Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Low serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression. RESULTS: The GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta=-0.013, p=6.1x10(-9)). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta=-0.028, p=7.3x10(-5)) than in those without any hormone use (beta=-0.011, p=7.0x10(-8), p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (<80 pmol/L: beta=-0.013, p=1.6x10(-7); ≥80 pmol/L: beta=-0.008, p=1.8x10(-2), p for interaction 0.03). CONCLUSIONS: We identified three loci that explained 2.8% of the variance in serum magnesium concentration in ARIC African-American participants. Following-up on functional studies of gene expression identified gene-environment interactions between progestin use and MUC1 and between insulin and TRPM6 on serum magnesium concentration in ARIC European-American participants. These results extend our understanding of the metabolism of serum magnesium.

Ideal cardiovascular health is inversely associated with incident cancer: the Atherosclerosis Risk In Communities study.

BACKGROUND: The American Heart Association (AHA) has defined the concept of ideal cardiovascular health in promotion of the 2020 Strategic Impact Goals. We examined whether adherence to ideal levels of the 7 AHA cardiovascular health metrics was associated with incident cancers in the Atherosclerosis Risk In Communities (ARIC) study over 17 to 19 years of follow-up. METHODS AND RESULTS: After exclusions for missing data and prevalent cancer, 13 253 ARIC participants were included for analysis. Baseline measurements were used to classify participants according to 7 AHA cardiovascular health metrics. Combined cancer incidence (excluding nonmelanoma skin cancers) from 1987 to 2006 was captured using cancer registries and hospital surveillance; 2880 incident cancer cases occurred over follow-up. Cox regression was used to calculate hazard ratios for incident cancer. There was a significant (P trend <0.0001), graded, inverse association between the number of ideal cardiovascular health metrics at baseline and cancer incidence. Participants meeting goals for 6 to 7 ideal health metrics (2.7% of the population) had 51% lower risk of incident cancer than those meeting goals for 0 ideal health metrics. When smoking was removed from the sum of ideal health metrics, the association was attenuated with participants meeting goals for 5 to 6 health metrics having 25% lower cancer risk than those meeting goals for 0 ideal health metrics (P trend =0.03). CONCLUSIONS: Adherence to the 7 ideal health metrics defined in the AHA 2020 goals is associated with lower cancer incidence. The AHA should continue to pursue partnerships with cancer advocacy groups to achieve reductions in chronic disease prevalence.

Synovial xanthomatosis: are there clues to mechanisms for this rare disease?

We report a 64-year-old man with arthritis and nodules to describe that this picture can be caused by normo-lipidemic xanthomas. Light and electron microscopy (EM) plus polymerase chain reaction (PCR) studies were performed for diagnosis and investigation. These showed features typical of xanthomas plus PCR and EM evidence of possible infection with Chlamydia pneumoniae as a pathogenetic mechanism deserving consideration. With such rare diseases, any clues to possible mechanisms seem important to record and thus to encourage future investigations. This uncommon cause of arthritis and nodules had been confused with rheumatoid arthritis by others in this case.

Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma.

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumors in children. Apparently sporadic cases of PGL may harbor germline mutations in the succinate dehydrogenase (SDHx) gene. SDHB mutations are associated with malignant disease. We report a 13-year-old African American boy with diffusely metastatic PGL and compound heterozygous mutation leading to a novel splice donor region DNA sequence variant in the SDHB gene. Family history was positive for non-classical congenital adrenal hyperplasia and pituitary adenoma. After surgical resection of the primary PGL and chemotherapy, he was treated with metaiodobenzy lguanidine (MIBG) combined with arsenic trioxide. At 3-year follow-up, he had stable disease.

Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication.

BACKGROUND: Interstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported. RESULTS: In this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. De novo and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities. CONCLUSION: Our report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.

Novel COL4A3 mutations in African American siblings with autosomal recessive Alport syndrome.

We describe a novel mutational study in 2 African American siblings with autosomal recessive Alport syndrome. Both siblings were compound heterozygotes for 2 abnormal DNA sequences in exon 49 of the COL4A3 gene, p.Arg1496X (CGA-->TGA) and p.Arg1516X (CGA-->TGA). These are nonsense mutations in the noncollagenous domain resulting in premature termination codons and have not been previously reported. In an African American population in which autosomal recessive Alport syndrome is rarely seen, complete sequencing of the COL4A3 and COL4A4 genes may be necessary to identify the underlying mutation and confirm the diagnosis.

Recent developments in ovarian cancer genetics.

PURPOSE OF REVIEW: This review attempts to provide an update on recent research on inherited susceptibility to ovarian cancer. It covers articles mainly published in 2002 and 2003, with an emphasis on genetic counseling issues. RECENT FINDINGS: The major areas on which recent reports have focused include: (1) an expanded understanding of the BRCA1 and BRCA2 mutation spectrum and the frequencies of deleterious alleles in various ethnic groups; (2) investigations on how information is best transmitted to high-risk family members via genetic counseling; (3) an analysis of patient management changes based on genotype results; (4) social issues surrounding predictive testing for breast/ovarian cancer genes, including health insurance and discrimination concerns; and (5) an investigation into gynecologists' knowledge of ovarian cancer genetics, and their ability to provide genetic counseling for ovarian cancer to their patients. Preliminary reports from scientific meetings that have not yet been published in peer-reviewed journals are also discussed. SUMMARY: Recent developments in ovarian cancer genetics expand many of the areas that have been studied previously. A major focus of recent research has dealt with genetic counseling for families affected by hereditary breast and ovarian cancer.

The role of DNA testing in breast, ovarian, and colon cancers.

A proportion of cases of breast and colon cancers are caused by inherited mutations that confer a greatly increased susceptibility to malignancy. Certain clinical features may help distinguish patients with a genetic cause for their cancer from the larger number of patients with sporadic tumors. A thorough family medical history is also necessary to identify those at high risk for developing cancer. Many of the normal functions of these genes are understood, and mutation analysis for patients and their families is now available as a clinical service. Presymptomatic detection of mutations allows the patient to pursue preventive measures to reduce the probability of developing a malignancy. Evidence is now available that some prophylactic measures do reduce the incidence of cancer and reduce mortality in mutation carriers, and the standard of care is evolving rapidly. The essential elements necessary to provide accurate interpretations of molecular genetics test results to patients are described.

An internist's update on cholesterol management.

Coronary heart disease (CHD) remains the leading cause of death in the United States. It is now well established that cholesterol is an important, reversible risk factor for CHD. This article provides a brief background on classification of the dyslipidemias, then discusses current recommendations for the evaluation and treatment of hyperlipidemia. Other risk factors currently being investigated as they relate to the development of CHD are discussed.

Omodysplasia: an affected mother and son.

We describe a second family with mother to son transmission of omodysplasia, a rare skeletal dysplasia characterized by shortened humeri, shortened first metacarpals and craniofacial dysmorphism. The mother in this family had been diagnosed previously with Robinow syndrome; subsequently, her diagnosis was reclassified. Her pregnancy was closely monitored antenatally with serial ultrasound examinations. Delayed ossification of the humerus was noted prenatally. Her son had ambiguous genitalia and similar skeletal manifestations as his mother. A comparison to other known and suspected cases of dominant omodysplasia is presented. Our observations confirm the existence of a dominant variant of omodysplasia, document genital hypoplasia as an important feature of this syndrome in males and highlight the need to differentiate this entity from Robinow syndrome.