Reliability, validity, and responsiveness of the Japanese version of the EORTC QLQ-ELD14 in evaluating the health-related quality of life of elderly patients with cancer.

PURPOSE: This study evaluated the reliability, validity, and responsiveness of the Japanese version of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-ELD14 and measured the health-related quality of life (HRQOL) of elderly Japanese patients with cancer aged ≥ 60 and ≥ 70 years. METHODS: The study recruited elderly Japanese patients with cancer aged ≥ 60 (≥ 70) years (n = 1803 [n = 1236]). The EORTC QLQ-ELD14 was evaluated for reliability, validity, responsiveness, and correlations of changes in score between the EORTC QLQ-ELD14 and the EORTC QLQ-C30 before and after the commencement of the COVID-19 pandemic. RESULTS: In both age groups, the proportion of missing items was low (< 3%). Cronbach's α was good at ≥ 0.70, except for two of the seven items. All the intraclass coefficient constants were good at ≥ 0.70. The concurrent validity was good but correlation with the EORTC QLQ-C30 was not strong, except for the hypothesis items. Regarding the assessment of responsiveness, only one item ("maintaining purpose") of the EORTC QLQ-ELD14 worsened (- 6.14 ± 29.20, standard response of mean > 0.2) after the commencement of the COVID-19 pandemic. The changes in score between the EORTC QLQ-ELD14 and the "global health status/QOL" and "summary score" of the EORTC QLQ-C30 had moderate-to-high negative correlations for all items, except two. Hypotheses to evaluate construct validity were accepted at 90%, while responsiveness was accepted at 80%. CONCLUSION: The Japanese version of the EORTC QLQ-ELD14 questionnaire appears to have acceptable reliability, validity, and responsiveness to evaluate HRQOL in elderly Japanese people with cancer.

Long-term effects of laparoscopic lateral pelvic lymph node dissection on urinary retention in rectal cancer.

BACKGROUND: The addition of lateral pelvic lymph node dissection (LPLND) in rectal cancer surgery has been reported to increase the incidence of post-operative urinary retention. Here, we assessed the predictive factors and long-term outcomes of urinary retention following laparoscopic LPLND (L-LPLND) with total mesorectal excision (TME) for advanced lower rectal cancer. METHODS: This retrospective single-institutional study reviewed post-operative urinary retention in 71 patients with lower rectal cancer who underwent L-LPLND with TME. Patients with preoperative urinary dysfunction or who underwent unilateral LPLND were excluded. Detailed information regarding patient clinicopathologic characteristics, post-void residual urine volume, and the presence or absence of urinary retention over time was collected from clinical and histopathologic reports and telephone surveys. Urinary retention was defined as residual urine > 100 mL and the need for further treatment. RESULTS: Post-operative urinary retention was observed in 25/71 patients (35.2%). Multivariate analysis revealed that blood loss ≥ 400 mL [odds ratio (OR) 4.52; 95% confidence interval (CI) 1.24-16.43; p = 0.018] and inferior vesical artery (IVA) resection (OR 8.28; 95% CI 2.46-27.81; p < 0.001) were independently correlated with the incidence of urinary retention. Furthermore, bilateral IVA resection caused urinary retention in more patients than unilateral IVA resection (88.9% vs 47.1%, respectively; p = 0.049). Although urinary retention associated with unilateral IVA resection improved relatively quickly, urinary retention associated with bilateral IVA resection tended to persist over 1 year. CONCLUSION: We identified the predictive factors of urinary retention following L-LPLND with TME, including increased blood loss (≥ 400 mL) and IVA resection. Urinary retention associated with unilateral IVA resection improved relatively quickly. L-LPLND with unilateral IVA resection is a feasible and safe procedure to improve oncological curability. However, if oncological curability is guaranteed, bilateral IVA resection should be avoided to prevent irreversible urinary retention.

Successful Management of a Severe Sacral Pressure Injury Penetrating to the Retroperitoneum.

