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Recent data from mainly homogeneous European and African populations implicate a 140-bp region 5' to the transcriptional start site of LCT (the lactase gene) as a regulatory site for lactase persistence and nonpersistence. Because there are no studies of US nonhomogeneous populations, we performed genotype/phenotype analysis of the -13910 and -22018 LCT single nucleotide polymorphisms (SNPs) in New England children, mostly of European ancestry.Duodenal biopsies were processed for disaccharidase activities, RNA quantification by reverse transcription polymerase chain reaction (RT-PCR), allelic expression ratios by PCR, and genotyping and SNP analysis. Results were compared with clinical information.Lactase activity and mRNA levels, and sucrase-to-lactase ratios of enzyme activity and mRNA, showed robust correlations with genotype. None of the other LCT SNPs showed as strong a correlation with enzyme or mRNA levels as did -13910. Data were consistent, with the -13910 being the causal sequence variant instead of -22018. Four individuals heterozygous for -13910T/C had allelic expression patterns similar to individuals with -13910C/C genotypes; of these, 2 showed equal LCT expression from the 2 alleles and a novel variant (-13909CA) associated with lactase persistence.The identification of -13910C/C genotype is likely to predict lactase nonpersistence, consistent with prior published studies. A -13910T/T genotype will frequently, but not perfectly, predict lactase persistence in this mixed European-ancestry population; a -13910T/C genotype will not predict the phenotype. A long, rare haplotype in 2 individuals with -13910T/C genotype but equal allele-specific expression contains a novel lactase persistence allele present at -13909.

Our data indicate that genetic influences due to stature-associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD.

The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.

Studies indicate that estrogen receptor β, encoded by the ESR2 gene on chromosome 14q, may play a role in ovarian carcinogenesis. Using the genetic structure data generated by the Breast and Prostate Cohort Consortium (BPC3), we have comprehensively characterized the role of haplotype diversity in ESR2 and risk of ovarian cancer. Five haplotypes with a frequency of ≥5% were observed in White subjects and five haplotype tagging SNPs (htSNP) were selected to capture the locus diversity with a minimum Rh2 of 0.81. The htSNPs were genotyped in 574 White controls, 417 White invasive ovarian cancer cases, and 123 White borderline ovarian cancer cases from case-control studies carried out in Los Angeles County from 1994 through 2004. No statistically significant association was observed between the five htSNPs and related haplotypes and risk of ovarian cancer overall. Haplotype D was associated with a nonstatistically significant increased risk of invasive ovarian cancer overall (odds ratio, 1.38; 95% confidence interval, 0.93-2.02; P = 0.11) relative to the most common haplotype and a statistically significant increased risk of invasive clear cell ovarian cancer (odds ratio, 3.88; 95% confidence interval, 1.28-11.73; P = 0.016). Haplotype D was also reported by the BPC3 to be associated with increased risk of breast cancer. This haplotype warrants further investigation to rule out any effect with invasive ovarian cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(2):393–6)

