Atherosclerosis and stroke — Coronary heart disease remains the No. 1 cause of death in the U.S., resulting in approximately 500,000-700,000 deaths per year, and an additional 1.3 million cases of nonfatal myocardial infarction (MI). Stroke is the third leading cause of death (behind heart disease and cancer) and the leading neurological cause of long-term disability. About 25 percent of people who recover from their first stroke will have another stroke within 5 years. Several studies have shown that elevated homocysteine levels are an independent risk factor for stroke, heart disease, and dementia. Genetic factors have been shown to influence homocysteine, the development of atherosclerosis, and ischemic events such as stroke and MI. In order to identify individuals most at risk of stroke and MI, and develop novel interventional strategies, we are investigating genetic contributions to vascular disease using human population studies. The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled over 6,000 participants aged 45-85 without existing evidence of clinical cardiovascular disease. Participants were drawn from four racial/ethnic groups: European Americans, African Americans, Hispanic individuals, and Chinese Americans, and have been evaluated for subclinical measures of atherosclerosis such as coronary and carotid artery calcification and intima-media thickness at regular intervals in ongoing studies. The Vitamin Intervention for Stroke Prevention (VISP) trial enrolled over 3,000 stroke patients 35 years and older. Patients were randomized to either a high dose or a low dose of folic acid, vitamin B 6 and vitamin B12 to investigate the impact of the two treatments on homocysteine levels and recurrent stroke or MI. There was a persistent and graded association between baseline homocysteine level and vascular outcomes in both treatment groups. Genetic studies using both populations aim to (1) understand the genetic determinants of homocysteine levels in both subclinical atherosclerosis and following stroke; (2) gain insights into individual responses to vitamin therapy; (3) investigate mechanisms of homocysteine risk.

Otitis media — Every year, over 10 million children in the U.S. are treated for ear infections. Otitis media is an inflammation of the middle ear caused by infection, which often begins when viral or bacterial respiratory infections spread to the middle ear. Three out of four children experience otitis media by the time they are 3 years old, and almost half of these will have three or more ear infections during their first 3 years. Insertion of plastic tubes into the middle ear to assist fluid drainage (myringotomy) is the most common childhood surgery performed in the U.S. Otitis media not only causes severe pain, but may result in other infections including meningitis, lead to permanent hearing loss, or impact speech and language development. While environmental factors such as smoking contribute to chronic otitis media, family studies have also demonstrated an independent role for genetic factors. We have recruited families with at least two siblings who have experienced chronic and/or recurrent otitis media with effusion (fluid), and conducted the first otitis media genome scan. This study has revealed two regions of the genome that harbor otitis media susceptibility genes. Projects underway aim to (1) identify these genes, and (2) evaluate other candidate genes that contribute to either the anatomical development of the ear canal, or immune responses to infection.

Selected References

Sale MM, Smith SG, Mychaleckyj JC, Keene KL, Langefeld CD, Leak TS, Hicks PJ,Bowden DW, Rich SS, Freedman BI. (2007) "Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy." Diabetes. 56(10):2638-42. Epub 2007 Jun 29. [PubMed]

Gallagher CJ, Langefeld CD, Gordon CJ, Campbell JK, Mychaleckyj JC, Bryer-Ash M,Rich SS, Bowden DW, Sale MM. (2007) "Association of the estrogen receptor-alpha gene with the metabolic syndrome and its component traits in African-American families: the Insulin Resistance Atherosclerosis Family Study." Diabetes. 56:2135-41. Epub 2007 May 18. [PubMed]

Sale MM, Hsu FC, Palmer ND, Gordon CJ, Keene KL, Borgerink HM, Sharma AJ,Bergman RN, Taylor KD, Saad MF, Norris JM. (2007) "The uncoupling protein 1 gene, UCP1, is expressed in mammalian islet cells and associated with acute insulin response to glucose in African American families from the IRAS Family Study." BMC Endocr Disord. Mar 7:1. [PubMed]

Gallagher CJ, Keene KL, Mychaleckyj JC, Langefeld CD, Hirschhorn JN, HendersonBE, Gordon CJ, Freedman BI, Rich SS, Bowden DW, Sale MM. (2007) "Investigation of the estrogen receptor-alpha gene with type 2 diabetes and/or nephropathy in African-American and European-American populations." Diabetes. 56:675-84. [PubMed]