Genetic Modifiers of the Age at Diagnosis of Diabetes (MODY3) in Carriers of Hepatocyte Nuclear Factor-1α Mutations Map to
Chromosomes 5p15, 9q22, and 14q24
Sung-Hoon Kim 1 2 ,
Xiaowei Ma 1 2 ,
...Tomasz Klupa 1 2 ,
Christine Powers 1 ,
Marcus Pezzolesi 1 ,
James H. Warram 1 ,
Stephen S. Rich 3 ,
Andrzej S. Krolewski 1 2 and
Alessandro Doria 1 2
1 Research Division, Joslin Diabetes Center, Boston, Massachusetts
2 Department of Medicine, Harvard Medical School, Boston, Massachusetts
3 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to Alessandro Doria, MD, PhD, Section on Genetics and Epidemiology, Joslin Diabetes
Center, One Joslin Place, Boston, MA 02215. E-mail: alessandro.doria{at}joslin.harvard.edu
Abstract
Mutations in hepatocyte nuclear factor (HNF)-1α (MODY3) account for the largest proportion of maturity-onset diabetes of the
young (MODY) cases in the U.S. This form of diabetes is characterized by impaired insulin secretion in response to glucose,
but wide variability exists in the severity of hyperglycemia and in the age at which it becomes clinically manifest. We have
previously shown that the age at onset of diabetes in MODY3 families is influenced by familial factors (including modifying
genes) and exposure to diabetes in utero. To identify genes influencing the onset of MODY3, we conducted a genome scan in
13 extended MODY families in which diabetes segregates with an HNF-1α mutation. Linkage with age at onset of diabetes was
assessed by genetic variance component analysis using SOLAR. The locus with the strongest evidence of linkage was on chromosome
14q24 (D14S588; logarithm of odds LOD = 2.58, P = 0.0004). This location overlaps with IDDM11 and includes SEL1L , a negative regulator of the Notch pathway that may control islet development. Linkage evidence also supported loci on 5p15
(D5S817; LOD = 2.44, P = 0.0004) and 9q22 (D9S910; LOD = 2.02, P = 0.0018). The latter matches a region linked to 2-h insulin levels in Pima Indians. Less strong linkage evidence was observed
at three other regions: chromosomes 3p24 (LOD = 1.44), 7q21 (1.20), and 16q23 (1.51). Our data are consistent with the existence
of multiple loci that contribute to the expression of the MODY3 phenotype. Identification of these genes will offer new insights
into the pathophysiology of MODY that may, in turn, increase our understanding of the cellular events underlying more common
forms of diabetes.
HNF, hepatocyte nuclear factor
IGT, impaired glucose tolerance
LOD, logarithm of odds
MODY, maturity-onset diabetes of the young
Ngn3, neurogenin 3
OGTT, oral glucose tolerance test
WHO, World Health Organization
Footnotes
Current affiliation for S.-H.K.: Division of Endocrinology, Samsung Cheil Hospital and Women’s Healthcare Center, Sungkyunkwan
University School of Medicine, Seoul, Korea.
Accepted May 12, 2003.
Received February 7, 2003.
DIABETES
Abstract only
Introduction:
Sex differences in the systolic blood pressure (SBP) trajectories have been described previously. However, the contribution of underlying genetic architecture to the sex ...associated differences in SBP trajectories has not been assessed.
Methods:
Multiancestry sex-specific SBP polygenic risk scores (SBP-PRS), accumulating 1.1 million variants each, were calculated in the participants of the ARIC, JHS, CARDIA, CHS, MESA, FHS, and JHS who underwent whole genome sequencing under the TransOmics for Precision Medicine Program. Based on the SBP-PRS, the cohort was stratified into low (<20
th
centile), intermediate (20
th
-80
th
centile), and high (>80
th
centile) genetic risk of SBP. For individuals on antihypertensive medications, SBP measurements were corrected by adding 15 mmHg. Multivariable adjusted restricted cubic splines were used to depict the non-linear relationship of SBP with age in each sex separately. Bootstrapping using 1000 samples was used to estimate the age and 95% CIs at which the sex-specific SBP trajectories crossed over in each SBP-PRS group.
