Published online October 2, 2006
PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1553-1559 (doi:10.1542/peds.2006-0542)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lehtimäki, T.
Right arrow Articles by Raitakari, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lehtimäki, T.
Right arrow Articles by Raitakari, O.
Related Collections
Right arrow Nutrition & Metabolism
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

ARTICLE

The Effects of Adult-Type Hypolactasia on Body Height Growth and Dietary Calcium Intake From Childhood Into Young Adulthood: A 21-Year Follow-up Study—The Cardiovascular Risk in Young Finns Study

Terho Lehtimäki, MD, PhDa, Jukka Hemminki, BMa, Riikka Rontu, PhDa, Vera Mikkilä, MScb, Leena Räsänen, PhDb, Marika Laaksonen, MScb, Nina Hutri-Kähönen, PhDc, Mika Kähönen, PhDd, Jorma Viikari, PhDe and Olli Raitakari, PhDf

a Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland
b Division of Nutrition, University of Helsinki, Helsinki, Finland
c Departments of Pediatrics
d Clinical Physiology, Tampere University Hospital, Tampere, Finland
e Departments of Medicine
f Clinical Physiology, University of Turku, Turku, Finland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. The effect of adult-type hypolactasia, caused by the lactase-phlorizin hydrolase C/C-13910 genotype, on growth is unknown. We studied whether this polymorphism was associated with body height growth, the use of milk products, or dietary calcium intake.

METHODS. A prospective cohort study was performed among 3596 randomly selected Finnish children and adolescents (3–18 years of age) in 1980, with reexamination in 1983, 1986, and 2001 (after a 21-year follow-up period). Lactase-phlorizin hydrolase C/T-13910 polymorphism was determined for 2265 participants in 2002. Nutrient intakes were measured for 1137, 858, and 1031 subjects in 1980, 1986, and 2001, respectively.

RESULTS. The lactase-phlorizin hydrolase C/T-13910 polymorphism was not related to mean height growth speed for either boys or girls or to final mean body height in adulthood. The consumption of milk products, protein, and calcium was lowest for female subjects with the lactase-phlorizin hydrolase C/C-13910 genotype over the study years, but there were no genotype-related differences in the intake of vitamin D. For boys, significant differences were found in the consumption of milk products but not in the mean dietary intake of calcium, protein, or vitamin D.

CONCLUSIONS. The lactase-phlorizin hydrolase C/C-13910 genotype was not associated with mean growth speed or final mean body height for either boys or girls. However, it contributed significantly to milk product consumption and dietary calcium intake from childhood into young adulthood.

Key Words: hypolactasia • lactase-phlorizin hydrolase • genotype • lactose intolerance • calcium intake • body height • growth • children • adolescents

Abbreviations: LCT—lactase-phlorizin hydrolase • ATH—adult-type hypolactasia • RANOVA—repeated-measures analysis of variance

Adult-type hypolactasia (ATH) (see Online Mendelian Inheritance in Man), also known as lactase persistence/nonpersistence, is the most common cause of lactase enzyme deficiency, which affects approximately one half of the world's population.1 The prevalence of ATH in the Finnish population is ~17%.1–4 Milk and several dairy products contain lactose, a disaccharide that is hydrolyzed to glucose and galactose by the lactase enzyme located in the brush border of the intestinal wall.5,6 In addition to ATH, lactase enzyme deficiency and resulting lactose malabsorption may originate from a rare congenital lactase deficiency or may be caused by conditions that damage intestinal cells (gastrointestinal infections such as rotavirus, giardiasis, cancer of the small intestine, radiotherapy, or untreated celiac disease).5,6 Lactose intolerance is a clinical phenotype that covers all conditions in which the malabsorption of lactose is suspected to cause symptoms (e.g., diarrhea, bloating, flatulence, and abdominal pain).5,6

