Fernando Rivadeneira

Low prevalence of NOD2 SNPs in Behçet's disease suggests protective association in Caucasians

OBJECTIVEnIt has been shown previously that three nucleotide-binding oligomerization domain containing 2 (NOD2) variants (Arg702Trp, Gly908Arg and Lue1007fs) are associated with Crohns disease (CD), a disorder clinically resembling Behçets disease (BD). We studied the frequency of these variants in BD patients.nnnMETHODSnDNA samples of 200 BD patients [59 Caucasians, 139 Middle Easterns (MEs) of Arab descent and 2 Asians] and 520 healthy controls (444 Caucasians and 76 MEs) were genotyped using a Taqman assay.nnnRESULTSnBoth the Arg702Trp and Leu1007fs (frameshift) variants were significantly less frequently present among BD patients compared with healthy controls (0.5 vs 5.8%; P < 1.10(-5) and 0.0 vs 1.8%; P < 0.007, respectively). In the Caucasian subpopulation, Arg702Trp was significantly less frequent in the BD group as compared with the controls (P = 0.04); whereas in the ME subpopulation, a trend was observed (P < 0.06).nnnCONCLUSIONSnOf the three CD-associated single nucleotide polymorphisms, one of the variant NOD2 alleles, was found to be present significantly less in Caucasian BD patients.

CHAPTER 28 – The Role of Genetic Variation in Osteoporosis

Over the past decades, epidemiological research of the so-called complex diseases, that is, common age-related disorders such as cancer, cardiovascular disease, diabetes, and osteoporosis, has identified anthropometric, behavioral, and serum parameters as risk factors. Recently, genetic polymorphisms have gained considerable interest, propelled by the Human Genome Project and its sequela that have identified most genes and uncovered a plethora of polymorphic variants, some of which embody the genetic risk factors. In all fields of complex disease genetics (including osteoporosis), progress in identifying these genetic factors has been hampered by often controversial results. Because of the small effect size for each individual risk polymorphism, this is mostly due to low statistical power and limitations of analytical methods. Genome-wide scanning approaches can be used to find the responsible genes. It is by now clear that linkage analysis is not suitable for this, but genome-wide association analysis has much better possibilities, as is illustrated by the successful identification of risk alleles for several complex diseases. Candidate gene association analysis followed by replication and prospective multicentered meta-analysis, is currently the best way forward to identify genetic markers for complex traits, such as osteoporosis. To accomplish this, one needs large (global) collaborative studies using standardized methodology and definitions, to quantify by meta-analysis the subtle effects of the responsible gene variants, and assess heterogeneity in these associations between populations.