Cindy Boer

16 | Chapter 1.1 risk for osteoarthritis that can be contributed to genetics is estimated to be ~39%-65% depending on the joint affected[20]. The heritability component of knee osteoarthritis is ~40%, hip osteoarthritis ~60% and for osteoarthritis of the hand ~39%-65%depend- ing on the hand joint[26-28]. Thus, a large part of the risk for osteoarthritis is deter- mined by genetic variation. Understanding how and which genetic variations contrib- ute to OA risk is important, as this will lead to more knowledge of disease pathogenesis, which in turn could lead to the development of new treatment or preventive strategies. Genetics: a primer Genetics is the study of heredity, genes and genetic variation. DNA, or deoxyribonu- cleic acid, is a complex molecule that stores all of the genetic information, the instruc- tions for development, function and maintenance of an organism. The DNA consists of two strands that wind around each other in a double helix, like a twisted ladder[29]. Each strand consists of a sugar-phosphate ‘backbone’ to which one of four nucleotides (bases) are bound; Adenine (A), Thymine (T), Cytosine (C) or Guanine (G). Each “rung” of the ladder consists of a base pair (bp), which are two nucleotides held together by hydrogen bonds; A always pairs with T, and C always pairs with G. The human DNA contains the genetic code for ~20.000-25.000 genes (average number of parts in a car is ~30.000). A gene is a part of the DNA that gets copied (transcribed) into RNA, which is translated into proteins. Proteins are the essential building blocks and machinery of a cell, performing all manner of functions. The transcription of DNA to RNA and the translation of RNA to protein is called the “central dogma of molecular biology” [30] ( Figure 3 ). Although the DNA sequence between any two humans is for ~99.5% similar, each individual is unique, as is their DNA sequence. Variations in the genetic code can explain differences between individuals, such as hair colour, height, shape of the face, or disease risk. On average, an individuals’ genome differs on 4.000.000 to 5.000.000 sites from the human reference genome[31]. Many different types of genetic variation exist, of which the most common in the human genome is the Single Nucleotide Variation (SNV or SNP)[32] ( Figure 3 ). Each SNV, named with its reference SNV cluster ID (rsID), rep- resents a single nucleotide difference on the DNA from the human reference genome. In total there are currently ~335.000.000 SNVs known based on ~1 million human ge- nomes sequenced [33] , and they can occur anywhere on the DNA, both in coding and in non-coding regions. In the coding regions a SNV could affect the translation of a gene into a protein, and in the non-coding regions it could affect the regulation of gene ex- pression (gene transcription).