The definitive diagnosis of lactase persistence/nonpersistence is based on the measurement of disaccharidase enzyme activities and the lactase/saccharase ratio in intestinal biopsies.1–4 The invasive nature of this technique has prevented large-scale population studies on the effect of ATH on body height growth and dietary calcium intake. The expression of lactase-phlorizin hydrolase (LCT) mRNA in the intestinal mucosa is regulated by a functional,7,8 single-nucleotide polymorphism, C/T-13910, residing in chromosome 2, ~14 kilobases upstream of the 5' end of the LCT gene.9,10 Individuals with the persistent LCT T-13910 allele have >11 times greater LCT mRNA content in their intestinal mucosa, compared with homozygotic individuals with the C-13910 allele.6,9 In Finnish adults, both the lactase activity and the lactase/saccharase ratio in intestinal biopsies increased in the LCT genotype in the order of C/C, C/T, and T/T.9 LCT C/T-13910 heterozygotes have intermediate levels of lactase, measured as enzyme activity,9 and a majority of them produce enough lactase to be classified as having lactase persistence with the standard physiologic test for lactose tolerance11 or the hydrogen breath test.5 However, the correlation between molecularly defined ATH and self-reported lactose intolerance is poor.12,13 The LCT gene C/C-13910 genotype was found to be associated completely with ATH in a study sample with biochemically verified lactase persistence/nonpersistence status,2,10 and molecular epidemiologic studies showed that the prevalence of the C/C-13910 genotype is consistent with previously published epidemiologic data on ATH in >70 countries.6 Therefore, the diagnosis of ATH is now based on DNA testing in Finland.

In the Finnish population, the C/C-13910 genotype is associated with very low lactase activity (<10 U/g protein) in intestinal biopsies taken from the majority of children tested at 8 years of age and every child >12 years of age.2 At the same time, the use of milk and milk products in Finland is common, and such products constitute approximately two thirds of the total calcium intake.14

Because lactase deficiency may limit the use of milk and dairy products, it may lead to lower calcium intake for C/C-13910 genotype carriers and thus may modify bone growth in childhood. The purpose of this study was to test whether this polymorphism is associated with body height growth.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The Cardiovascular Risk in Young Finns Study is an ongoing multicenter follow-up study of atherosclerosis risk factors for young Finns.15,16 The first cross-sectional survey was conducted in 1980. The total sample size was 4320 subjects, 3, 6, 9, 12, 15, and 18 years of age. The subjects were selected randomly from the national population register, from 5 university cities in Finland and the rural municipalities in their vicinity. A total of 3596 subjects (83.2% of those invited) participated in 1980.17 Follow-up studies were performed, and the same subjects were reexamined in 1983 and 1986, as well as after a 21-year follow-up period, in 2001, at the age of 24 to 39 years.

We analyzed the relationship of LCT C/T-13910 polymorphism, measured for 2265 adults, with body height measured in childhood and adulthood. Body height was measured with a Seca anthropometer (Oriola, Espoo, Finland), according to standard procedures, and height data were available for 3573, 2886, 2501, and 2278 subjects in 1980, 1983, 1986, and 2001, respectively; for all 4 study years, data were available for 1628 subjects. Subjects gave their written informed consent, and the study was approved by local ethics committees of the participating universities.

LCT Genotyping
Genomic DNA was extracted from peripheral blood leukocytes with a commercially available kit (Qiagen, Hilden, Germany) in 2001. LCT C/T-13910 genotyping (single nucleotide polymorphism rs4988235) was performed by using the 5'-nuclease assay and fluorogenic, allele-specific, TaqMan probes (Applied Biosystems, Foster City, CA) and primers,18 with the ABI Prism 7000 sequence detection system (Applied Biosystems). Known control samples were run in parallel with unknown DNA samples.

