C-reactive protein (CRP) is a sensitive marker of systemic low-grade inflammation. Increased plasma levels of CRP predict the risk of cardiovascular and metabolic diseases. Although genetic factors account for 30-40% of individual differences in plasma CRP levels, genomic regions contributing to CRP levels remain unknown. We performed a genome-wide linkage scan for plasma CRP levels in healthy whites from the HERITAGE Family Study. CRP was measured with a high-sensitivity assay. Multipoint linkage analyses were performed in 280 sibling pairs with 654 markers using regression and variance components-based methods. Data were adjusted for independent correlates of plasma CRP. We showed the strongest evidence of linkage for plasma CRP levels on chromosome 20q13. Markers which gave suggestive linkages in this region were D20S52 [logarithm of odds (LOD) score 3.18, P = 0.00006], D20S857 (LOD score 2.87, P = 0.00014), D20S869 (LOD score 2.75, P = 0.0002), D20S480 (LOD score 2.59, P = 0.0003), D20S501 (LOD score 2.55, P = 0.0003), D20S840 (LOD score 2.18, P = 0.0008), and D20S876 (LOD score 2.07, P = 0.001). We also detected suggestive linkage on chromosome 5p13 for marker D5S1470 (LOD score 2.23, P = 0.0007). Chromosome 20q13 may contribute to plasma CRP levels in healthy whites. This region contains genes that are important in the inflammatory process and may play a role in the development of chronic inflammatory diseases. The present findings may be useful in the ongoing effort to search for genes contributing to inflammation and to identify individuals at an increased risk of chronic inflammatory diseases.
To investigate a major gene hypothesis for body mass index (BMI) in a large sample of probands (n = 2580, ages 37-57 years) who were selected for obesity (BMI> or =34 kg/m2 for males and > or =38 kg/m2 for females), along with their spouses and first-degree relatives (n = 11,204 family members). The probands were recruited as part of an intervention trial assessing whether mortality and morbidity were improved after surgical intervention for obesity as part of the Swedish Obese Subjects (SOS) study.
The current analyses were based on BMI measures obtained before intervention. Segregation analysis was carried out using the mixed model implementation in PAP (Pedigree Analysis Package), which allowed for ascertainment correction and for genotype-dependent effects of covariates (sex and age) in both the major gene component and the multifactorial (i.e., polygenic and familial environment) component.
Both a major effect and a multifactorial effect were significant. The percentage of the total variance accounted for by the multifactorial effect was 17%-24% (increasing as a function of age), and by the major effect, 8%-34% (decreasing as a function of age). Although tests on the transmission probabilities (taus) were not compatible with Mendelian expectations of 1, 1/2, and 0, the equal taus model was rejected (i.e., the effect is transmitted in families) and the point estimates (0.96, 0.60, and 0.17) compared favorably to Mendelian expectations. The major effect was transmitted in a codominant fashion, consistent with a gene-environment interaction.
These results suggest both multifactorial and major effect etiologies for BMI in these families of extremely obese probands. Before 20 years of age, the major effect dominates the BMI expression, but after age 20, multifactorial effects account for the most variance. Although the major effect is transmitted in these families, the pattern does not appear to be consistent with a simple Mendelian trait. The possibility of additional major loci (i.e., epistasis) and gene by environment interactions may explain these findings.