Avoidance of Cow's Milk-Based Formula for At-Risk Infants Does Not Reduce Development of Celiac Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Feeding during the first months of life might affect risk for celiac disease. Individuals with celiac disease or type 1 diabetes have been reported to have high titers of antibodies against cow's milk proteins. Avoidance of cow's milk-based formula for infants with genetic susceptibility for type 1 diabetes reduced the cumulative incidence of diabetes-associated autoantibodies. We performed a randomized controlled trial in the same population to study whether weaning to an extensively hydrolyzed formula reduced the risk of celiac disease autoimmunity or celiac disease. METHODS: We performed a double-blind controlled trial of 230 infants with HLA-defined predisposition to type 1 diabetes and at least 1 family member with type 1 diabetes. The infants were randomly assigned to groups fed a casein hydrolysate formula (n = 113) or a conventional formula (control, n = 117) whenever breast milk was not available during the first 6-8 months of life. Serum samples were collected over a median time period of 10 years and analyzed for antibodies to tissue transglutaminase (anti-TG2A) using a radiobinding assay, to endomysium using an immunofluorescence assay, and antibodies to a deamidated gliadine peptide using an immunofluorometry assay. Duodenal biopsies were collected if levels of anti-TG2A exceeded 20 relative units. Cow's milk antibodies were measured during the first 2 years of life. RESULTS: Of the 189 participants analyzed for anti-TG2A, 25 (13.2%) tested positive. Of the 230 study participants observed, 10 (4.3%) were diagnosed with celiac disease. We did not find any significant differences at the cumulative incidence of anti-TG2A positivity (hazard ratio, 1.14; 95% confidence interval, 0.51-2.54) or celiac disease (hazard ratio, 4.13; 95% confidence interval, 0.81-21.02) between the casein hydrolysate and cow's milk groups. Children who developed celiac disease had increased titers of cow's milk antibodies before the appearance of anti-TG2A or celiac disease. CONCLUSIONS: In a randomized controlled trial of 230 infants with genetic risk factors for celiac disease, we did not find evidence that weaning to a diet of extensively hydrolyzed formula compared with cow's milk-based formula would decrease the risk for celiac disease later in life. Increased titers of cow's milk antibody before anti-TG2A and celiac disease indicates that subjects with celiac disease might have increased intestinal permeability in early life. ClinicalTrials.gov Number: NCT00570102.

Geographic origin as a determinant of carotid artery intima-media thickness and brachial artery flow-mediated dilation: the Cardiovascular Risk in Young Finns study.

OBJECTIVE: People living in eastern Finland have approximately 40% higher coronary heart disease mortality rates than western Finns. Whether this is because of genetic or environmental factors is unknown. We examined the effect of geographic family origin on subclinical atherosclerosis among young Finns. METHODS AND RESULTS: As part of a longitudinal follow-up study, we measured carotid intima-media thickness (IMT) in 2264 and brachial flow-mediated dilation (FMD) in 2109 white adults, aged 24 to 39 years. Subjects from eastern Finland had greater IMT and lower FMD compared with western subjects. These differences accentuated when the subjects' family origin (grandparents' birthplace) was taken into account and remained significant after adjusting for several environmental factors. Among subjects with all grandparents born in eastern or western Finland, IMTs were (mean+/-SEM) 0.592+/-0.003 versus 0.565+/-0.005 mm (P<0.0001), respectively. The corresponding FMD values were 7.61+/-0.15% versus 8.75+/-0.26%; P<0.01. The number of grandparents born in eastern Finland was directly related to IMT (P<0.0001) and inversely to FMD (P<0.05). CONCLUSIONS: Young adults originating from eastern Finland have greater carotid IMT and lower brachial FMD than western Finns. Consistent with a hereditable component predisposing to or protecting from atherosclerosis, these differences accentuated when subjects' family origin was taken into account. We studied whether an east-west difference exists in markers of subclinical atherosclerosis in 2264 Finns aged 24 to 39 years. Subjects with family origin in eastern Finland had greater carotid IMT and lower brachial FMD compared with western subjects, suggesting that hereditable factors play a role in excess atherosclerosis risk in eastern Finland.

Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study.