Dietary Survey
The consumption of milk and milk products was assessed with dietary questionnaires regarding habitual eating behavior and food choices. The questionnaire was modified slightly during the study years but always included questions regarding the habitual amount of milk used daily and the frequency of consumption of other milk products, such as cheese, sour milk, yogurt, and ice cream. On the basis of these data, we constructed a variable representing the subject's usual monthly consumption of milk and milk products. These data were available for 2278, 2210, and 1791 subjects in 1980, 1986, and 2001, respectively, and for 1731 subjects for all 3 study years (similar to the genotype data).

Values representing the daily intakes of dietary protein, fat, carbohydrates, calcium, vitamin D, and total energy were based on the information obtained with detailed dietary interviews. The subjects participated in a 48-hour dietary recall, and data on the intakes of nutrients were available for 1137, 858, and 1031 subjects in 1980, 1986, and 2001, respectively; for all 3 study years, data were available for 770 subjects. Details of the dietary study included in the project were described previously.19–21

Statistical Analyses
Statistical analyses were conducted with Statistica for Windows 6.0 (Stat Soft, Tulsa, OK) and SPSS 13.0 for Windows (SPSS, Chicago, IL) software. The levels of continuous clinical and dietary variables for different LCT genotypes were compared by using one-way analysis of variance and by calculating 95% confidence intervals for each group. The longitudinal data were analyzed with repeated-measures analysis of variance (RANOVA), by using the LCT genotype as a categorical factor and body height, consumption of milk and milk products, protein, vitamin D, and calcium, or intake of other nutrients at different points in time (one at a time) as the dependent repeated variable. These analyses were performed separately for male and female subjects and, within these gender groups, before and after the expected onset of the lactose intolerance phenotype (<10 years and >10 years of age in 1980). The results for body height growth were also analyzed by using baseline dietary calcium intake, age, pubertal stage, and study area as covariates in RANOVA.

For subgroup comparisons, we calculated 95% confidence intervals for each subgroup. The distributions of categorical variables among LCT genotypes were compared with the {chi}2 test. A P value of <.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The prevalence rates of LCT C/T-13910 genotypes C/C, C/T, and T/T in our population were 17.6% (399 of 2265 subjects), 48.9% (1106 of 2265 subjects), and 33.6% (760 of 2265 subjects), respectively. The baseline clinical characteristics and the intakes of nutrients for girls and boys in 1980, at the age of 3 of 18 years, according to LCT C/T-13910 genotype are shown in Table 1.


View this table:
[in this window]
[in a new window]
  		TABLE 1 Clinical Characteristics and Dietary and Energy Intakes of Girls and Boys According to LCT C/T-13910 Genotype at Baseline in 1980, at the Age of 3 to 18 Years

 
Among boys and girls 3 to 18 years of age in 1980 or among young men and women 24 to 39 years of age in 2001, there were no statistically significant differences between LCT genotypes in the prevalence of smoking or in alcohol consumption.

In our study, 10.7% and 6.0% of the female and male subjects, respectively, reported being on a lactose-free or low-lactose diet (yes/no) at some stage of the follow-up period (gender difference in {chi}2 test, P < .0001). Among all subjects, 19.1%, 7.92%, and 7.12% of those carrying LCT genotypes C/C, C/T, and T/T, respectively (genotype difference in {chi}2 test, P < .0001) reported using a lactose-free or low-lactose diet at some stage of the follow-up period. Of the female subjects with the C/C, C/T, and T/T genotypes, 25.2%, 9.0%, and 9.4%, respectively, reported being on a low-lactose or lactose-free diet at some stage of the follow-up period (genotype difference in {chi}2 test, P < .0001). The respective values for the LCT genotypes C/C, C/T, and T/T in men were 11.9%, 6.6%, and 4.2% (genotype difference in {chi}2 test, P = .004).

For male subjects, there were no statistically significant LCT genotype differences in the intake of calcium over the study years (main effect in RANOVA, P = .665) (Fig 1A), but the consumption of milk and milk products was significantly lower for subjects with the C/C-13910 genotype over the study years from 1980 to 2001 (main effect for LCT genotype in RANOVA, P = .001 and P = .003, respectively) than for subjects with other genotypes. For male subjects <10 years or >10 years of age in 1980, there were no statistically significant LCT genotype differences in the intake of calcium over the study years (data not shown; main effect in RANOVA, P = .672 and P = .916, respectively).