INTRODUCTION: Reports of retroperitoneal infection related to a sacral pressure injury (PI) are rare, and none of the reports described the direct spread of infection through the sacrum to the retroperitoneum. The authors present, to their knowledge, the first report of a severely infected PI that showed full-thickness sacral destruction and direct retroperitoneal penetration. CASE REPORT: A 63-year-old female was referred for management of a stage 4 sacral PI complicated by a retroperitoneal abscess. The patient's comorbidities were diabetes mellitus and pemphigus foliaceus with steroid therapy-induced immunosuppression. Upon admission, the patient presented with a sacral PI producing copious purulent discharge that measured 5 cm × 3 cm. Magnetic resonance imaging revealed full-thickness sacral bone destruction and a massive retroperitoneal abscess, suggesting the sacral PI directly penetrated to the retroperitoneal space. Antibiotics were administered, and surgical debridement and sequestrectomy were performed. Negative pressure wound therapy (NPWT) with continuous saline irrigation was initiated. The patient's mesorectum was exposed within the retroperitoneal space. Therefore, a nonadhesive wound dressing was applied before placing the irrigation tube to avoid perforating the rectum. Because the patient had fragile skin secondary to long-standing pemphigus foliaceus and steroid treatment, a liquid skin protectant and hydrocolloid wound dressing were applied. The infection was successfully controlled with NPWT with saline irrigation. The patient experienced no rectal injury or skin rupture, and surgical closure was performed after 75 days. Although partial wound dehiscence occurred because of the poor condition of the skin, the resultant open wound was managed conservatively. The patient showed no retroperitoneal abscess recurrence 6 months later. CONCLUSIONS: A rare case of an intractable sacral PI complicated by retroperitoneal abscess was successfully managed in an immunocompromised patient. Notably, NPWT with saline irrigation was useful in controlling the patient's severe retroperitoneal infection.

Laparoscopic spacer placement for recurrent sacral chordoma before carbon ion radiotherapy: A case report.

Recently, several scholars have demonstrated the efficacy of carbon ion radiotherapy (CIRT). To treat abdominal or pelvic tumors by CIRT, it is necessary to separate the tumor from the adjacent organs. Surgical placement of a GORE-TEX sheet as a spacer has been reported as a separation method. Usually, surgical spacer placement is done by open surgery. Here, we report a case of surgical spacer placement undertaken by a "pure" laparoscopic procedure. A 47-year-old man with recurrent sacral chordoma was referred for surgical spacer placement before CIRT. Laparoscopic dissection of the rectum and placement of a GORE-TEX sheet as a spacer were successfully performed. Surgical spacer placement by a pure laparoscopic procedure was safe and effective, and it seems to play an important part before CIRT.

Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin-treated rectal cancer: In situ visualization of platinum via synchrotron radiation X-ray fluorescence spectrometry.

Oxaliplatin (l-OHP), a platinum-based drug, is a key chemotherapeutic agent for colorectal cancer (CRC), but drug resistance and toxic effects have been major limitations of its use. Synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) is a rapid, nondestructive technique for monitoring the distribution of metals and trace elements in cells or tissue samples. We applied SR-XRF to visualize the distribution of platinum and other elements in 30 rectal cancer specimens resected from patients who received l-OHP-based preoperative chemotherapy and quantified platinum concentration in the tumor epithelium and stroma, respectively, using calibration curves. The platinum concentration in rectal cancer tissue ranged 2.85-11.44 ppm, and the detection limit of platinum was 1.848 ppm. In the tumor epithelium, the platinum concentration was significantly higher in areas of degeneration caused by chemotherapy than in nondegenerated area (p < 0.001). Conversely, in the tumor stroma, the platinum concentration was significantly higher in patients with limited therapeutic responses than in those with strong therapeutic responses (p < 0.001). Furthermore, multivariate analysis illustrated that higher platinum concentration in the tumor stroma was an independent predictive factor of limited histologic response (odds ratio; 19.99, 95% confidence interval; 2.04-196.37, p = 0.013). This is the first study to visualize and quantify the distribution of platinum in human cancer tissues using SR-XRF. These results suggest that SR-XRF analysis may contribute to predicting the therapeutic effect of l-OHP-based chemotherapy by quantifying the distribution of platinum.

