Longitudinal exome-wide association study to identify genetic susceptibility loci for hypertension in a Japanese population.

Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) 'CAAAA' comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype 'TGGGT'. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5, was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time.

Association of smoking with prevalence of common diseases and metabolic abnormalities in community-dwelling Japanese individuals.

Smoking is a significant risk factor for cardiovascular diseases (CVDs). Given that certain common pathologies, including hypertension, dyslipidemia and type 2 diabetes mellitus, are major risk factors for CVDs, the association of smoking with CVDs may be attributable, at least in part, to its effects on common diseases. The aim of the present study was to determine the association of smoking with the prevalence of common diseases and metabolic abnormalities in community-dwelling Japanese individuals. The study included 5,959 subjects (1,302 current smokers, 1,418 past smokers and 3,239 nonsmokers) recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. Various metabolic parameters and prevalence of common diseases were compared between smokers and nonsmokers using multivariable regression or logistic regression analysis with adjustments for age. Analysis indicated significantly higher serum concentrations of triglycerides and lower concentrations of high-density lipoprotein (HDL)-cholesterol in current smokers compared with nonsmokers in men and women. Serum concentrations of creatinine and systolic blood pressure were significantly lower and estimated glomerular filtration rate was higher in male current smokers. In addition, body weight was higher in female current smokers. In multivariable logistic regression analysis, smoking was significantly associated with the prevalence of dyslipidemia [P=6.3×10-10; odds ratio (OR), 1.81], hypertriglyceridemia (P=2.3×10-20; OR, 2.39), hypo-HDL-cholesterolemia (P=2.0×10-9; OR, 2.14), metabolic syndrome (P=0.0003; OR, 1.61) and chronic kidney disease (P=4.4×10-15; OR, 0.54) in men, but not in women. The results indicated that smoking is significantly associated with various metabolic abnormalities and prevalence of common diseases in Japanese individuals, with certain sex differences, which may lead to accelerated development of CVDs.

Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome­wide association study.

An exome­wide association study (EWAS) was performed to identify genetic variants, particularly low­frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome­12 DNA Analysis BeadChip or Infinium Exome­24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher's exact test. Based on Bonferroni's correction, a P<1.21x10­6 was considered statistically significant. The EWAS for atrial fibrillation revealed that 122 SNPs were significantly associated with this condition. The association of the identified SNPs to atrial fibrillation was further examined by multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension. Eight SNPs were related (P<0.01) to atrial fibrillation, among which three polymorphisms, rs11552708 [G/A (G67R)]of TNF superfamily member 13 (TNFSF13; dominant model; P=9.36x10­9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10­5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10­5; odds ratio, 1.77), were significantly (P<1.02x10­4) associated with this condition. The minor T allele of rs113710653 and the minor C allele of rs11231397 were risk factors for atrial fibrillation, whereas the minor A allele of rs11552708 was protective against this condition. In addition, rs77538589 [C/T (G117R)] of SALL4 exhibited a tendency to be associated with atrial fibrillation (dominant model; P=0.0002; odds ratio, 1.88), with the minor T allele representing a risk factor for this condition. TNFSF13, SPATC1L, SLC22A25 and SALL4 may thus be novel susceptibility loci for atrial fibrillation in the Japanese population.

Association of genetic variants with atrial fibrillation.