Figure 1
View larger version (25K):
[in this window]
[in a new window]
  		FIGURE 1 Dietary calcium intake in the Cardiovascular Risk in Young Finns Study. Mean calcium intakes calculated from the 48-hour dietary recall data (n = 770) and 95% confidence intervals, from 1980 to 2001, according to LCT C/T-13910 genotype, are shown. At baseline, there were no differences in mean age between LCT C/T-13910 genotype groups, for either male subjects (A) or female subjects (B) (analysis of variance, P = not significant for both). In RANOVA, the main effects of LCT C/T-13910 genotype were P = .665 for male subjects (A) and P = .009 for female subjects (B). There were no statistically significant time-LCT genotype interactions in either gender group. LPH indicates lactase-phlorizin hydrolase.

 
For male subjects >10 years of age, the consumption of milk and dairy products was significantly lower for subjects with the C/C-13910 genotype over the study years from 1980 to 2001 (main effect for LCT genotype in RANOVA, P = .020 and P = .027, respectively) than for those with other genotypes. In a corresponding analysis for male subjects <10 years of age, a similar trend was found, but the differences were not as statistically significant (main effect for LCT genotype in RANOVA, P = .056 for milk and P = .104 for dairy products). There were no longitudinal LCT genotype differences in the intakes of total energy, protein, fat, or carbohydrates (main effect for LCT genotype in RANOVA, P = .492, P = .478, P = .331, and P = .431, respectively) for all male subjects or after stratification into those <10 years or >10 years of age (data not shown; main effect for LCT genotype in RANOVA, P = not significant for all subgroup comparisons).

For female subjects, the longitudinal differences in dietary intakes of calcium (Fig 1B), milk, and milk products (data not shown) between the LCT C/T genotypes remained stable during the 21-year follow-up period; the intakes were significantly lower for subjects with the C/C-13910 genotype than the other genotypes over the study years 1980, 1986, and 2001 (main effect for LCT genotype in RANOVA, P < .0001 for all). Similarly, for female subjects <10 years or >10 years of age (in 1980), the intakes in both age groups were significantly lower for subjects with the C/C-13910 genotype than for those with the other genotypes over the study years 1980, 1986, and 2001 (data not shown; main effect for LCT genotype in RANOVA, P = .015 and P = .027 for calcium, P = .001 and P = .007 for milk, and P < .0001 and P = .023 for dairy products). Moreover, the intakes of protein and fat were lower for girls with the C/C-13910 genotype, compared with other genotypes, over these years (data not shown; main effect for LCT genotype in RANOVA, P = .009 and P = .043, respectively), but there were no differences between LCT genotypes in intake of total energy (P = .105) or intake of carbohydrates (data not shown; P = .237).

For female subjects <10 years of age, the total intakes of energy, protein, carbohydrates, and fat tended to be lower for subjects with the C/C-13910 genotype over the study years from 1980 to 2001 (main effect for LCT genotype in RANOVA, P = .034, P = .113, P = .042, and P = .099, respectively) than for subjects with the other genotypes. In a similar analysis for female subjects >10 years of age, the respective significance values in RANOVA for LCT genotype differences were P = .364 for total energy, P = .017 for protein, P = .971 for carbohydrates, and P = .165 for fats.