Application of ultrasonography to high-tie and low-tie vascular ligation of the inferior mesenteric artery in laparoscopic colorectal cancer surgery: technical notes.

BACKGROUND: Two ligation techniques can be applied in laparoscopy for left-sided colorectal cancer: (1) high-tie (HT), transection at the level of the inferior mesenteric artery (IMA); and (2) low-tie (LT), transection below the IMA, at the level of superior rectal artery (SRA), preserving the left colic artery (LCA). However, even with preoperative images, it can still be a challenge to identify these structures due to intraoperative individual conditions. In this study, we assess the use intraoperative ultrasonography (IOUS) to aid us in identifying the IMA and its branches to the SRA, LCA, and sigmoid artery. METHODS: We performed IOUS in 18 patients diagnosed with left-sided colorectal cancer. Preoperatively, a three-dimensional computed tomography (3D-CT) angiography was obtained in majority of the patients, to visualize the IMA and its branches. Two patients were contraindicated to receive a contrast study, hence, was unable to undergo 3D-CT angiography. The resected specimen was grossly examined for the study. The bifurcation types were identified and compared using different modalities: preoperative 3D-CT, IOUS, and gross examination of the resected specimen. RESULTS: The branching of the IMA revealed by IOUS was consistent to the findings preoperatively by the 3D-CT and postoperatively by the resected specimen. The IOUS result of the two patients without preoperative 3D-CT evaluation was also consistent with the post-operative bifurcation type. CONCLUSIONS: IOUS is an easy and feasible modality which aids in detecting the branching of the IMA during LT and HT ligation in laparoscopic left-sided colorectal surgery. It can serve as an adjunct modality for 3D-CT angiography and can also be considered a safe alternative option for cases wherein 3D-CT angiography is unavailable.

Laparoscopic excision of neurogenic retrorectal tumors.

Retrorectal tumors (RT) are uncommon and usually managed by open surgical excision. Laparoscopic excision for RT has been reported in only a small number of papers. We aimed to assess the laparoscopic approach for RT and to discuss the factors that made this procedure difficult. We performed laparoscopic excision using a five-trocar technique for neurogenic RT in three patients. Tumors were successfully excised laparoscopically in two patients. However, the third patient required open conversion because the tumor was strongly adhered to the sacrum and could not be mobilized by dissection, resulting in poor visualization of the dissected site. Laparoscopic excision for RT provides excellent intraoperative visualization and good cosmesis in selected patients, but firm adherence to the sacrum may cause difficulty with this procedure.

IgG4-related sclerosing mesenteritis causing bowel obstruction: a case report.

Sclerosing mesenteritis (SM) is a rare inflammatory and fibrosing disease primarily involving the small-bowel mesentery. Recently, SM was reported to be closely related to IgG4-related disease (IgG4-RD). This report describes a patient with SM associated with IgG4-RD. A 77-year-old woman with a history of surgery for ectopic pregnancy and wound dehiscence presented with intestinal obstruction. Abdominal enhanced computed tomography (CT) revealed an enhanced, radially shaped, oval mass, 3 cm in diameter, with an unclear rim in the mesentery of the distal ileum, which may have involved the distal ileum. To remove the cause of bowel obstruction, the SM was resected completely and the ileum was resected partially. Histologic examination showed that the mass was composed of spindle cells arranged in a fascicular or storiform pattern; moreover, fibrous stroma was observed, with dense lymphoplasmacytic infiltration and lymphoid follicles. Immunohistochemically, numerous IgG4-positive plasma cells were observed, at a density of 253 per high-powered field, and the IgG4/IgG ratio was about 50 %. Elastica van Gieson (EVG) staining also showed obstructive phlebitis. These findings indicated IgG4-related SM. Although the accurate diagnosis of SM remains difficult without histological analysis, IgG4-RD should be included in the differential diagnosis of unknown mesenteric tumors. Identification of IgG4-RD may prevent unnecessary surgery because corticosteroids may be effective in these patients.

Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model.

Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction.

Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL.

Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P=0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.

Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer.