Because GnRH and its receptor (GnRHR) are pivotal regulators of the reproductive endocrine axis and mutations in GNRHR lead to hypogonadotropic hypogonadism, we investigated whether genetic variation in GNRHR or GNRH1 affects pubertal timing in the general population. To screen for missense mutations in these genes that might affect pubertal timing, we resequenced the coding regions of these genes in 48 probands with late but otherwise normal pubertal development. No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development. To search for common variants that might affect pubertal timing, we took a haplotype-based association approach. To identify common haplotypes in these genes, we genotyped 41 SNPs in DNA from commercially available European-derived multigenerational pedigrees and participants in a multiethnic cohort (MEC). Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes. A set of haplotype-tagging SNPs that mark these common haplotypes in all five ethnic groups within the MEC were defined and used to perform association studies among 125 trios (probands with late pubertal development and their parents) and 506 women from the MEC who had early (menarche11 yr of age, n = 216) or late (menarcheor = 15 yr of age, n = 290) pubertal development. Three SNPs in GNRHR showed modest association with late pubertal development in the trios; among the 506 women, a different SNP was associated with late menarche, and one rare haplotype was associated with early age of menarche. All of the observed associations were relatively modest and only nominally statistically significant; replication is needed to determine their validity. We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. It is frequently associated with obesity, insulin resistance and features of the metabolic syndrome.1,2 The histologic phenotype of NAFLD extends from fatty liver to steatohepatitis.3 Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and cytologic ballooning with varying degrees of fibrosis.3 NASH progresses to cirrhosis in approximately 15% of subjects.4 The factors that predispose to the risk of progression and the mechanisms that drive disease progression in those who develop cirrhosis are not well understood. Recently, genetic association studies successfully identified genetic variants that associate with many polygenic diseases and traits.5 Seven genetic variants were associated with liver function tests (LFTs) (near PNPLA3, CPN1, ABO, GPLD1, JMJD1C, GGT1, HNF1A).6,7 An allele in PNPLA3-(rs738409[G] encoding L148M) was also associated with an increased risk of hepatic steatosis by magnetic resonance spectroscopy.6,8,9 PNPLA3, also known as patatin like phospholipase-3 or adiponutrin, is expressed in adipose tissue10 and has recently been shown to function as a lipase.11 Elevations of liver enzymes are nonspecific markers of hepatocyte injury and liver imaging is an indirect measure of liver fat that can be influenced by other components in liver, including glycogen, iron and water content. The objective of the current study was to determine the impact of genetic variants that associate with LFTs or liver steatosis by magnetic resonance spectroscopy on histologically-defined NAFLD in subjects with histologically-characterized NAFLD from the NASH Clinical Research Network (CRN).

Variation in the peroxisome proliferator-activated receptor γ gene alters the risk for adiposity in adults, with evidence of interaction with diet. We investigated the age-related association between the Pro12Ala variant (rs1801282) and diet in obesity-related traits in children. The Pro12Ala variant was assayed in 2102 young children aged 1 to 6 years and in 794 periadolescent children aged 10 to 12 years of Greek origin. In both cohorts, no differences were found in obesity traits between the Ala allele carriers and Pro/Pro homozygotes. Sex-stratified analysis showed that, in periadolescent boys, Ala carriers exhibited lower measures of skinfolds (triceps: 16.9 ± 6.9 vs 19.4 ± 7.9 mm, P = .01; subscapular: 9.6 ± 4.5 vs 11.2 ± 5.4 mm, P = .02). On the other hand, young girls who were Ala carriers presented higher measures of triceps skinfold thickness (10.5 ± 3.0 vs 9.9 ± 2.8 mm, P = .04). Nominal gene-diet interactions were revealed in periadolescents for saturated fatty acid (SFA) intake and skinfolds (P for interaction = .05). In Pro/Pro homozygous young girls, SFA and total fat (TF) intake was positively associated with higher body mass index (BMI) (P = .01), waist circumference (P = .02), and skinfold thickness (triceps-SFA: P = 10⁻⁵, triceps-TF: P = 10⁻⁹, subscapular-SFA: P = 10⁻⁶, subscapular-TF: P = 10⁻⁴). For Pro/Pro homozygotes, unsaturated fat intake was inversely associated with BMI (P = .04) in young girls, and with BMI (P = .03), waist circumference (P = .03), and triceps (P = .02) in periadolescent boys. Our results suggest that adiposity in children is influenced by the Pro12Ala polymorphism in a sex-specific and age-dependent manner. We also demonstrate evidence of an age-dependent gene-diet (SFA, TF) interaction, suggesting that the type of fat intake modifies the effect of the Pro12 allele on obesity-related measures.