We also divided the dietary calcium intake data of 1980 and 2001 into 2 separate categories according to current Finnish recommendations for adult calcium intake (800 mg/day). In 2001, there was a significant difference in LCT C/T-13910 genotype distribution between these 2 categories for both women (P = .011) and men ({chi}2 test, P = .009). At the age of 24 to 39 years, the dietary calcium intake of 36% of the women and 23.5% of the men with the C/C-13910 genotype did not meet the recommendations. The corresponding values in 1980, at the age of 3 to 18 years, were 39.8% and 14.4% ({chi}2 test, P = .022 and P = .421 for female and male subjects, respectively). In the longitudinal analysis, there were no statistically significant differences between LCT genotypes in vitamin D intake (main effect for LCT genotype in RANOVA, P = .921 and P = .311 for all female and male subjects, respectively) or after stratification of these gender groups according to age, into those <10 years or >10 years of age (main effect for LCT genotype in RANOVA, P = not significant for all subgroup comparisons).

Growth curves are known to be different for male and female subjects; therefore, the statistical analyses were conducted separately for male and female subjects. Because the age of onset for lactose intolerance in the Finnish population is 12 years,2 the follow-up analyses over the study years were performed for all subjects starting from the mean age of 10.5 years (ages between 3 and 18 years) (Fig 2) at baseline in 1980 and also separately for different age cohorts (3, 6, 9, 12, and 15 years at baseline; data not shown). Moreover, we conducted similar analyses for the 2 subgroups of <10 years and >10 years of age (ie, before and after the assumed onset of lactose intolerance).


Figure 2
View larger version (27K):
[in this window]
[in a new window]
  		FIGURE 2 Body height in the Cardiovascular Risk in Young Finns Study. Body heights (means and 95% confidence intervals) from 1980 to 2001, according to LCT C/T-13910 genotype, are shown. For male subjects (A), the changes (mean ± SD) in body height from 1980 to 2001 were 34.7 ± 28.5 cm for T/T, 34.9 ± 27.7 cm for C/T, and 34.9 ± 26.0 cm for C/C; for female subjects (B), the changes were 25.5 ± 24.2 cm for T/T, 25.6 ± 23.6 cm for C/T, and 24.0 ± 24.5 cm for C/C. The height of all subjects was monitored from 3 to 18 years of age (mean age: 10.5 years) onward. At baseline, there were no differences in mean age between LCT C/T-13910 genotype groups, for either male subjects (A) or female subjects (B) (analysis of variance, P = not significant for both). In RANOVA, time-LCT genotype interactions were P = .836 for male subjects (A) and P = .473 for female subjects (B).

 
The LCT gene C/T-13910 genotype was not related significantly to growth speed for either boys or girls (time-LCT genotype interactions in RANOVA, P = .836 and P = .473, respectively) (Fig 2). For male subjects, the changes (mean ± SD) in body height from 1980 to 2001 were 34.7 ± 28.5 cm for T/T, 34.9 ± 27.7 cm for C/T, and 34.9 ± 26.0 cm for C/C (Fig 2A); for female subjects, the changes were 25.5 ± 24.2 cm for T/T, 25.6 ± 23.6 cm for C/T, and 24.0 ± 24.5 cm for C/C (Fig 2B). In adulthood, the final mean body heights were therefore almost the same for all genotypes. An otherwise similar statistical follow-up analysis for separate birth cohorts or for the subgroups before and after the assumed onset of lactose intolerance did not reveal any statistically significant genotype-related differences in body height growth for either male or female subjects (data not shown). The results remained statistically insignificant after adjustment for baseline dietary calcium intake, pubertal stage, age, and study area. There were no LCT C/T-13910 genotype differences in birth height for either gender (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first long-term (21-year follow-up period), general population-based, follow-up study suggesting that the genetic polymorphism that causes ATH is not associated with mean height growth speed for either male or female subjects. The intake of dietary calcium (Fig 1B) was lower for girls with the C/C-13910 genotype than for those with other genotypes over the study years. This difference in girls was probably attributable to the lower intake of milk and milk products (which are the main sources of calcium in the diet) for subjects with the C/C-13910 genotype, compared with other genotypes. Contradicting our hypothesis and despite genotype differences in the intake of calcium and other nutrients, there were no LCT C/T-13910 genotype differences in body height growth speed or final mean body height in adulthood for female subjects (or male subjects) (Fig 2). One possible explanation might be that reduced calcium intake, caused by a low-calcium diet, results in a compensatory increase in calcium absorption for subjects with low lactase activity (ie, subjects with the C/C-13910 genotype).22 Furthermore, we cannot exclude the possibility that subjects with the LCT C/C-13910 genotype have used more calcium supplements than did those with other genotypes, because the use of calcium supplements was not monitored in the present study. However, our results are in line with a recently published, cross-sectional study in which no association was observed between body height and LCT genotype for Scandinavian individuals.23

