Common and rare exonic MUC5B variants associated with type 2 diabetes in Han Chinese

Chen, Guanjie; Zhang, Zhenjian; Adebamowo, Sally N.; Liu, Guozheng; Adeyemo, Adebowale; Zhou, Yanxun; Doumatey, Ayo P.; Wang, Chuntao; Zhou, Jie; Yan, Wenqiang; Shriner, Daniel; Tekola‐Ayele, Fasil; Bentley, Amy R.; Jiang, Congqing; Rotimi, Charles N.

doi:10.1371/journal.pone.0173784

Cited by 11 publications

(4 citation statements)

References 63 publications

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“…However, the effects of this SNP on the expression of MUC5B in ATII cells is unclear. The previous study showed that the expression of MUC5B was significantly elevated in pancreatic tissue of patients with T2DM compared to those without T2DM ( 38 ), therefore, we speculated that MUC5B rs2943512 (A>C) might cause the over-expression of MUC5B in lung tissue of T2DM patients. Even beyond the potential influence of the genetic factor of MUC5B SNP rs2943512, whether high glucose itself could cause the over-expression of MUC5B to mediate ATII cells injury and thus trigger pulmonary fibrosis is unclear.…”

Section: Discussionmentioning

confidence: 90%

Clinical characteristics and genetic analysis of a Chinese pedigree of type 2 diabetes complicated with interstitial lung disease

Zhang

Wang²,

Tian³

et al. 2023

Front. Endocrinol.

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PurposeDiabetes mellitus is a systemic metabolic disorder which may target the lungs and lead to interstitial lung disease. The clinical characteristics and mechanisms of type 2 diabetes mellitus (T2DM) complicated with interstitial lung disease (ILD) have been studied. However, little work has been done to assess genetic contributions to the development of T2DM complicated with ILD.MethodA pedigree of T2DM complicated with ILD was investigated, and the whole genome re-sequencing was performed to identify the genetic variations in the pedigree. According to the literature, the most valuable genetic contributors to the pathogenesis of T2DM complicated with ILD were screened out, and the related cellular functional experiments were also performed.ResultsA large number of SNPs, InDels, SVs and CNVs were identified in eight subjects including two diabetic patients with ILD, two diabetic patients without ILD, and four healthy subjects from the pedigree. After data analysis according to the literature, MUC5B SNP rs2943512 (A > C) was considered to be an important potentially pathogenic gene mutation associated with the pathogenesis of ILD in T2DM patients. In vitro experiments showed that the expression of MUC5B in BEAS-2B cells was significantly up-regulated by high glucose stimulation, accompanied by the activation of ERK1/2 and the increase of IL-1β and IL-6. When silencing MUC5B by RNA interference, the levels of p-ERK1/2 as well as IL-1β and IL-6 in BEAS-2B cells were all significantly decreased.ConclusionThe identification of these genetic variants in the pedigree enriches our understanding of the potential genetic contributions to T2DM complicated with ILD. MUC5B SNP rs2943512 (A > C) or the up-regulated MUC5B in bronchial epithelial cells may be an important factor in promoting ILD inT2DM patients, laying a foundation for future exploration about the pathogenesis of T2DM complicated with ILD.

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Section: Discussionmentioning

confidence: 90%

Clinical characteristics and genetic analysis of a Chinese pedigree of type 2 diabetes complicated with interstitial lung disease

Zhang

Wang²,

Tian³

et al. 2023

Front. Endocrinol.

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“…We conducted an African ancestry T2D meta-analysis that included this GWAS and an African American meta GWAS 7 consisting of five studies ( n = 8599); the Atherosclerosis Risk in Communities (ARIC), the Cleveland Family Study (CFS), the Howard University Family Study (HUFS), Jackson Heart Study (JHS), and Multi-Ethnic Study of Atherosclerosis (MESA). This African ancestry meta-analysis revealed four genome-wide significant loci (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

et al. 2019

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Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10 −9 ). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.

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“…Individual-level genotype and phenotype data were obtained by authorized access to dbGaP. The China America Diabetes Mellitus (CADM) study is a case-control study of T2D in China [17]. The Africa America Diabetes Mellitus (AADM) study is a case-control study of type 2 diabetes in Africans [18,19].…”

Section: Replication Analysismentioning

confidence: 99%

Additive genetic effect of GCKR, G6PC2, and SLC30A8 variants on fasting glucose levels and risk of type 2 diabetes

et al. 2022

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Impaired glucose tolerance is a major risk factor for type 2 diabetes (T2D) and several cardiometabolic disorders. To identify genetic loci underlying fasting glucose levels, we conducted an analysis of 9,232 individuals of European ancestry who at enrollment were either nondiabetic or had untreated type 2 diabetes. Multivariable linear mixed models were used to test for associations between fasting glucose and 7.9 million SNPs, with adjustment for age, body mass index (BMI), sex, significant principal components of the genotypes, and cryptic relatedness. Three previously discovered loci were genome-wide significant, with the lead SNPs being rs1260326, a missense variant in GCKR (p = 1.06×10−8); rs560887, an intronic variant in G6PC2 (p = 3.39×10−11); and rs13266634, a missense variant in SLC30A8 (p = 4.28×10−10). Fine mapping, genome-wide conditional analysis, and functional annotation indicated that the three loci were independently associated with fasting glucose. Each copy of an alternate allele at any of these three SNPs was associated with a reduction of 0.012 mmol/L in fasting glucose levels (p = 8.0×10−28), and this association was replicated in trans-ethnic analysis of 14,303 individuals (p = 2.2×10−16). The three SNPs were jointly associated with significantly reduced T2D risk, with an odds ratio (95% CI) of 0.93 (0.88, 0.98) per protective allele. Our findings implicate additive effects across pathophysiological pathways involved in type 2 diabetes, including glycolysis, gluconeogenesis, and insulin secretion. Since none of the individuals homozygous for the alternate alleles at all three loci has T2D, it might be possible to use a genetic predictor of fasting glucose levels to identify individuals at low vs. high risk of developing type 2 diabetes.

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Common and rare exonic MUC5B variants associated with type 2 diabetes in Han Chinese

Cited by 11 publications

References 63 publications

Clinical characteristics and genetic analysis of a Chinese pedigree of type 2 diabetes complicated with interstitial lung disease

Clinical characteristics and genetic analysis of a Chinese pedigree of type 2 diabetes complicated with interstitial lung disease

ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

Additive genetic effect of GCKR, G6PC2, and SLC30A8 variants on fasting glucose levels and risk of type 2 diabetes

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