Results:
In this study of 21,542 individuals (median age: 56 years; 56.0% females; 35.8% non-White individuals), the non-linear association of SBP with age varied by sex (P
interaction
: <0.001) and SBP-PRS groups (P
interaction
: 0.05). On stratifying by SBP-PRS, females had a higher age-related increase in SBP compared with males across the groups (p<0.001 in low, intermediate, and high SBP-PRS groups). The age at which the SBP in females surpassed that of males progressively decreased with increasing genetic risk of SBP low: 66.7 (66.4-67.0) years, intermediate: 64.3 (64.1-64.6) years, high: 55.8 (54.4-57.1) years; p: <0.001. In the high SBP-PRS group, the sex-associated differences in SBP trajectories were modest with females and males having nearly similar SBP values in old age.
Conclusion:
The underlying genetic architecture may contribute to sex difference of SBP trajectories.
The molecular basis for the genetic risk of ischemic stroke is likely to be multigenic and influenced by environmental factors. Several small case-control studies have suggested associations between ...ischemic stroke and polymorphisms of genes that code for coagulation cascade proteins and platelet receptors. Our aim is to investigate potential associations between hemostatic gene polymorphisms and ischemic stroke, with particular emphasis on detailed characterization of the phenotype.
The Ischemic Stroke Genetic Study is a prospective, multicenter genetic association study in adults with recent first-ever ischemic stroke confirmed with computed tomography or magnetic resonance imaging. Patients are evaluated at academic medical centers in the United States and compared with sex- and age-matched controls. Stroke subtypes are determined by central blinded adjudication using standardized, validated mechanistic and syndromic classification systems. The panel of genes to be tested for polymorphisms includes beta-fibrinogen and platelet glycoprotein Ia, Iba, and IIb/IIIa. Immortalized cell lines are created to allow for time- and cost-efficient testing of additional candidate genes in the future.
The study is designed to minimize survival bias and to allow for exploring associations between specific polymorphisms and individual subtypes of ischemic stroke. The data set will also permit the study of genetic determinants of stroke outcome. Having cell lines will permit testing of future candidate risk factor genes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the ...pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
Twinship and Risk of Postmenopausal Breast Cancer Cerhan, James R.; Kushi, Lawrence H.; Olson, Janet E. ...
JNCI : Journal of the National Cancer Institute,
02/2000, Letnik:
92, Številka:
3
Journal Article
Recenzirano
Odprti dostop
BACKGROUND: Intrauterine exposure to high levels of endogenous estrogens has been hypothesized to increase the risk of breast cancer. Because estrogens and other pregnancy hormones are substantially ...elevated in twin pregnancies, and possibly more so in dizygotic twin pregnancies, we evaluated the association between aspects of twin membership (i.e., belonging to a twin pair) and the risk of breast cancer. METHODSs: In a cohort of 29 197 postmenopausal Iowa women with no prior diagnosis of cancer (except for nonmelanoma skin cancer), breast cancer risk factors were determined by use of a mailed questionnaire in 1986 (baseline); twin membership, sex of the twin, and zygosity were determined by use of a follow-up questionnaire in 1992. RESULTS: Within the cohort, 1.8% (n = 538) of the women reported being a twin; of these, 24% (n= 130) were monozygotic twins, 63% (n = 337) were dizygotic twins, and 13% (n = 71) did not know their zygosity. From 1986 through 1996, 1230 breast cancers in the cohort were ascertained by linkage to the Iowa Cancer Registry. Compared with singletons, women who belonged to a twin pair were at elevated risk of breast cancer (multivariate-adjusted risk ratio RR = 1.72; 95% confidence interval CI = 1.22-2.42), with adjustment for educational level, family history of breast cancer, height, body mass index, body fat distribution, age at menarche, age at first live birth, use of hormone replacement therapy, and alcohol use. Multivariate-adjusted risk was elevated (in comparison with singletons) if the sex of the other twin was female (RR = 1.82; 95% CI= 1.20-2.75); however, this risk was limited to female dizygotic twins (RR = 2.14; 95% CI= 1.21-3.79), since no excess risk was evident for monozygotic twins (RR = 1.04; 95% CI = 0.43-2.50). The risk to women with a male twin was also elevated (RR= 1.49; 95% CI = 0.80-2.78) in comparison with singletons, but this estimate was not statistically significant. CONCLUSIONS: This cohort study lends further support to the theory that there are important intrauterine influences on carcinogenesis of the breast.
Summary
Elevated C‐reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for ...association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib‐ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes‐affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African‐American (16%), 53% female, and had an average age of 62.2 ± 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin‐use and anti‐inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed.