The effects of dietary calcium intake and calcium supplementation on bone density, bone consolidation, and metabolism in growing subjects are well documented.24–26 However, in 12-month26,27 or 24-month24 studies, there were no significant differences between the placebo- and calcium supplement-treated female groups with respect to gains in height and weight.24 This is in line with our results for female subjects, indicating that, despite a constantly lower intake of dietary calcium for C/C-13910 genotype subjects, there were no growth differences between subjects with the C/C-13910 genotype and subjects with other genotypes.

Damaged mucosa in connection with several intestinal diseases, including lactose intolerance, may lead to differences in nutrient and calcium absorption, as well as bone changes.28 One might ask why, in the present study, these possible consequences of lactose intolerance were not seen as growth differences between subjects with molecularly defined lactase deficiency (C/C-13910 genotype) and subjects without lactase deficiency. One explanation might be that the most effective growth period for Finnish girls extends until 15 years of age and that for boys extends until 18 years of age. Therefore, the window of time from the onset of lactose deficiency to the end of the growth phase is located between 12 and 15 years of age for female subjects and between 12 and 18 years of age for male subjects. The lactose deficiency exposure time thus might be too short to cause mucosal damage or, alternatively, the mucosal damage might occur in most subjects just after the phase of growth. Furthermore, low-lactose dairy products have been available in Finland since the 1980s, and the replacement of normal lactose-containing dairy products with low-lactose products might have prevented the development of mucosal damage.

Although there are no previous studies indicating the importance of the LCT genotype for skeletal growth, some studies have suggested that adequate calcium intake during the growth period may be critical for reaching optimal bone growth during the growing years.29 A previous study with substantially fewer subjects (30 boys and 20 girls) suggested that, for growing children, long-term avoidance of cow milk is associated with small stature and poor bone health.30 One recent work with adults showed clear associations between the C/T-13910 genotype, calcium intake, and bone density,31 and another study showed that the C/T-13910 genotype could represent a genetic risk factor for bone fractures in elderly people.32

For girls, we found consistently (ie, in all of the study years) lower intake of protein and calcium and consumption of milk and milk products for subjects with the C/C-13910 genotype, compared with other genotypes. The lower intake of dairy products for women with the C/C-13910 genotype might have led to a lower intake of dietary protein, because an average of 30% of the total protein intake in Finland comes from milk products (L.R. and V.M., unpublished data, 1980). At the age of 24 to 39 years, 64% of the women and 76% of the men with the C/C-13910 genotype exceeded the current recommendations for dietary intake of calcium (800 mg/day). The corresponding values in 1980, at the age of 3 to 18 years, were 60.2% and 85.6%. The average calcium intake for both genders and all LCT genotype groups exceeded current Finnish recommendations for adults (800 mg/day). Because we investigated the use of low-lactose products only as part of the overall diet and not separately, we cannot say whether the relatively high average intake of dietary calcium for C/C-13910 genotype subjects was partly attributable to the wide range and long-term availability of low-lactose dairy products in Finland.

In Finland, it seems that the dietary calcium intake of subjects with the LCT C/C-13910 genotype in the year 2001 was within current recommendations for 64% of female subjects and 76.5% of male subjects; the rest of the subjects remained below this limit and might benefit from additional dietary calcium supplementation. For growing children with the ATH genotype (C/C-13910), it is important to ensure that calcium is supplied at appropriate levels.


