作者： 蔡昇達
今天讀到安南醫院神經內科杜宜憲醫師寫的第 254 期頭痛電子報，很有啟發：
杜醫師原文：
寒冷感知與偏頭痛的交易
大約50,000年前，人類祖先走出非洲，向高緯度遷徙。為了在寒冷的氣候中生存，人類必須適應低溫。人類第二對染色體的短臂上有一個 TRPM8 基因，是已知唯一能對「中度寒冷」產生內源性反應的溫度受體，同時也參與疼痛感知。遺傳研究發現，TRPM8 基因上游的一個變異位點（rs10166942），出現頻率與緯度呈現高度正相關：在炎熱的西非奈及利亞只有 5%；到了高緯度的芬蘭，頻率高達88%。然而，這個極具生存優勢的變異卻是一把雙面刃。它的原始等位基因（ancestral allele）對偏頭痛具有保護作用；但為了適應寒冷而演化出的 rs10166942 變異，反而是與偏頭痛風險強烈相關的 single-nucleotide polymorphism 之一。人類為了抵抗嚴寒氣候所付出的代價之一，或許正是偏頭痛，而歐洲地區的偏頭痛盛行率也確實高於非洲。演化往往伴隨著基因之間的利弊權衡，而 TRPM8 基因或許是偏頭痛在天擇中被保留的其中一種理由。
圖一、文獻中的圖片，左方可以見到帶有此變異位點的人在芬蘭(FIN)高達 88% (圓餅圖的深藍色)，在左下方的非洲國家比例皆相當低，約 5% 左右 (圓餅圖的黃色)
在美國明尼蘇達州進修的一年多的期間，常覺得住在高緯度的人(明州是美國除了阿拉斯加外緯度最高的一州)和住在低緯度的人是不一樣的，最明顯的是在寒冷的冬天，常可見他們穿著短袖在路上走，幼稚園的小朋友亦然，冬天穿短袖短褲的並不少見，而女兒和我早已冷到受不了。6-8 月的夏天亦很明顯，當地人對超過攝氏 25 度的高溫難以忍受，多要待在冷氣房中。讀了這篇基因分析的文章，我想或許每個人皆有自己適合生存的溫度和環境，也可以理解為何長住在美國的華人，退休後喜歡搬到溫暖的加州南部生活。感謝杜宜憲醫師的文獻整理和分享！
English version:
Today, I read Issue No. 254 of the Headache Newsletter written by Dr. Yi-Hsien Tu from the Department of Neurology at An-Nan Hospital, which I found highly insightful:
Original text by Dr. Tu:
The Trade-off Between Cold Sensation and Migraine
Approximately 50,000 years ago, human ancestors migrated out of Africa toward higher latitudes. To survive in colder climates, humans had to adapt to low temperatures. On the short arm of human chromosome 2 lies the TRPM8 gene, which is currently the only known temperature receptor capable of generating an endogenous response to moderate cold and is also involved in pain perception.
Genetic studies have identified a variant located upstream of the TRPM8 gene (rs10166942), whose frequency shows a strong positive correlation with latitude: it is present in only about 5% of individuals in hot regions such as Nigeria in West Africa, but rises dramatically to as high as 88% in high-latitude regions such as Finland. However, this variant, which confers a significant survival advantage, is also a double-edged sword. The ancestral allele of TRPM8 appears to be protective against migraine, whereas the rs10166942 variant that evolved as an adaptation to cold climates is, conversely, one of the single-nucleotide polymorphisms strongly associated with an increased risk of migraine.
One of the evolutionary costs humans may have paid for adapting to harsh, cold environments could be migraine itself. Indeed, the prevalence of migraine is higher in Europe than in Africa. Evolution is often accompanied by trade-offs among genetic traits, and the TRPM8 gene may represent one of the reasons why migraine susceptibility has been retained through natural selection.
Figure 1. An image from the literature shows that the frequency of this variant is as high as 88% in Finland (FIN; dark blue in the pie chart). In contrast, the frequency is much lower in African countries (yellow in the pie charts), at approximately 5%.
During my more than one year of training in Mayo Clinic, Rochester, Minnesota, USA, I often felt that people living at higher latitudes (Minnesota is the northernmost state in the U.S. after Alaska) differ from those living at lower latitudes. The most noticeable difference is during the cold winter: it is common to see people walking outside in short sleeves, including kindergarten children. In contrast, my daughter and I often found the cold unbearable. The difference is equally evident in summer (June to August), when local residents often find temperatures above 25°C difficult to tolerate and prefer to stay indoors with air conditioning.
After reading this genetic analysis, I began to think that perhaps each individual has an optimal temperature and environment suited for survival. This may also help explain why many ethnic Chinese individuals who have lived long-term in the United States choose to relocate to warmer regions, such as Southern California, after retirement.
I am grateful to Dr. Yi-Hsien Tu for compiling and sharing this literature.
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