The increasing number of genetic association studies conducted in multiple populations provides an unprecedented opportunity to study how the genetic architecture of complex phenotypes varies between ...populations, a problem important for both medical and population genetics. Here, we have developed a method for estimating the transethnic genetic correlation: the correlation of causal-variant effect sizes at SNPs common in populations. This methods takes advantage of the entire spectrum of SNP associations and uses only summary-level data from genome-wide association studies. This avoids the computational costs and privacy concerns associated with genotype-level information while remaining scalable to hundreds of thousands of individuals and millions of SNPs. We applied our method to data on gene expression, rheumatoid arthritis, and type 2 diabetes and overwhelmingly found that the genetic correlation was significantly less than 1. Our method is implemented in a Python package called Popcorn.
Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared ...3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Endoglin is an accessory receptor molecule that, in association with transforming growth factor β (TGF-β) family receptors Types I and II, binds TGF-β1, TGF-β3, activin A, bone morphogenetic ...protein (BMP)-2 and BMP-7, regulating TGF-β dependent cellular responses. Relevant to diabetic nephropathy, endoglin, expressed in vascular endothelial and smooth muscle cells, fibroblasts, and mesangial cells, negatively regulates extracellular matrix (ECM). The aim of this study was to evaluate endoglin expression in cultured skin fibroblasts from patients with Type 1 diabetes with and without diabetic nephropathy. Kidney and skin biopsies were performed in 125 Type 1 diabetic patients. The 20 with the fastest rate of mesangial expansion (estimated by electron microscopy) and proteinuria (“fast-track”) and the 20 with the slowest rate and normoalbuminuria (“slow-track”), along with 20 controls were studied. Endoglin mRNA expression was assessed by microarray and quantitative real-time polymerase chain reaction (QRT-PCR) and protein expression by Western blot. Age and sex distribution were similar among groups. Diabetes duration was similar (20±8 vs. 24±7 years), hemoglobin A1c lower (8.4±1.2% vs. 9.4±1.5%), and glomerular filtration rate higher (115±13 vs. 72±20 ml/min per 1.73 m2 ) in slow-track vs. fast-track patients. Microarray endoglin mRNA expression levels were higher in slow-track (1516.0±349.9) than fast-track (1211.0±274.9; P =.008) patients or controls (1223.1±422.9; P =.018). This was confirmed by QRT-PCR. Endoglin protein expression levels correlated with microarray (r=0.59; P =.044) and QRT-PCR (r=0.61; P =.034) endoglin mRNA expression. These studies are compatible with the hypothesis that slow-track Type 1 diabetic patients, strongly protected from diabetic nephropathy, have distinct cellular behaviors that may be associated with reduced ECM production.
Abstract only Introduction: Even though various risk estimators are widely used to predict atherosclerosis from subclinical levels to hard CHD, there is a remarkable proportion of low-risk ...individuals with inordinately high coronary artery calcification (CAC) or with hard CHD events. Rare pathogenic variants (<0.1%) in the atherosclerosis gene panel with larger effect sizes may predispose low-risk individuals to develop atherosclerosis. Hypothesis: There are rare pathogenic variants in the atherosclerosis gene panel in low-ASCVD-risk individuals with high CAC scores or hard CHD events than low-risk individuals with a CAC score of zero or no events. Methods: The MESA whole-genome sequencing data (2000-02) was evaluated to capture variants in 224 atherosclerosis-related genes. Coding variants with a frequency of <0.1% in each racial/ethnic group and damaging effects were assessed by the ClinVar and ACMG-AMP guidelines for pathogenicity. Participants with an ASCVD score of <7.5% were defined as low risk. Two different case groups were defined based on (1) hard CHD events and (2) CAC scores higher than the 90 th percentile of age, sex, and race-adjusted reference scores. Associated control groups were age-, sex-, and race-matched participants with no CHD events or zero CAC score. Results: A total of 159 cases with high CAC and 1256 matched controls were evaluated within the low-risk group. In the case group, there were three rare, likely pathogenic variants ( LDLR c.681C>G, p.D227E and c.2026G>A, p.G676S; and AHI1 c.2168G>A, p.R723Q ) . None of these variants were observed in the control group. A total of 86 cases had a hard CHD event, among whom two had rare, likely pathogenic variants ( KCNQ1 c.517G>A, p.A173T and LDLR c.1201C>G, p.L401V). None of the 1546 controls had these variants. The LDLR c.1201C>G variant is currently a variant of uncertain significance that would be likely pathogenic with the assumption of genotype-phenotype specificity pathogenicity supporting criterion 4. Conclusions: We observed five likely pathogenic variants in atherosclerosis-related genes in low-risk individuals for ASCVD who had high CAC scores or hard CHD events. Rare variants with large effect sizes may unravel the missed risk prediction of a common trait like atherosclerosis.
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