Recent genome-wide association studies (GWASs) identified various genes and loci that confer susceptibility to coronary artery disease or myocardial infarction among Caucasian populations. As myocardial ischemia is an important risk factor for atrial fibrillation, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to atrial fibrillation through affecting the susceptibility to coronary artery disease. The aim of the present study was to examine the possible association of atrial fibrillation in Japanese individuals with 29 polymorphisms identified as susceptibility loci for coronary artery disease or myocardial infarction in the meta-analyses of GWASs in Caucasian populations. The study subjects comprised 5,470 Japanese individuals (305 subjects with atrial fibrillation and 5,165 controls). Genotypes for 29 polymorphisms were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test revealed that rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (PSRC1, P=0.0084) and rs11556924 (C→T, Arg363His) of the zinc finger, C3HC-type containing 1 gene (ZC3HC1, P=0.0076) were significantly (P<0.01) associated with atrial fibrillation. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, estimated glomerular filtration rate, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidemia revealed that rs599839 (P=0.0043; odds ratio, 1.56; dominant model) and rs11556924 (P=0.0043; odds ratio, 1.93; dominant model) were significantly associated with atrial fibrillation, with the minor G and T alleles, respectively, representing risk factors for this condition. PSRC1 and ZC3HC1 may thus be susceptibility loci for atrial fibrillation in Japanese individuals.

Association of FURIN and ZPR1 polymorphisms with metabolic syndrome.

Although genome-wide association studies (GWASs) have identified various genes and loci in predisposition to metabolic syndrome (MetS) or each component of this condition, the genetic basis of MetS in individuals remains to be identified definitively. The aim of the present study was to examine the possible association of MetS in individuals with 29 polymorphisms that were previously identified as susceptibility loci for coronary artery disease or myocardial infarction by meta-analyses of GWASs. The study population comprised 1,822 subjects with MetS and 1,096 controls. Subjects with MetS had ≥3 of the 5 components of the diagnostic criteria for MetS, whereas control individuals had 0-1 of the 5 components. The genotypes for the 29 polymorphisms were determined by the multiplex bead-based Luminex assay. Comparisons of allele frequencies by the χ2 test revealed that rs17514846 (A→C) of the furin (paired basic amino acid-cleaving enzyme) gene (FURIN; P=0.0006), rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1; P=0.0078) and rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (P=0.0486) were significantly (P<0.05) associated with the prevalence of MetS. Multivariable logistic regression analysis with adjustment for age, gender and smoking status revealed that rs17514846 of FURIN (P=0.0016; odds ratio, 0.76; dominant model) and rs964184 of ZPR1 (P=0.0164; odds ratio, 1.21; dominant model) were significantly associated with MetS. The minor A allele of rs17514846 of FURIN was significantly associated with a decrease in the serum concentration of triglycerides (P=0.0293) and to an increase in the serum concentration of high-density lipoprotein (HDL) cholesterol (P=0.0460). The minor G allele of rs964184 of ZPR1 was significantly associated with increases in the serum concentration of triglycerides (P=6.2×10-9) and fasting plasma glucose level (P=0.0028) and to a decrease in the serum concentration of HDL cholesterol (P=0.0105). FURIN and ZPR1 may thus be susceptibility loci for MetS.

Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke.

Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P<0.05) associated with the prevalence of ischemic stroke. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, smoking status and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that rs2075650 of TOMM40 (P=0.0443; recessive model; odds ratio=0.50) and rs273909 of SLC22A4 (P=0.0123; dominant model; odds ratio=0.45) were significantly associated with ischemic stroke with the minor G and C allele, respectively, being protective against this condition. TOMM40 and SLC22A4 may thus be susceptibility loci for ischemic stroke in Japanese individuals.

Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population-based genetic epidemiological study.