Pancreatic stellate cells (PSCs) enhance the malignant behavior of pancreatic cancer by interacting with cancer cells and producing extracellular matrix (ECM). To date, several stroma-targeted therapies for pancreatic cancer have been attempted, but these therapies are still not in practical use. Integrins expressed in stromal cells are involved in fibrosis of several organs, as well as promoting tumor malignancy. We investigated whether CD51, also known as integrin αV, expressed in PSCs was associated with stromal formation of pancreatic cancer and enhancement of tumor malignancy. We also assessed the effects of suppression of CD51 in PSCs on pancreatic cancer. Immunohistochemistry for CD51 in resected pancreatic cancer tissues showed that high expression of CD51 in the tumor stroma was associated with lymph node metastasis (P=0.025), positive pathologic margin (P=0.025), and shorter patient survival times (P=0.043). Lentivirus-mediated short hairpin RNA knockdown of CD51 decreased the proliferation and migration of PSCs. Quantitative real-time polymerase chain reaction showed that expression levels of genes related with ECM and tumor-stromal interactions were decreased by CD51 knockdown in PSCs. In a co-implantation model of pancreatic cancer cells and PSCs, tumor growth in vivo was inhibited by CD51 knockdown in PSCs (P<0.05). We also found reduced tumor stroma and decreased proliferation of cancer cells in implanted cancer tissues with CD51-silenced PSCs (P<0.05). Our results showed that CD51 expression in pancreatic cancer stroma is associated with enhanced tumor malignancy and that CD51 may be a potential therapeutic target for pancreatic cancer.

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes.

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.

Genome-wide association study identifies three novel loci for type 2 diabetes.

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

Kindlin-2 expression in peritumoral stroma is associated with poor prognosis in pancreatic ductal adenocarcinoma.

OBJECTIVES: Kindlin-2 is a novel focal adhesion protein reported to be expressed in breast, lung, and gastric cancers. This study aimed to investigate the significance of kindlin-2 expression in pancreatic ductal adenocarcinomas (PDACs). METHODS: We performed immunohistochemical analysis on kindlin-2 on PDAC samples from 95 patients. We investigated the association between kindlin-2 expression and clinicopathological parameters of PDAC and the survival time of patients with PDAC who underwent pancreatectomy. RESULTS: Kindlin-2 was highly expressed in the peritumoral stroma of PDACs. Stromal kindlin-2 expression was related to nodal metastasis (P = 0.03). Univariate analysis showed that patients with positive kindlin-2 expression had significantly shorter survival times than those with negative kindlin-2 expression (P = 0.01). In addition, multivariate analysis revealed that kindlin-2 expression was an independent factor of poor prognosis in patients with PDAC after R0 resection (RR = 2.15; P = 0.04). CONCLUSIONS: Kindlin-2 expression in stromal components is significantly associated with poor prognosis of patients with PDAC, suggesting that kindlin-2 is a prognostic marker for patients with PDAC.

Apolipoprotein C-II deficiency with no rare variant in the APOC2 gene.

AIM: Familial apolipoprotein C-II (apoC-II) deficiency is a rare autosomal recessive disorder with marked hypertriglyceridemia resulting from impaired activation of lipoprotein lipase. In most cases of apoC-II deficiency, causative mutations have been found in the protein-coding region of APOC2; however, several atypical cases of apoC-II deficiency were reported to have markedly reduced, but detectable levels of plasma apoC-II protein (hereafter referred to as hypoapoC-II), which resulted from decreased promoter activity or improper splicing of apoC-II mRNA due to homozygous mutations in APOC2. Here we aim to dissect the molecular bases of a new case of hypoapoC-II. METHODS: We performed detailed biochemical/genetic analyses of our new case of hypoapoC-II, manifesting severe hypertriglyceridemia (plasma triglycerides, 3235 mg·dL(-1)) with markedly reduced levels of plasma apoC-II (0.6 mg·dL(-1)). RESULTS: We took advantage of a monocyte/macrophage culture system to prove that transcription of apoC-II mRNA was decreased in the patient's cells, which is compatible with the reported features of hypoapoC-II. Concomitantly, transcriptional activity of the minigene reporter construct of the patient's APOC2 gene was decreased; however, no rare variant was detected in the patient's APOC2 gene. Fifty single nucleotide variants were detected in the patient's APOC2, but all were common variants (allele frequencies ＞35%) that are supposedly not causative. CONCLUSIONS: A case of apoC-II deficiency was found that is phenotypically identical to hypoapoC-II but with no causative mutations in APOC2, implying that other genes regulate apoC-II levels. The clinical entity of hypoapoC-II is discussed.

