Leslie J. Raffel

A functional variant of SUMO4, a new I|[kappa]|B|[alpha]| modifier, is associated with type 1 diabetes

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 × 10−7). SUMO4 conjugates to IκBα and negatively regulates NFκB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFκB transcriptional activity and ∼2 times greater expression of IL12B, an NFκB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Family history: A comprehensive genetic risk assessment method for the chronic conditions of adulthood

Targeting individuals with increased risk for common, chronic disease can improve the efficiency and efficacy of preventive efforts by improving the predictability of screening tests and participant compliance. Individuals with the greatest risk for these disorders are those with a genetic susceptibility. The purpose of this study was to determine the feasibility of using a single, comprehensive family history as a method for stratifying risk for many preventable, common genetic disorders. Family histories obtained in a prenatal diagnostic clinic were reviewed regarding cardiovascular diseases, diabetes and several cancers; 42.5% of individuals reported a family history for at least one of the disorders under study. Familial coronary artery disease was most commonly reported (29% of participants), followed by noninsulin-dependent diabetes (14%). Qualitative characterization of disease susceptibility was also accomplished using family history data. For example, occurrence of different cancers within pedigrees was suggestive of familial cancer syndromes, and clustering of noninsulin-dependent diabetes and cardiovascular disease suggested an insulin resistance syndrome. Depending on the specific disease, 5 to 15% of at-risk individuals had a moderately increased risk (2 to 5 times the population risk), and approximately 1 to 10% had a high risk (absolute risks approaching 50%). Family history reports of common, chronic disease are prevalent among the population at large, and collection and interpretation of comprehensive family history data is a feasible, initial method for risk stratification for many preventable, chronic conditions. These findings may have important implications for disease prevention and management.

Early Presentation of Type 2 Diabetes in Mexican-American Youth

OBJECTIVE To describe features of pediatric-onset type 2 diabetes in the Hispanic population. RESEARCH DESIGN AND METHODS The medical records of 55 Hispanic subjects with diabetes who were treated from 1990 to 1994 in a pediatric clinic serving lower income Mexican-Americans were reviewed to assess the frequency and clinical features of type 2 diabetes. Additionally, nondiabetic siblings of several patients underwent oral glucose tolerance testing, and a survey of six high schools in the same county was performed. RESULTS Seventeen of 55 (31%) of the diabetic children and adolescents had type 2 diabetes. An additional 4 Hispanic children with type 2 diabetes treated in other clinics were also identified, yielding a total of 21 subjects who were used to describe the characteristics of childhood type 2 diabetes. At presentation, all were obese (mean BMI 32.9 ± 6.2 kg/m2), 62% had no ketonuria, and fasting C-peptide levels were elevated (4.28 ± 3.43 ng/ml). Diabetes was easily controlled with diet, sulfonylureas, or low-dose insulin. No autoantibodies were present in those tested, and family histories were positive for type 2 diabetes. Compliance was poor, and 3 subjects developed diabetic complications. Of the tested siblings, 2 of 8 had impaired glucose tolerance and 5 of 8 had stimulated hyperinsulinemia, correlated with BMI (r = 0.80, P < 0.05). The school survey identified 28 diabetic adolescents, 75% more than expected (P < 0.01). The Hispanic enrollment at each school was highly correlated with the number of diabetic students (r = 0.87, P = 0.011). CONCLUSIONS Genetic susceptibility to type 2 diabetes, when coupled with obesity, can produce type 2 diabetes in Mexican-American children. This diagnosis should be considered in young Hispanic patients, who might otherwise be assumed to have type 1 diabetes, and also when caring for overweight Hispanic youth with a family history of type 2 diabetes, in whom intervention may prevent or delay diabetes onset.

Actionable exomic incidental findings in 6503 participants: challenges of variant classification

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.

Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer: implications for ovarian cancer screening.

OBJECTIVE Our purpose was to report the cancers arising during a familial ovarian cancer screening program and investigate the tumors clonality and association with BRCA1 and BRCA2 mutations. STUDY DESIGN Program participants with a diagnosis of ovarian cancer or peritoneal serous papillary carcinoma were identified and their demographic characteristics, ultrasonographic findings, CA 125 results, operative reports, and pathology slides reviewed. Immunohistochemical analysis of p53, bcl-2, HER-2/neu, and nm23 H1 expression was performed on tumor tissues from multiple metastatic sites, and germline BRCA1 and BRCA2 mutations were identified. RESULTS Three stage I ovarian cancers and 7 cases of peritoneal serous papillary carcinoma were diagnosed from among 1261 program participants. Ultrasonographic abnormalities triggered surgical exploration in all 3 cases of stage I disease. Elevated levels of CA 125 were the harbinger in 2 of 7 cases of peritoneal serous papillary carcinoma, abnormal ultrasonographic findings prompted diagnosis in 2 of 7 cases, and 3 of 7 women had abdominal symptoms 5, 6, and 16 months after screening. Results of immunohistochemical studies suggested multifocal disease in 5 of 7 patients with peritoneal serous papillary carcinoma. At least 3 of the patients with peritoneal serous papillary carcinoma carry BRCA1 185delAG mutations. CONCLUSION Multifocal peritoneal serous papillary carcinoma may be a phenotypic variant of familial ovarian cancer, and screening strategies for these women cannot rely on ultrasonography and CA 125 testing to detect early disease.