Our previous studies identified nine genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke or chronic kidney disease by genome-wide or candidate gene association studies. As coronary artery disease (CAD) and ischemic stroke may share genetic architecture, certain genetic variants may confer susceptibility to the two diseases. The present study examined the association of 13 polymorphisms at these 10 loci with the prevalence of CAD or ischemic stroke in community-dwelling individuals, with the aim of identifying genetic variants that confer susceptibility to the two conditions. Study subjects (170 with CAD, 117 with ischemic stroke and 5,718 controls) were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited for an annual health checkup and they were followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation, and with adjustment for age, gender, body mass index, smoking status, the prevalence of hypertension, diabetes mellitus and dyslipidemia and the serum concentration of creatinine, revealed that rs2074380 (G→A) and rs2074381 (A→G) of the α-kinase 1 (ALPK1) gene and rs8089 (T→G) of the thrombospondin 2 (THBS2) gene were significantly (P<2×10-16) associated with the prevalence of CAD, with the AA genotype of rs2074380 and GG genotypes of rs2074381 and rs8089 being protective against this condition. Similar analysis revealed that rs9846911 (A→G) at chromosome 3q28, rs2074381 of ALPK1, rs8089 of THBS2 and rs6046 (G→A) of the coagulation factor VII gene were significantly (P<2×10-16) associated with the prevalence of ischemic stroke, with the GG genotypes of rs9846911, rs2074381 and rs8089 and the AA genotype of rs6046 being protective against this condition. ALPK1 and THBS2 may thus be susceptibility loci for CAD and ischemic stroke.

Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study.

We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for Japanese patients with myocardial infarction, ischemic stroke, or chronic kidney disease by genome-wide or candidate gene association studies. In the present study, we investigated the possible association of 13 single nucleotide polymorphisms (SNPs) at these 10 loci with the prevalence of hypertension or their association with blood pressure (BP) in community-dwelling individuals in Japan. The study subjects comprised 6,027 individuals (2,250 subjects with essential hypertension, 3,777 controls) who were recruited into the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study on atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center of Inabe General Hospital for an annual health checkup, and they are followed up each year (mean follow­up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender, body mass index and smoking status revealed that rs2116519 of family with sequence similarity 78, member B (FAM78B; P=0.0266), rs6929846 of butyrophilin, subfamily 2, member A1 (BTN2A1; P=0.0013), rs146021107 of pancreatic and duodenal homeobox 1 (PDX1; P=0.0031) and rs1671021 of lethal giant larvae homolog 2 (Drosophila) (LLGL2; P=0.0372) were significantly (P<0.05) associated with the prevalence of hypertension. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender, body mass index and smoking status among individuals not taking anti-hypertensive medication revealed that rs6929846 of BTN2A1 was significantly associated with systolic (P=0.0017), diastolic (P=0.0008) and mean (P=0.0005) BP, and that rs2116519 of FAM78B, rs146021107 of PDX1 and rs1671021 of LLGL2 were significantly associated with diastolic (P=0.0495), systolic (P=0.0132), and both diastolic (P=0.0468) and mean (0.0471) BP, respectively. BTN2A1 may thus be a susceptibility gene for hypertension.

Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals.

AIM: Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. METHODS: The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of <60 mL min(-1) 1.73 m(-2) ] and 659 controls (eGFR of ≥90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined. RESULTS: The χ(2) test revealed that rs4845625 (T→C) of IL6R, rs4773144 (A→G) of COL4A1, rs9319428 (G→A) of FLT1, and rs46522 (T→C) of UBE2Z were significantly (P < 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype. CONCLUSION: The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals.

Association of a transcription factor 21 gene polymorphism with hypertension.

Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P<0.05) associated with hypertension. Allele frequencies for rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1) and genotype distributions for rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1) were also significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs12190287 of TCF21 (P=0.0014; recessive model; odds ratio, 1.21) was significantly associated with hypertension, and the C allele represented a risk factor for this condition. Similar analyses revealed that rs1122608 of SMARCA4 (P=0.0305; dominant model; odds ratio, 0.86), rs9369640 of PHACTR1 (P=0.0119; dominant model; odds ratio, 0.82) and rs599839 of PSRC1 (P=0.0248; dominant model; odds ratio, 0.84) were also related to hypertension, with the minor T, C and G alleles, respectively, being protective against this condition. Thus, the present results indicate that rs12190287 (G→C) of TCF21 is a susceptibility locus for hypertension.

Association of a butyrophilin, subfamily 2, member A1 gene polymorphism with hypertension.