Background: Variation in the peroxisome-proliferator-activated receptor γ (PPARγ) gene has been reported to alter the risk for adiposity in adults. Methods: We investigated the gender related association between the Pro12Ala variant (rs1801282) in obesity and insulin resistance traits in 794 peri-adolescent children aged 10–12 years of Greek origin from the Gene and Diet Attica Investigation (GENDAI) cohort. Results: Gender stratified analysis suggested that in peri-adolescent boys, Ala carriers exhibited lower measures of skinfold (triceps: 16.9±6.9 vs. 19.4±7.9 mm, p=0.014; subscapular: 9.6±4.5 vs. 11.2±5.4 mm, p=0.016) and lower adiponectin concentrations (3.9±1.3 vs. 4.7±2.4 μg/mL, p=0.05). In peri-adolescent girls, Ala carriers had lower insulin concentrations (7.3±3.7 vs. 8.5±4.4 μU/mL, p=0.026) and lower values of homeostasis model assessment of insulin resistance (HOMA-IR) (1.5±0.8 vs. 1.8±0.96, p=0.019). Linear regression analysis revealed that the presence of the Ala allele in boys was a nominally significant predictor of obesity indices, including skin-folds (triceps: β±SE: –2.3±1.1, p=0.032; subscapular: β±SE: –2.3±1.1, p=0.04) and adiponectin concentrations (β±SE: –0.7±0.4, p=0.05) after adjusting for potential covariates. In girls, the Ala allele was a predictor of insulin concentrations (β±SE: –1.2±0.6, p=0.037) and HOMA-IR (β±SE: –0.24±0.13, p=0.037).Conclusions: Our results suggest that adiposity in children is influenced by the Pro12Ala polymorphism in a gender specific manner. Clin Chem Lab Med 2009;47:1047–50.

Context: Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH).Objective: Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing.Design: We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age < 11 yr) or late (age > 14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing.Setting and Patients/Other Participants: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated.Main Outcome Measures: We assessed the association of genetic variation with age at menarche.Results: We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche.Conclusions: Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.

Coronary artery disease continues to be one of the leading causes of death and disability around the globe, challenging the efficacy of currently applied schemes to predict the risk for future coronary events. In fact, algorithms such as the Framingham risk score that are based on traditional risk factors like hypertension and dyslipidemia are not very sensitive, leaving a majority of the population at intermediate risk.Advances in multidetector computed tomography (MDCT) technology with submillimeter slice collimation (approximately 0.6 mm) and high temporal resolution now permit contrast-enhanced imaging of the coronary artery lumen and wall in a single breath hold. The current generation of MDCT provided in-plane resolution of 0.5 mm and a temporal resolution of 210 ms. The simultaneous acquisition of 16/64 parallel cross-sections reduces image acquisition time to about 10-20s using 60-80 ml of contrast agents to opacify the coronary artery lumen. CT imaging for coronary calcification is an established method with low radiation exposure. The amount of calcification is expressed as an Agatston Score (AS).The presence and amount of coronary calcification significantly increases the relative risk for future coronary events, independent from traditional risk factors (risk ratio 8.7 [95% Cl, 2.7-28.1]). Especially, individuals with a high AS (400) who are at intermediate 10-y Framingham event risk may benefit from this additional risk stratification. However, calcification is rarely present in children and adolescents. However, there is a growing body of evidence suggesting that contrast-enhanced MDCT can detect both calcified and noncalcified plaques with high sensitivity and specificity for the detection of plaques0.5 mm when compared to intravascular ultrasound. Moreover, initial data suggest that plaque characteristics such as plaque area, volume, quantify and coronary plaque remodeling index can be quantified in good agreement with IVUS. The composition of noncalcified plaque may be further stratified into predominantly fibrous or lipid-rich plaque. Noncalcified plaque may be present already in children and adolescents with multiple risk factors.The available data indicate that high resolution MDCT can reliably detect, quantify and characterize calcified and noncalcified coronary atherosclerotic plaque. With MDCT, we now have a unique opportunity to study the natural history and response to therapy of noncalcified coronary plaques, which may be already present in obese children or children with multiple risk factors.