewis (Le) gene. No enzyme activity genotype (se/se) of secretor (Se) gene is known to have an association with high serum CA19‐9 levels. There are also variations in serum CA19‐9 levels independent of the genotypes. This study aimed to examine the associations of serum CA19‐9 levels with smoking, alcohol drinking and body mass index (BMI; kg/m2), after the adjustments of Le and Se genotypes. Subjects were 486 health check‐up examinees (158 males and 328 females) aged from 39 to 90 years in Hokkaido, Japan. Genotyping was conducted for 3 polymorphisms; Le T59G (59T for Le allele and 59G for le allele), Se A385T (385A for Se allele and 385T for sej allele), and Se pseudogene (se5 allele). The genotypes of Le and Se were deterministic factors of serum CA19‐9. Those with Le/Le & se/se had the highest mean, while CA19‐9 was not detected or very low in those with le/le. Although no associations were observed with alcohol drinking and BMI, a significant association was observed with smoking. Among those with Le/Le, the geometric mean of CA19‐9 was significantly lower for current smokers than for noncurrent smokers (p = 0.011 in 4‐way ANOVA with age, sex and Se genotype). When hemoglobin A1c was further adjusted, the association became stronger (p = 0.0027). In addition to polymorphic variations, some components of cigarette smoke may influence the production or destruction of CA19‐9.

Significant association between PTPN11 polymorphism and gastric atrophy among Japanese Brazilians.

BackgroundHelicobacter pylori, especially the cytotoxin-associated antigen A (cagA)-positive strains, plays a crucial role in the development of gastric atrophy and gastric cancer. CagA delivered into gastric epithelial cells combines with src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2), possibly leading to atrophy/cancer. Our previous study found that a single-nucleotide polymorphism (SNP; IMS-JST057927) of the PTPN11 gene encoding SHP-2, was associated with gastric atrophy among H. pylori-seropositive subjects. This study aimed to examine the reproducibility of the association among Japanese residing in a different circumstance.MethodsThe subjects were 918 healthy adult Japanese Brazilians from four different areas in Brazil. Blood was sampled from March to May 2001. The target SNP in intron 3 of PTPN11 was genotyped by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Gastric atrophy was evaluated with serum pepsinogens (PGs); PG I, less than 70 ng/dl and PG I/II ratio, less than 3.ResultsThe genotype frequency of PTPN11 was in Hardy-Weinberg equilibrium: 65.5% for G/G, 30.4% for G/A, and 4.1% for A/A. The PTPN11 polymorphism had no significant association with H. pylori seropositivity. Among the H. pylori-seropositive subjects, the odds ratios (ORs) of gastric atrophy were 0.93 (95% confidence interval [CI], 0.59–1.47) for the G/A genotype and 0.31 (95% CI, 0.10–0.95) for the A/A genotype, compared with the G/G genotype.ConclusionsThe present study reproduced the significant association between the A/A genotype and reduced risk of gastric atrophy among Japanese outside Japan. According to the Japan Single Nucleotide Polymorphisms (JSNP) database (db)SNP data, the G allele is very frequent among Japanese and rare in Caucasians. This fact may partly explain the distribution of gastric atrophy/cancer in the world.

Associations of plasma IL-8 levels with Helicobacter pylori seropositivity, gastric atrophy, and IL-8 T-251A genotypes.

There are few data on circulatory pro-inflammatory cytokine levels and cytokine gene polymorphisms in H. pylori-positive patients. A cross-sectional study was conducted to examine the effects of H. pylori infection, gastric atrophy, and the IL-8 T-251A polymorphism on plasma IL-8 levels in 98 Japanese adults. Seventy-one subjects were positive for H. pylori infection. The geometric mean of plasma IL-8 concentration was significantly higher in subjects with H. pylori infection than in those without (P=0.001). The development of atrophy was negatively associated with IL-8 levels in the H. pylori-positive subjects, although not significantly. Plasma IL-8 levels in the T/T genotype were associated with H. pylori infection and atrophy status (P=0.016). Our findings suggested that circulating IL-8 levels were associated with H. pylori infection. The effect of H. pylori infection on plasma IL-8 levels was not clearly modified by the IL-8 T-251A polymorphism.

Association between Decreased Kidney Function and Endotoxin Receptor CD14 C-159T Polymorphism among Japanese Health Check-up Examinees

Background. A recently identified promoter polymorphism of the endotoxin receptor (CD14 C-159T) was shown to be associated with atherosclerotic diseases such as myocardial infarction. This study was conducted to determine whether this polymorphism is associated with decreased kidney function. Methods. A total of 281 male and 522 female health check-up examinees, aged 39–88 years, were genotyped for CD14 C-159T. The glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease (MDRD) Study equation. Estimated GFR (eGFR) and the proportion of subjects with mildly decreased eGFR (eGFR under 90 mL/min/1.73 m2) were compared among the genotypes. Results. Subjects carrying the T allele showed decreased age- and sex-adjusted eGFR compared with those with CC genotype (101±22 vs. 105±23 mL/min/1.73 m2; mean±SD, p = 0.012). The proportion of subjects with mildly decreased eGFR was higher in T allele carriers (34.2% for TT+CT and 26.3% for CC genotype, p = 0.041), but not statistically significant when adjusted for age and sex (odds ratio [OR] 1.41, 95% CI 0.97–2.05, p = 0.076). In subjects under 65 years, T allele carriers had a significantly increased risk for mildly decreased eGFR (27.1% for TT+CT and 18.0% for CC; age- and sex-adjusted OR 1.82, 95% CI 1.06–3.12, p = 0.030). Conclusion. CD14-159T allele was associated with decreased eGFR compared with CC genotype, and with a higher prevalence of mildly decreased eGFR in younger subjects under 65.

Alternative genotyping method of GSTT1 null/present polymorphism

Glutathione S-transferase (GST) θ is an enzyme to detoxify xenobiotic compounds. The gene GSTT1 has a null/present polymorphism in one of the targets for cancer susceptibility research. The polymorphism is classified into two types: present type with at least one present allele (heterozygote and homozygote) and null type without a present allele. Although one report showed a method to distinguish the heterozygote from the present homozygote, its use has been limited possibly owing to the difficulty of successful genotyping of long DNA sequences (1460 base pairs). This article reports an alternative method utilizing typical PCR primers specific to the null allele (566 base pairs) and the present allele (458 base pairs). All samples of the GSTT1 null genotype processed by the present PCR method (n = 331), were correctly classified as the null genotype by a conventional method, and the samples of heterozygous (n = 364) or present homozygous (n = 108) genotype as the present genotype; this indicates that it is appropriate for future research to utilize three genotypes of the GSTT1 null/present polymorphism.