The C→T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 (BTN2A1) gene has been previously identified as a susceptibility locus for myocardial infarction by a genome-wide association study. As hypertension is a major risk factor for myocardial infarction, the association between the BTN2A1 polymorphism, rs6929846, and myocardial infarction may be partly due to its effect on hypertension susceptibility. The aim of the present study was to examine the possible association of rs6929846 with hypertension. The study subjects comprised 5,959 community-dwelling individuals (2,183 subjects with hypertension and 3,776 controls) who were recruited to a population-based cohort study. The rs6929846 genotype was determined by a method that combined polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons between the genotype distributions (P=0.0090) and allele frequencies (P=0.0051) by the χ2 test revealed that rs6929846 was significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs6929846 was significantly associated with hypertension (P=0.0008; odds ratio, 1.29; dominant model), with the minor T allele representing a risk factor for this condition. Among all the individuals, systolic, diastolic and mean blood pressure was significantly higher in the combined group of individuals with the CT or TT genotypes compared to the CC genotype group. BTN2A1 may thus be a susceptibility gene for hypertension. Therefore, determining the genotype for this polymorphism may provide genetic risk assessment information for hypertension.

Association of a polymorphism of BTN2A1 with dyslipidemia in community-dwelling individuals.

We have previously shown that the C→T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with myocardial infarction. Considering that dyslipidemia is a significant risk factor for coronary heart disease, it was hypothesized that the association between rs6929846 of BTN2A1 and myocardial infarction may be attributable, at least in part, to its effect on the susceptibility to dyslipidemia. The purpose of the present study was to examine a possible association of rs6929846 of BTN2A1 with dyslipidemia in community­dwelling individuals. The study subjects were comprised of 5,958 community­dwelling individuals (2,909 subjects with dyslipidemia and 3,049 controls) who were recruited into a population­based cohort study in Inabe, Japan. Dyslipidemia was defined by a serum concentration of triglycerides of ≥1.65 mmol/l, a serum high­density lipoprotein­cholesterol concentration of <1.04 mmol/l or a serum low­density lipoprotein (LDL)­cholesterol concentration of ≥3.64 mmol/l. A comparison of the allele frequencies or genotype distributions by the χ2 test revealed that rs6929846 of BTN2A1 was significantly associated with dyslipidemia (P<0.05). A multivariable logistic regression analysis adjusted for age, gender, body mass index, smoking status and the prevalence of diabetes mellitus revealed that rs6929846 of BTN2A1 was significantly (dominant model; P=2.4x10-4; odds ratio, 1.29) associated with dyslipidemia, with the minor T allele representing a risk for this condition. Among all the individuals, the serum concentrations of total cholesterol, triglycerides and LDL­cholesterol were significantly greater for individuals in the combined CT and TT genotype groups than for those with the CC genotype. BTN2A1 may thus be a susceptibility gene for dyslipidemia in community­dwelling individuals.

Association of genetic variants of CELSR1 and 3q28 with hypertension in community-dwelling individuals.

Findings of previous studies demonstrated that rs6007897 (C→T, Ala2268Thr) of the cadherin, epidermal growth factor (EGF) laminin A G-type repeats (LAG) seven-pass G-type receptor 1 gene (CELSR1) and rs9846911 (A→G) at chromosome 3q28 were significantly associated with ischemic stroke and chronic kidney disease, respectively. Given that hypertension is a risk factor for both ischemic stroke and chronic kidney disease, it was hypothesized that the association of rs6007897 with ischemic stroke or of rs9846911 with chronic kidney disease might be attributable, at least in part, to their effects on genetic susceptibility to hypertension. The purpose of the present study was to examine a possible association of rs6007897 of CELSR1 or rs9846911 at 3q28 with hypertension in community-dwelling individuals. Study subjects comprised 5,959 community-dwelling individuals (1,670 subjects with hypertension and 4,289 controls) who were recruited to a population-based cohort study. Comparisons of allele frequencies by the Chi-square test revealed that rs6007897 of CELSR1 (P=0.0280) and rs9846911 at 3q28 (P=0.0171) were significantly associated with the prevalence of hypertension. Multivariate logistic regression analysis with adjustment for age, gender, body mass index (BMI), smoking status, the serum concentration of creatinine and the prevalence of dyslipidemia and diabetes mellitus revealed that rs6007897 (P=0.0308; recessive model; odds ratio, 1.56) and rs9846911 (P=0.0353; dominant model; odds ratio, 1.22) were significantly associated with hypertension with the T allele rs6007897 and the G allele rs984691 representing risk factors for this condition. CELSR1 and 3q28 may thus be susceptibility loci for hypertension.