Kindlin-1 expression is involved in migration and invasion of pancreatic cancer.

Kindlin-1 is a novel focal adhesion protein that belongs to the kindlin family. Expression of kindlin-1 has recently been reported in lung and colon cancers, but there have been no studies on its expression in pancreatic cancer. This study aimed to investigate the expression and function of kindlin-1 in pancreatic cancer. Quantitative RT-PCR of Kindlin-1 mRNA was performed in various pancreatic cancer cell lines as well as normal pancreatic epithelial cells and fibroblasts. Immunohistochemical analysis of kindlin-1 was performed for pancreatic cancer tissues. The effects of kindlin-1 on the proliferation, migration and invasion of pancreatic cancer cells were investigated using an RNA interference technique. Kindlin-1 mRNA was highly expressed in the pancreatic cancer cell lines, but only slightly expressed in normal pancreatic epithelial cells and fibroblasts. The Kindlin-1 protein was heterogeneously expressed in the cytoplasm and membrane of pancreatic cancer cells, while normal ductal epithelial cells and stromal cells showed no expression. In vitro experiments involving knockdown of kindlin-1 in AsPC-1 and KP-2 cells revealed that the migratory and invasive abilities of the cells were significantly decreased (P<0.001), while the proliferation abilities were not affected. The present findings suggest that kindlin-1 expression is involved in the progression of pancreatic cancer via enhancement of cell migration and invasion.

Variations with modest effects have an important role in the genetic background of type 2 diabetes and diabetes-related traits.

The aim of the present study was to explore the role of variations with modest effects (previously identified by a large-scale meta-analysis in European populations) in the genetic background of type 2 diabetes (T2D) and diabetes-related traits in a Japanese population. We enrolled 2632 Japanese subjects with T2D and 2050 non-diabetic subjects. We analyzed nine single-nucleotide polymorphisms (SNPs), including rs340874 (PROX1), rs4607517 (GCK), rs2191349 (DGKB-TMEM195), rs7034200 (GLIS3), rs10885122 (ADRA2A), rs174550 (FADS1), rs11605924 (CRY2), rs10830963 (MTNR1B) and rs35767 (IGF1). rs340874 (PROX1) and rs174550 (FADS1) were significantly associated with T2D (P=0.0078, OR: 1.12; and P=0.0071, OR: 1.12, respectively). Subjects with more risk alleles related to nine SNPs had an increased risk of T2D (P=0.0017), as well as a higher fasting plasma glucose level (P=0.018), higher HbA(1c) level (P=0.013) and lower HOMA-ß (P=0.033) compared with subjects who had fewer risk alleles. We identified a significant association of a SNP of FADS1 and a SNP near PROX1 with T2D in a Japanese population. The present findings suggest that inclusion of SNPs with a tendency to increase the disease risk captured more of the genetic background of T2D than that revealed by only assessing significant SNPs.

Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals.

OBJECTIVE: We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes. RESEARCH DESIGN AND METHODS: We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to ß-cell function (ß-GRS) and then assessing the association between each GRS and the clinical features. RESULTS: Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10(-21)). Among the subjects with type 2 diabetes, the ß-GRS was associated with individuals receiving insulin therapy (ß = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (ß = -0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (ß = -0.032, SE = 0.0140, P = 0.022), and C-peptide index (ß = -0.031, SE = 0.012, P = 0.0125). CONCLUSIONS: Our data suggest that the ß-GRS is associated with reduced ß-cell functions and may be useful for selecting patients who should receive more aggressive ß-cell-preserving therapy.

A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations.

To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.