CONTEXT: Exposure to cardiovascular risk factors during childhood and adolescence may be associated with the development of atherosclerosis later in life. OBJECTIVE: To study the relationship between cardiovascular risk factors measured in childhood and adolescence and common carotid artery intima-media thickness (IMT), a marker of preclinical atherosclerosis, measured in adulthood. DESIGN, SETTING, AND PARTICIPANTS: Population-based, prospective cohort study conducted at 5 centers in Finland among 2229 white adults aged 24 to 39 years who were examined in childhood and adolescence at ages 3 to 18 years in 1980 and reexamined 21 years later, between September 2001 and January 2002. MAIN OUTCOME MEASURES: Association between cardiovascular risk variables (levels of low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides; LDL-C/HDL-C ratio; systolic and diastolic blood pressure; body mass index; smoking) measured in childhood and adulthood and common carotid artery IMT measured in adulthood. RESULTS: In multivariable models adjusted for age and sex, IMT in adulthood was significantly associated with childhood LDL-C levels (P =.001), systolic blood pressure (P<.001), body mass index (P =.007), and smoking (P =.02), and with adult systolic blood pressure (P<.001), body mass index (P<.001), and smoking (P =.004). The number of risk factors measured in 12- to 18-year-old adolescents, including high levels (ie, extreme age- and sex-specific 80th percentile) of LDL-C, systolic blood pressure, body mass index, and cigarette smoking, were directly related to carotid IMT measured in young adults at ages 33 through 39 years (P<.001 for both men and women), and remained significant after adjustment for contemporaneous risk variables. The number of risk factors measured at ages 3 to 9 years demonstrated a weak direct relationship with carotid IMT at ages 24 to 30 years in men (P =.02) but not in women (P =.63). CONCLUSIONS: Risk factor profile assessed in 12- to 18-year-old adolescents predicts adult common carotid artery IMT independently of contemporaneous risk factors. These findings suggest that exposure to cardiovascular risk factors early in life may induce changes in arteries that contribute to the development of atherosclerosis.

Increased frequency of islet cell antibodies in unaffected brothers of children with type 1 diabetes.

AIM: To assess the relation between islet cell antibody (ICA) positivity and demographic characteristics in an extensive series of first-degree relatives of children with type 1 diabetes (T1D). METHODS: Family members of children diagnosed with T1D before the age of 16 years and attending one of 27 participating paediatric units in Finland taking care of children with diabetes were invited to volunteer for an ICA screening program aimed at identifying individuals eligible for inclusion in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The final series comprised 2,522 first-degree relatives (1,107 males) with a mean age of 20.4 (range 0.1-51.9) years, out of whom 390 were fathers, 622 mothers, 717 brothers, and 793 sisters of affected cases. RESULTS: Two hundred and four family members (8.1%) tested positive for ICA with levels ranging from 3 to 564 (median 18) Juvenile Diabetes Foundation (JDF) units. One hundred and five relatives (4.2%) had an ICA level of 18 JDF units or more. Males had detectable ICA more often than females (9.6 vs. 6.9%; p = 0.02). Antibody-positive family members under the age of 20 years had higher ICA levels than the older ones [median 18 (range 3-514) JDF units vs. 10 (range 3-564) JDF units; p = 0.008]. Among the adult relatives (>or=20 years of age) antibody-positive females had higher ICA levels than the males [median 10 (range 5-564) JDF units vs. 9 (range 3-130) JDF units; p = 0.04]. Siblings had an increased frequency of high-titre ICA (>or=18 JDF units) when compared to the parents (4.8 vs. 3.2%; p = 0.05). Among siblings, we found a higher frequency of ICA positivity in brothers than in sisters (10.8 vs. 6.9%; p = 0.01), and this was also true for high-titre ICA (6.0 vs. 3.8 %; p = 0.04). Geographically, the highest ICA prevalence was seen among relatives living in the middle of Finland (10.4 vs. 7.2% in the other parts of Finland; p = 0.01). CONCLUSIONS: These results imply that male gender and young age favour positive ICA reactivity among family members of children with T1D. Siblings test positive for high ICA titres (>or=18 JDF units) more frequently than parents. Accordingly, judged from demographic characteristics, the yield of ICA screening in first-degree relatives would be maximized by targeting young brothers of affected cases.