Association between polymorphisms of the α-kinase 1 gene and type 2 diabetes mellitus in community-dwelling individuals.

We previously demonstrated that the α-kinase 1 gene (ALPK1) is a susceptibility locus for chronic kidney disease in individuals with diabetes mellitus (DM) by a genome-wide association study. Although genetic variants of ALPK1 have been associated with chronic kidney disease in individuals with DM, whether ALPK1 is a susceptibility locus for DM has not been elucidated. The purpose of the present study was to investigate a possible association of the rs2074388 (A→G, Asp565Gly) or rs2074379 (A→G, Ile732Met) variants of ALPK1 with type 2 DM in community-dwelling individuals. The study subjects comprised 5,959 community-dwelling individuals (495 subjects with type 2 DM and 5,464 controls) who were recruited to a population-based cohort study in Inabe, Mie, Japan. The comparisons of allele frequencies or genotype distributions using the Chi-square test revealed that the rs2074388 and rs2074379 variants of ALPK1 were significantly associated with type 2 DM (P<0.05). A multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that the rs2074388 (P=0.0051; odds ratio, 1.32) and rs2074379 (P=0.0058; odds ratio, 1.32) variants were significantly associated with type 2 DM. The haplotype analysis of these polymorphisms revealed that the frequency of the major haplotype, A (rs2074388)-A (rs2074379), was significantly lower, whereas that of the minor haplotype G-G was significantly higher in subjects with type 2 DM compared to controls. Thus, ALPK1 may be a susceptible gene for type 2 DM in community-dwelling Japanese individuals.

Acute interstitial pneumonitis after implantation of paclitaxel-eluting stents: a report of two fatal cases.

Paclitaxel is an anti-neoplastic agent widely used as a coating substance for coronary stents to reduce the rate of restenosis. Although the release rate of paclitaxel from stents is quite slow and the dose of paclitaxel is extremely small, long-term safety and avoidance of potentially lethal pulmonary damage is not well established. We report two cases of paclitaxel-eluting stent implantation in ischemic heart disease patients who developed acute interstitial pneumonitis a few days afterward, and who succumbed to fatal respiratory dysfunction despite corticosteroid therapy. Based upon the clinical course and autopsy findings in these two patients, paclitaxel eluted from the stent may have played a causal role in the development of acute interstitial pneumonitis. Physicians should bear in mind that paclitaxel has the potential of causing acute interstitial pneumonitis not only when used for anti-neoplastic therapy, but also following stent implantation, where the objective is to inhibit coronary neointimal proliferation.

Paclitaxel-induced interstitial pneumonia after drug-eluting stent implantation: report of a fatal case.

We report a case of paclitaxel-eluting stent implantation in an angina patient who developed interstitial pneumonia a few days afterward, and succumbed to fatal respiratory dysfunction despite corticosteroid therapy. Paclitaxel is an anti-neoplastic agent currently used as a coating substance for coronary stents to reduce the rate of restenosis. Pulmonary toxicity related to paclitaxel is not very common; however, this adverse event may on occasion be lethal. Although the efficacy and safety of drug-eluting stents for the treatment of ischemic heart disease is well established, physicians should keep in mind that paclitaxel-eluting stents have the potential to cause interstitial pneumonia.