Ronald G. Munger

Cleft lip and palate

Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity. These defects arise in about 1.7 per 1000 liveborn babies, with ethnic and geographic variation. Effects on speech, hearing, appearance, and psychology can lead to longlasting adverse outcomes for health and social integration. Typically, children with these disorders need multidisciplinary care from birth to adulthood and have higher morbidity and mortality throughout life than do unaffected individuals. This Seminar describes embryological developmental processes, epidemiology, known environmental and genetic risk factors, and their interaction. Although access to care has increased in recent years, especially in developing countries, quality of care still varies substantially. Prevention is the ultimate objective for clefts of the lip and palate, and a prerequisite of this aim is to elucidate causes of the disorders. Technological advances and international collaborations have yielded some successes.

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635–0.778, P = 1.44 × 10−11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292–1.587, P = 5.01 × 10−12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Tobacco smoking and oral clefts: a meta-analysis

OBJECTIVE To examine the association between maternal smoking and non-syndromic orofacial clefts in infants. METHODS A meta-analysis of the association between maternal smoking during pregnancy was carried out using data from 24 case-control and cohort studies. FINDINGS Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35). There was evidence of a modest dose-response effect for cleft lip with or without cleft palate. CONCLUSION The evidence of an association between maternal tobacco smoking and orofacial clefts is strong enough to justify its use in anti-smoking campaigns.

Vascular factors predict rate of progression in Alzheimer disease.

Background: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. Objective: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. Methods: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. Results: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. Conclusion: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age. GLOSSARY: 3MS = revised Modified Mini-Mental State Examination for epidemiologic studies; AF = atrial fibrillation; CABG = coronary artery bypass graft surgery; CCHS = Copenhagen City Heart Study; CCSMHA = Cache County Study on Memory, Health, and Aging; CDR = Clinical Dementia Rating; CVD = cardiovascular disease; DM = diabetes mellitus; DPS = Dementia Progression Study; MI = myocardial infarction; MMSE = Mini-Mental State Examination; SBP = systolic blood pressure.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimers disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Incidence of hypertension and stroke in relation to body fat distribution and other risk factors in older women.

The relation between body fat distribution, as measured by the waist-to-hip circumference ratio, and the 2-year incidences of hypertension and stroke were examined in a cohort of 41,837 women aged 55-69 years. Women who developed hypertension were 2.1 (95% confidence interval 1.7-2.6) times more likely to be in the upper tertile of waist-to-hip ratio than those who did not. Adjustment for age, body mass index (kilograms per meter squared), cigarette smoking, physical activity, alcohol intake, and education level reduced this odds ratio to 1.6 (95% confidence interval 1.3-2.1). Women who developed a stroke were also 2.1 (95% confidence interval 1.5-2.9) times more likely to be in the upper tertile of waist-to-hip ratio than those who did not. Adjustment for the same covariates also lowered this odds ratio to 1.6 (95% confidence interval 1.1-2.4). Further adjustment for hypertension and diabetes mellitus reduced the estimated risk of stroke due to elevated waist-to-hip ratio to 1.3 (95% confidence interval 0.8-2.1). Hypertension, diabetes mellitus, and cigarette smoking remained significantly associated with stroke incidence in the multivariate model. These results indicate that abdominal adiposity, as measured by an increased waist-to-hip ratio, increases the risks of hypertension and stroke, even after accounting for overall body mass. The association of abdominal adiposity with risk of stroke is related, in part, to the association of abdominal adiposity with hypertension and diabetes.

Vascular Risk Factors for Incident Alzheimer Disease and Vascular Dementia: The Cache County Study

Vascular risk factors for Alzheimer disease (AD) and vascular dementia (VaD) have been evaluated; however, few studies have compared risks by dementia subtypes and sex. We evaluated relationships between cardiovascular risk factors (hypertension, high cholesterol, diabetes mellitus, and obesity), events (stroke, coronary artery bypass graft surgery, and myocardial infarction), and subsequent risk of AD and VaD by sex in a community-based cohort of 3264 Cache County residents aged 65 or older. Cardiovascular history was ascertained by self-report or proxy-report in detailed interviews. AD and VaD were diagnosed using standard criteria. Estimates from discrete-time survival models showed no association between self-reported history of hypertension and high cholesterol and AD after adjustments. Hypertension increased the risk of VaD [adjusted hazard ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44]. Obesity increased the risk of AD in females (aHR 2.23, 95% CI 1.09-4.30) but not males. Diabetes increased the risk of VaD in females after adjustments (aHR 3.33, 95% CI 1.03-9.78) but not males. The risk of VaD after stroke was increased in females (aHR 16.90, 95% CI 5.58-49.03) and males (aHR 10.95, 95% CI 2.48-44.78). The results indicate that vascular factors increase risks for AD and VaD differentially by sex. Future studies should focus on specific causal pathways for each of these factors with regard to sex to determine if sex differences in the prevalence of vascular factors have an influence on sex differences in dementia risk.

Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts

Previous studies suggest that the relationship between genes and nonsyndromic cleft lip +/- cleft palate (CLP) or cleft palate only (CP) may be modified by the environment. Using data from a population-based case-control study, we examined allelic variants for three genes, i.e., transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), and Msh (Drosophila) homeobox homolog 1 (MSX1), and their interactions with two exposures during pregnancy (maternal cigarette smoking and alcohol consumption) as risk factors for CLP and CP. For each cleft phenotype, risk estimates associated with most allelic variants tended to be near unity. Risk estimates for maternal smoking (> or = 10 cigarettes/day) were significantly elevated for CP and were most elevated among infants with allelic variants at the TGFB3 or MSX1 sites. By comparison, risk estimates for maternal alcohol consumption (> or = 4 drinks/month) were significantly elevated for CLP and were most elevated among infants with allelic variants at the MSX1 site. Our results suggest that development of CLP and CP may be influenced independently by maternal exposures but more significantly by interaction of such exposures and specific allelic variants.

Persistent elevation of blood pressure among children with a family history of hypertension: The Minneapolis children's blood pressure study

We examined the blood pressure of children with and without a family history of hypertension in a longitudinal study. Supine blood pressures were first measured in schoolchildren (mean age 8 years) in 1978 and then on nine more occasions until 1986. Blood pressures of parents were measured in the seated position and their medical histories were obtained in home interviews carried out between 1978 and 1979. Children with a family history of hypertension had a higher mean systolic blood pressure (SBP) at the first screening compared to children without such a family history. This difference persisted at each of the succeeding nine school visits. The parents in hypertensive families had a lower income, greater body weight, were less well-educated and were more likely to be black than parents in families without a history of hypertension. Mothers in hypertensive families were more likely to have a history of heart disease and elevated blood pressure during pregnancy than mothers in normotensive families. The correlations between blood pressure of mothers and their children tended to be higher than those between fathers and their children. Elevated blood pressure emerges well before adolescence among children with a family history of hypertension and the family environment appears to play an important role in its development.

Dietary protein intake and risk of osteoporotic hip fracture in elderly residents of Utah

The role of protein intake in osteoporosis is unclear. In a case‐control study in Utah (n = 2501), increasing level of protein intake was associated with a decreased risk of hip fracture in men and women 50–69 years of age but not in those 70–89 years of age. Protein intake may be important for optimal bone health.