Abstract:
:Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Chen G,Bentley A,Adeyemo A,Shriner D,Zhou J,Doumatey A,Huang H,Ramos E,Erdos M,Gerry N,Herbert A,Christman M,Rotimi Cdoi
10.1093/hmg/dds282subject
Has Abstractpub_date
2012-10-15 00:00:00pages
4530-6issue
20eissn
0964-6906issn
1460-2083pii
dds282journal_volume
21pub_type
杂志文章abstract::Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu406
更新日期:2014-12-20 00:00:00
abstract::Fragile X syndrome, a common cause of intellectual disability and autism, is due to mutational silencing of the FMR1 gene leading to the absence of its gene product, fragile X mental retardation protein (FMRP). FMRP is a selective RNA binding protein owing to two central K-homology domains and a C-terminal arginine-gl...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu586
更新日期:2015-03-15 00:00:00
abstract::The FMR1 gene, associated with fragile X syndrome, has recently been cloned and the sequence of partial cDNA clones is known. We have determined additional cDNA sequences both at the 5' and 3' end. We have characterized the expressed gene by means of RT-PCR in various tissues and have found that alternative splicing t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.4.399
更新日期:1993-04-01 00:00:00
abstract::Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv483
更新日期:2016-02-01 00:00:00
abstract::Migraine affects ∼14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sample Mendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine heada...
journal_title:Human molecular genetics
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1093/hmg/ddw416
更新日期:2017-02-15 00:00:00
abstract::Amelogenesis imperfecta (AI) describes a broad group of clinically and genetically heterogeneous inherited defects of dental enamel bio-mineralization. Despite identification of a number of genetic mutations underlying AI, the precise causal mechanisms have yet to be determined. Using a multi-disciplinary approach, we...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq001
更新日期:2010-04-01 00:00:00
abstract::The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy146
更新日期:2018-07-15 00:00:00
abstract::Mutations in RP2 cause the second most frequent form of X-linked retinitis pigmentosa, a severe retinal degeneration that leads to loss of visual acuity and blindness. The RP2 gene encodes a protein with homology to cofactor C, a tubulin-folding chaperone. By searching protein sequence databases, we identified a whole...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.11.1177
更新日期:2001-05-15 00:00:00
abstract::Genomic data offer a goldmine of information for understanding the contribution of genetic variation makes to health and disease. The potential of genomic medicine, to predict, diagnose, manage and treat genetic disease, is underpinned by accurate variant interpretation. This in itself hinges on the ability to access ...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddy084
更新日期:2018-05-01 00:00:00
abstract::Adoptively transferred antigen-specific T cells that recognize tumor antigens through their native receptors have many potential benefits as treatment for virus-associated diseases and malignancies, due to their ability to selectively recognize tumor antigens, expand and persist to provide long-term protection. Infusi...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddv270
更新日期:2015-10-15 00:00:00
abstract::Huntington's disease (HD) is caused by a pathological expansion of a CAG repeat in the first exon of the gene coding for huntingtin, resulting in an abnormally long polyglutamine stretch. Despite its widespread expression, mutant huntingtin leads to selective neuronal loss in the striatum and cortex. Here we report th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.21.2547
更新日期:2002-10-01 00:00:00
abstract::Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (αDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective αDG glycosylation and reduced ligand binding by α...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt021
更新日期:2013-05-01 00:00:00
abstract::Most quantitative trait loci (QTL) studies have focused on detecting the genetic effects of individual QTLs. This study thoroughly dissected the genetic components of type 2 diabetic mice, including a search for epistatic interactions and multi-locus additive effects that result in variation in diabetes-related phenot...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi433
更新日期:2006-01-01 00:00:00
abstract::Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu199
更新日期:2014-09-15 00:00:00
abstract::Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding v...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt365
更新日期:2013-12-20 00:00:00
abstract::The fragile X syndrome is characterized at the molecular level by expansion and methylation of a CGG trinucleotide repeat located within the FMR1 locus. The tissues of most full mutation carriers are mosaic for repeat size, but these mutational patterns tend to be well conserved when comparing multiple tissues within ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.12.2293
更新日期:1999-11-01 00:00:00
abstract::The deposition of amyloid-beta (Aβ) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Aβ is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by γ-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notc...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu449
更新日期:2015-01-15 00:00:00
abstract::A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw094
更新日期:2016-06-01 00:00:00
abstract::Focal facial dermal dysplasia (FFDD) Type IV is a rare syndrome characterized by facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. To identify the causative gene(s), exome sequencing was performed in a family with two affected s...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds477
更新日期:2013-02-15 00:00:00
abstract::Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor gene on 22q...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.10.1495
更新日期:2000-06-12 00:00:00
abstract::The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expres...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt034
更新日期:2013-05-01 00:00:00
abstract::Changes to islet cell identity in response to type 2 diabetes (T2D) have been reported in rodent models, but are less well characterized in humans. We assessed the effects of aspects of the diabetic microenvironment on hormone staining, total gene expression, splicing regulation and the alternative splicing patterns o...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz094
更新日期:2019-08-15 00:00:00
abstract::Lysosomal storage diseases are due to inherited deficiencies in various enzymes involved in basic metabolic processes. As with other genetic diseases, accurate structure data for these enzymatic proteins should help in better understanding the molecular effects of mutations identified in patients with the correspondin...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/9.6.967
更新日期:2000-04-12 00:00:00
abstract::The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD) is causally related to a short Eco RI fragment detected by probe p13E-11. This remnant fragment is the result of a deletion of an integral number of tandemly arrayed 3.3 kb repeat units (D4Z4) on 4q35. Despite intensive efforts, no transcrib...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.8.1207
更新日期:1998-08-01 00:00:00
abstract::Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotid...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt460
更新日期:2014-02-01 00:00:00
abstract::NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and li...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg321
更新日期:2003-11-15 00:00:00
abstract::Retinitis pigmentosa (RP), a genetically heterogeneous group of retinopathies that occur in both non-syndromic and syndromic forms, is caused by mutations in ∼100 genes. Although recent advances in next-generation sequencing have aided in the discovery of novel RP genes, a number of the underlying contributing genes a...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu291
更新日期:2014-11-01 00:00:00
abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major path...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx214
更新日期:2017-09-01 00:00:00
abstract::The MELAS syndrome is a mitochondrial encephalomyopathy associated with a point mutation at nucleotide 3243 of mitochondrial DNA (mtDNA). The same mutation has also been found in patients with maternally inherited diabetes mellitus. The mutation occurs within a sequence needed for termination of mitochondrial transcri...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.5.525
更新日期:1993-05-01 00:00:00
abstract::Lung cancer demonstrates the highest mortality in the UK. Previous studies have implicated allelic loss at chromosome 17q in the development of non-small cell lung carcinoma (NSCLC), and a number of known and putative tumour-suppressor genes reside within this region. One candidate tumour-suppressor gene is cytoglobin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl128
更新日期:2006-07-01 00:00:00