   ACKNOWLEDGMENTS
 
This study was supported financially by the Emil Aaltonen Foundation (T.L.), the Academy of Finland (grants 53392 and 34316), the Social Insurance Institution of Finland, the Turku University Foundation, the Juho Vainio Foundation, the Finnish Foundation of Cardiovascular Research, the Finnish Cultural Foundation, and the Tampere and Turku University Central Hospital Medical Fund.


   FOOTNOTES
 
Accepted May 30, 2006.

Address correspondence to Terho Lehtimäki, MD, PhD, Department of Clinical Chemistry, Tampere University Hospital, PO Box 2000, FI33521 Tampere, Finland. E-mail: terho.lehtimaki{at}uta.fi

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Sahi T, Isokoski M, Jussila J, Launiala K, Pyörälä K. Recessive inheritance of adult-type lactose malabsorption. Lancet. 1973;2 :823 –826[Web of Science][Medline]
  2. Rasinperä H, Savilahti E, Enattah NS, et al. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut. 2004;5 :1571 –1576
  3. Sahi T, Isokoski M, Jussila J, Launiala K. Lactose malabsorption in Finnish children of school age. Acta Paediatr Scand. 1972;6 :11 –16[Medline]
  4. Jussila J, Isokoski M, Launiala K. Prevalence of lactose malabsorption in a Finnish rural population. Scand J Gastroenterol. 1970;5 :49 –56[Web of Science][Medline]
  5. Högenauer C, Hammer HF, Mellitzer K, Renner W, Krejs GJ, Toplak H. Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence. Eur J Gastroenterol Hepatol. 2005;17 :371 –376[CrossRef][Web of Science][Medline]
  6. Järvelä IE. Molecular genetics of adult-type hypolactasia. Ann Med. 2005;37 :179 –185[CrossRef][Web of Science][Medline]
  7. Olds LC, Sibley E. Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Hum Mol Genet. 2003;12 :2333 –2340[Abstract/Free Full Text]
  8. Troelsen JT, Olsen J, Möller J, Sjöström H. An upstream polymorphism associated with lactase persistence has increased enhancer activity. Gastroenterology. 2003;125 :1686 –1694[CrossRef][Web of Science][Medline]
  9. Kuokkanen M, Enattah NS, Oksanen A, Savilahti E, Orpana A, Järvelä I. Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia. Gut. 2003;52 :647 –652[Abstract/Free Full Text]
  10. Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30 :233 –237[CrossRef][Web of Science][Medline]
  11. Nilsson TK, Johansson CA. A novel method for diagnosis of adult hypolactasia by genotyping of the –13910 C/T polymorphism with Pyrosequencing technology. Scand J Gastroenterol. 2004;39 :287 –290[CrossRef][Web of Science][Medline]
  12. Enattah N, Pekkarinen T, Välimäki MJ, Löyttyniemi E, Järvelä I. Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women. Eur J Clin Nutr. 2005;59 :1105 –1111[CrossRef][Web of Science][Medline]
  13. Gugatschka M, Dobnig H, Fahrleitner-Pammer A, et al. Molecularly-defined lactose malabsorption, milk consumption and anthropometric differences in adult males. QJM. 2005;98 :857 –863[Abstract/Free Full Text]
  14. Männistö S, Ovaskainen M, Valsta L. The National FINDIET 2002 study. Publ Natl Public Health Inst. 2003;B3 :130
  15. Åkerblom HK, Viikari J, Raitakari OT, Uhari M. Cardiovascular Risk in Young Finns Study: general outline and recent developments. Ann Med. 1999;31 (suppl 1):45–54
  16. Raitakari OT, Juonala M, Kähönen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003;290 :2277 –2283[Abstract/Free Full Text]