Heritability of Subclinical Atherosclerosis in Latino Families Ascertained Through a Hypertensive Parent

Although clinical coronary heart disease and many cardiovascular risk factors are well known to aggregate within families, the heritability of carotid artery intima-media thickness (IMT) is less well documented. We report IMT heritability estimates in Mexican American, Salvadoran American, or Guatemalan American (all referred to as Latino) families ascertained through a hypertensive proband. IMT and cardiovascular risk factors (age, sex, blood pressure, body mass index, lipids, fasting glucose, and insulin sensitivity) were measured in 204 adult offspring of 69 hypertensive probands, along with 82 parents (54 probands and 28 spouses). In the offspring, variance component analysis revealed a heritability for IMT of 64% (P < 0.0001) after adjustment for significant cardiovascular risk factors. Genetic factors accounted for 50% of the total variation in IMT, whereas significant cardiovascular risk factors explained 22% (14% were due to age). For offspring and parents combined, adjusted IMT heritability was less, 34% (P =0.0005), with genetic factors accounting for 18% of the total IMT variation, whereas significant cardiovascular risk factors explained 46% (38% were due to age). We conclude that variation in c ommon carotid artery IMT is heritable in Latino families with a hypertensive proband. Heritability is particularly evident in younger family members, suggesting that acquired factors contribute progressively to IMT variability with aging.

A multidisciplinary approach to the early detection of ovarian carcinoma: Rationale, protocol design, and early results

OBJECTIVE This study was undertaken to determine the feasibility of currently available tests to detect ovarian cancer at a curable stage. By studying women at risk for the disease on the basis of their family histories of cancer, we hope to gain insight into the genetics and biologic characteristics of ovarian cancer. STUDY DESIGN Asymptomatic women with a family history of cancer are interviewed by geneticists to obtain accurate pedigree and epidemiologic data. Screening tests including transvaginal ultrasonography, color Doppler imaging, CA 125 measurement, and other investigative biomarkers are performed between cycle days 3 and 8 and repeated biannually. RESULTS A total of 597 women without symptoms were screened between July 1991 and June 1992. Cystic or complex adnexal masses were detected in 6.2% of patients. A pulsatile index value < 1.0 was measured in 80% of premenopausal patients and 24% of postmenopausal patients, whereas a resistance index value < 0.4 occurred in 12% of premenopausal and 3% of postmenopausal patients. A CA 125 level > 35 U/ml was found in 11.4% of the study participants. To date, one stage IA borderline ovarian tumor and one endometrial carcinoma have been found. CONCLUSIONS Ovarian cancer screening needs to be investigated in a controlled fashion to determine means that will ultimately improve the survival from the disease.

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure–associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein–protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure–associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

The GENNID Study: A resource for mapping the genes that cause NIDDM

OBJECTIVE To develop a resource, consisting of comprehensive data and lymphoblastoid cell lines, of well-characterized NIDDM families that will be available to the scientific community for genetic studies of NIDDM. RESEARCH DESIGN AND METHODS Non-Hispanic white, Hispanic, African-American, and Japanese-American multiplex NIDDM families, with a minimum of one affected sib-pair, are being collected by the eight Harold Rifkin Family Acquisition Centers. Detailed family and medical histories are obtained from all participants. Family members with diabetes have fasting blood samples drawn, while nondiabetic family members have an oral glucose tolerance test and, when possible, insulin sensitivity and insulin secretion measurements by frequently sampled intravenous glucose tolerance testing or euglycemic insulin clamp. Lymphoblastoid cell lines are established for all participants. RESULTS Over 1,400 individuals from ∼220 families have been studied since the start of the GENNID (Genetics of NIDDM) program in July 1993. The goal is that by July 1997, data from 300 non-Hispanic white families, > 100 Hispanic families, > 100 African-American families, and 15 Japanese-American families will have been collected. CONCLUSIONS The identification of the genes responsible for NIDDM may now be achievable, but only if sound phenotypic data are linked to genetic material from a large number of well-described multiplex families. The GENNID project of the American Diabetes Association is creating a comprehensive resource that will expedite the identification of the genetic basis of NIDDM.