The CFTR gene variants in Japanese children with idiopathic pancreatitis

Iso, Manami; Suzuki, Mitsuyoshi; Yanagi, Kumiko; Minowa, Kei; Sakurai, Yumiko; Nakano, Satoshi; Satou, Kazuhito; Shimizu, Toshiaki; Kaname, Tadashi

doi:10.1038/s41439-019-0049-7

Cited by 11 publications

(5 citation statements)

References 29 publications

(64 reference statements)

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“…The comprehensive systematic search and selection process identified 22 case-control studies that reported on some or all of the 9 CFTR BD variants and met the inclusion criteria for quantitative synthesis (Fig 1) [9,11,12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. We noted significant geographic/ethnic differences in the distribution of the CFTR BD variants.…”

Section: Resultsmentioning

confidence: 99%

Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Berke

Gede²,

Szadai³

et al. 2022

PLoS ONE

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Introduction Cystic fibrosis transmembrane conductance regulator (CFTR) plays a central role in pancreatic ductal fluid secretion by mediating Cl- and HCO3- ion transport across the apical membrane. Severe CFTR mutations that diminish chloride conductance cause cystic fibrosis (CF) if both alleles are affected, whereas heterozygous carrier status increases risk for chronic pancreatitis (CP). It has been proposed that a subset of CFTR variants characterized by a selective bicarbonate conductance defect (CFTRBD) may be associated with CP but not CF. However, a rigorous genetic analysis of the presumed association has been lacking. Aims To investigate the role of heterozygous CFTRBD variants in CP by meta-analysis of published case-control studies. Materials and methods A systematic search was conducted in the MEDLINE, Embase, Scopus, and CENTRAL databases for published studies that reported the CFTRBD variants p.R74Q, p.R75Q, p.R117H, p.R170H, p.L967S, p.L997F, p.D1152H, p.S1235R, and p.D1270N in CP patients and controls. Results Twenty-two studies were eligible for quantitative synthesis. Combined analysis of the 9 CFTRBD variants indicated enrichment in CP patients versus controls (OR = 2.31, 95% CI = 1.17–4.56). Individual analysis of CFTRBD variants revealed no association of p.R75Q with CP (OR = 1.12, 95% CI = 0.89–1.40), whereas variants p.R117H and p.L967S were significantly overrepresented in cases relative to controls (OR = 3.16, 95% CI = 1.94–5.14, and OR = 3.88, 95% CI = 1.32–11.47, respectively). The remaining 6 low-frequency variants gave inconclusive results when analyzed individually, however, their pooled analysis indicated association with CP (OR = 2.08, 95% CI = 1.38–3.13). Conclusion Heterozygous CFTRBD variants, with the exception of p.R75Q, increase CP risk about 2-4-fold.

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Section: Resultsmentioning

confidence: 99%

Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Berke

Gede²,

Szadai³

et al. 2022

PLoS ONE

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“…In addition, CFTR polymorphisms were believed to contribute to the genetic etiology of acute pancreatitis in young HTG Japanese patients (Fujita et al, 2022). The CFTR p.I566V was established most frequently in idiopathic and acute pancreatitis patients in the Chinese and Japanese populations (Chang et al, 2007;Iso et al, 2019). In the first study of the relationship between CFTR variants and hyperlipidemic pancreatitis, p.I566V was the most common variant present in patients with HTG with the onset of hyperlipidemic pancreatitis (HLP) compared with patients with HTG who do not have HLP (Chang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Variants APOA5 p.G185C and p.S19W associated with early-onset severe hypertriglyceridemia-induced pancreatitis and diabetes complications in a Vietnamese girl

Hong Thu,

Thuy Linh,

Huyen Thuong

et al. 2024

Vietnam J. Biotechnol.

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An imbalance of glucose and severely high triglyceride are the key characteristics driving hypertriglyceridemia and hyperlipidemic pancreatitis. Hereditary factors considerably promote the increase of triglyceride levels and secondary complications. This study explored the clinical characteristics and genetic causes of a young girl with recurrent severe hypertriglyceridemia-developed pancreatitis at 9-year-olds and diabetes mellitus appearance at 14-year-olds. At 20 years old, she was admitted to the hospital in critical condition and had pancreatitis pain with triglyceride level at 26.22 mmol/L, HbA1c 15%, and glucose at 21.3 mmol/L. Whole exome sequencing analysis showed that she had two heterozygous variants of the APOA5 gene, (p.G185C and p.S19W), one homozygous variant of the APOE gene (p.C156R), which were previously reported to cause critical hypertriglyceridemia condition of patients. The results and analysis propose these variations were the underlying causes of a heightened of patient's plasma triglycerides and lead metabolic complication onset at a young age. These findings shed light on the molecular mechanism of her elevated plasma triglyceride and the early onset of diabetes following hyperlipidemic pancreatitis.

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“…Participants comprised 90 Japanese patients (50 girls, 40 boys) with ARP or CP, all of whom were under 15 years old; median age at onset, 8.0 years (range, 2–15 years). A total of 63 of the 90 patients had already been identified as having variants in at least 1 of PRSS1 , SPINK1 , CFTR , CTRC , or CPA1 (19,20), so 27 newly unreported cases were included in this study (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

The Coexistence of TRPV6 Variants With Other Pancreatitis-Associated Genes Affects Pediatric-Onset Pancreatitis

Hirai

Suzuki

Sakurai

et al. 2023

Journal of Pediatric Gastroenterology &Amp; Nutrition

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Objectives: Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). Interestingly, 20%–57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen, serine protease inhibitor Kazal type 1, chymotrypsin C, cystic fibrosis transmembrane conductance regulator, and carboxypeptidase A1. In this study, we focused on pediatric patients with acute recurrent pancreatitis or CP with at least 1 variant in these 5 genes and investigated the presence of coexisting TRPV6 mutations. Methods: Ninety Japanese pediatric patients (median age at first onset, 8.0 years) who had at least 1 variant of these 5 genes were enrolled in this study. DNA samples were extracted for analysis from peripheral blood leukocytes. Coding regions of TRPV6 were screened by Sanger sequencing. Results: Regardless of functional defects or non-defects in TRPV6 variants, 14 of the 90 patients (15.6%) were trans-heterozygous for TRPV6 variants [p.A18S (n = 3), p.C197R (n = 3), p.I223T (n = 3), p.D324N (n = 4), p.M418V (n = 3), p.V540F (n = 1), p.A606T (n = 1), and p.M721T (n = 3)] and the 5 susceptibility genes noted above. Of these variants, p.D324N, p.V540F, and p.A606T are associated with pancreatitis. Three patients had the ancestral haplotype [p.C197R + p.M418V + p.M721T]. Conclusions: Overall, 4 of 90 patients (4.4%) had the coexistence of clearly pathogenic TRPV6 variants with pancreatitis-associated variants. The cumulative accumulation of these genetic factors may contribute to the development of pancreatitis at a young age.

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The CFTR gene variants in Japanese children with idiopathic pancreatitis

Cited by 11 publications

References 29 publications

Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis

Variants APOA5 p.G185C and p.S19W associated with early-onset severe hypertriglyceridemia-induced pancreatitis and diabetes complications in a Vietnamese girl

The Coexistence of TRPV6 Variants With Other Pancreatitis-Associated Genes Affects Pediatric-Onset Pancreatitis

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