  17. Åkerblom HK, Viikari J, Uhari M, et al. Atherosclerosis precursors in Finnish children and adolescents, part I: general description of the cross-sectional study of 1980, and an account of the children's and families' state of health. Acta Paediatr Scand Suppl. 1985;318 :49 –63[Medline]
  18. Livak KJ. Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal. 1999;14 :143 –149[Medline]
  19. Räsänen L, Ahola M, Kara R, Uhari M. Atherosclerosis precursors in Finnish children and adolescents, part VIII: food consumption and nutrient intakes. Acta Paediatr Scand Suppl. 1985;318 :135 –153[Medline]
  20. Räsänen L, Laitinen S, Stirkkinen R, et al. Composition of the diet of young Finns in 1986. Ann Med. 1991;23 :73 –80[Web of Science][Medline]
  21. Mikkilä VV, Räsänen L, Raitakari OT, Pietinen P, Viikari J. Longitudinal changes in diet from childhood into adulthood with respect to risk of cardiovascular diseases: the Cardiovascular Risk in Young Finns Study. Eur J Clin Nutr. 2004;58 :1038 –1045[CrossRef][Web of Science][Medline]
  22. Norman DA, Fordtran JS, Brinkley LJ, et al. Jejunal and ileal adaptation to alterations in dietary calcium: changes in calcium and magnesium absorption and pathogenetic role of parathyroid hormone and 1,25-dihydroxyvitamin D. J Clin Invest. 1981;67 :1599 –1603[Web of Science][Medline]
  23. Campbell CD, Ogburn EL, Lunetta KL, et al. Demonstrating stratification in a European American population. Nat Genet. 2005;37 :868 –872[CrossRef][Web of Science][Medline]
  24. Cameron MA, Paton LM, Nowson CA, Margerison C, Frame M, Wark JD. The effect of calcium supplementation on bone density in premenarcheal females: a co-twin approach. J Clin Endocrinol Metab. 2004;89 :4916 –4922[Abstract/Free Full Text]
  25. Prentice A, Ginty F, Stear SJ, Jones SC, Laskey MA, Cole TJ. Calcium supplementation increases stature and bone mineral mass of 16- to 18-year-old boys. J Clin Endocrinol Metab. 2005;90 :3153 –3161[Abstract/Free Full Text]
  26. Lorenzen JK, Molgaard C, Michaelsen KF, Astrup A. Calcium supplementation for 1 y does not reduce bodyweight or fat mass in young girls. Am J Clin Nutr. 2006;83 :18 –23[Abstract/Free Full Text]
  27. Moyer-Mileur LJ, Xie B, Ball SD, Pratt T. Bone mass and density response to a 12-month trial of calcium and vitamin D supplement in preadolescent girls. J Musculoskelet Neuronal Interact. 2003;3 :63 –70[Medline]
  28. Walters JR. The role of the intestine in bone homeostasis. Eur J Gastroenterol Hepatol. 2003;15 :845 –849[CrossRef][Web of Science][Medline]
  29. Bonjour JP, Carrie AL, Ferrari S, et al. Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. J Clin Invest. 1997;99 :1287 –1294[Web of Science][Medline]
  30. Black RE, Williams SM, Jones IE, Goulding A. Children who avoid drinking cow milk have low dietary calcium intakes and poor bone health. Am J Clin Nutr. 2002;76 :675 –680[Abstract/Free Full Text]
  31. Obermayer-Pietsch BM, Bonelli CM, Walter DE, et al. Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures. J Bone Miner Res. 2004;19 :42 –47[CrossRef][Web of Science][Medline]
  32. Enattah NS, Sulkava R, Halonen P, Kontula K, Järvelä I. Genetic variant of lactase-persistent C/T is associated with bone fractures in very old age. J Am Geriatr Soc. 2005;53 :79 –82[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lehtimäki, T.
Right arrow Articles by Raitakari, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lehtimäki, T.
Right arrow Articles by Raitakari, O.
Related Collections
Right arrow Nutrition & Metabolism
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?